Vol 31, No.

3, 2009 ISSN 0243-3397

Medicographia
New advances
in the treatment of
type 2 diabetes

Quarterly Thematic Journal

of Clinical and Therapeutic Research
A Servier Publication
www.medicographia.com
Vol 31, No. 3, 2009
Medicographia
100
A Ser vier publication

New advances
in the treatment of
type 2 diabetes
M EDICOGRAPHIA N O . 100 !
215 J. Servier, France

E DITORIAL
217 ADVANCE: setting new standards for optimal management of patients
with type 2 diabetes. ADVANCE : nouvelles normes pour la prise en charge
optimale des patients atteints de diabète de type 2
J. Chalmers, Australia

T HEMED ARTICLES
223 Major findings from ADVANCE: blood pressure–lowering arm
N. R. Poulter, United Kingdom

232 Major findings from the ADVANCE study: glucose-lowering arm

M. E. Cooper, Australia

238 Implications of ADVANCE in the management of blood pressure

in diabetic patients
B. Williams, United Kingdom

245 Implications of ADVANCE in the management of glucose lowering

in diabetic patients
D. R. Matthews, United Kingdom

251 The burden of vascular disease in diabetes and hypertension:

from micro- to macrovascular disease—the “bad loop”
H. A. J. Struijker-Boudier, The Netherlands

257 Advanced glycation end products (AGEs) and their receptors (RAGEs)
in diabetic vascular disease
P. Marchetti, Italy

266 How should future guidelines implement the results of ADVANCE?

M. Marre, France

Contents continued on next page

Vol 31, No. 3, 2009
Medicographia
100
A Ser vier publication

C ONTROVERSIAL QUESTION
273 Is microalbuminuria a marker for microangiopathy or macroangiopathy?
M. Burnier, Switzerland - P. Fioretto, Italy - J. Gumprecht, Poland -
G. Halaby, Lebanon - R. Unnikrishnan and V. Mohan, India -
F. Puchulu, Argentina - R. Roussel, France - G. Schernthaner, Austria -
M. Shestakova, Russia - J.-G. Wang, Y. Li, and C.-S. Sheng, China

D IAMICRON MR - P RETERAX
284 Management of type 2 diabetes: a multifactorial approach to
a complex disease
S. Laroche and S. Corda, France

I NTERVIEW
295 How can the results of ADVANCE be applied to daily clinical practice?
J. Bringer, France

F OCUS
299 Blood pressure, blood glucose, and diabetic renal disease
C. E. Mogensen, Denmark

U PDATE
307 Will ADVANCE population genomic determinants improve upon
biomarkers in predicting vascular complications of diabetes?
P. Hamet and J. Tremblay, Canada

A TOUCH OF F RANCE
316 Famous French diabetics
C. Régnier, France

324 Late Renoir, 1892-1919

I. Spaak, France
 Medicographia No. 100!

b y D r J ac q u e s S e r v i e r
Dr Jacques Servier

W
ith this issue of Medicographia, we are celebrating a very special—dual—anniversary: 30 years and No. 100,
of a quarterly medical journal with a circulation of more than 15 000 copies in more than 130 countries. We
take special pride, at Servier, in this anniversary. Just look around and count how many other medical journals
of this kind—published by a pharmaceutical company and so highly respected by a demanding audience of
hospital and community clinicians and institutional researchers—have been able to pass with flying colors this test of time.
I personally know of none other. Medicographia stands alone and unchallenged.

We thought it was high time you, our readers, were asked, in an international survey carried out last year, about what you want-
ed to keep, and what changes would improve the journal. As your replies came in by fax and e-mail, we were both surprised
and thrilled to discover that although you thought the journal could do with a facelift to make the layout lighter, simpler, clearer,
more colorful, and with somewhat shorter articles, a larger font, and highlights to draw the attention to points of relevance,
the very structure itself of Medicographia was still earning unreserved kudos, and that you wanted it to be kept as it was.

This wish met one of our core values more than half way. Indeed, Medicographia is but one example among many of how ob-
sessed we are with excellence in the long term, whether this durability concerns our research and our discoveries, or our part-
nerships, our projects, our commitments. As a company, we have jealously preserved our independence by resisting the lure
of the stock exchange and the tyranny of short-term results driven by quarterly dividends—a freedom that has recently, in this
time of turmoil, acquired special meaning. It is that very freedom that enables us to commit to the long term, which is one of
the key features of the “Servier style” that is most appreciated by those who have come to rely on our projects, our drugs, and
our services to research, the medical community, and the patients who benefit from our therapeutic innovations.

The main reason for Medicographia’s longevity resides in the fact that it offers a unique form of partnership between Servier
and field leaders worldwide in giving doctors across all sectors of medicine an overview on a given subject. Few journals cur-
rently offer state-of-the-art summaries aimed, not just at specialists in the field, but at all clinicians, allowing them to keep abreast
of developments in fields other than their own and remain physicians of the whole person, rather than of a discrete “slice,”
whether organ, disease, or specialty. Medicographia could be described as a two-way partnership, since its quality makes
it an ambassador of Servier excellence, both to a readership that enjoys a broad sweep of information on a particular topic
and to field leaders in university hospitals and public or private research institutions. For them, it serves as a tribune from
which, alongside their peers, they can write papers that analyze developments within their specialty with complete editorial
independence.

Another aim of the journal, in its own modest way, is to represent France in the eyes of international doctors who are more
familiar with a world dominated by the English-language medical press. Medicographia editorials and abstracts are routinely
bilingual, in French and English, and each issue features two cultural articles, each profusely illustrated, in the “Touch of France”
section. One article touches on the history of medicine, based on a great figure in French medical history, while the other ad-
dresses broader topics, such as art, literature, and other aspects of France’s rich cultural heritage.

This is what Medicographia has been offering for 30 years, and, with its new layout and thanks to our readers’ unwavering
support, will continue to offer for, we hope, many more years to come.

Yours truly,
Doctor Jacques Servier

Medicographia No. 100! – Servier MEDICOGRAPHIA, Vol 31, No. 3, 2009 215
N
ous célébrons, avec ce numéro de Medicographia, un événement très spécial : les 30 ans et le 100e numéro d’une
revue médicale trimestrielle tirée à plus de 15 000 exemplaires et distribuée dans plus de 130 pays. Nous sommes
très fiers, chez Servier, de ce double anniversaire. En effet, il n’est que de regarder autour de soi : combien de re-
vues médicales similaires, publiées par l’industrie pharmaceutique, ont-elles ainsi résisté à l’épreuve du temps tout
en continuant de mériter le respect d’un public international exigeant de médecins et chercheurs hospitalo-universitaires
et institutionnels. Je n’en connais personnellement aucune autre. Medicographia est incontestablement un cas unique.

Cet anniversaire nous a paru l’occasion idéale pour interroger nos lecteurs, au moyen d’une enquête internationale, sur ce qui
devait changer pour améliorer la revue, et ce qui était digne d’être conservé. Vos réponses ont afflué, par fax et par e-mail, et
vos réactions nous ont à la fois surpris et ravis. En effet, si nombre de lecteurs se sont exprimés en faveur d’un renouvelle-
ment de la présentation de Medicographia, un consensus plus fort encore s’est dégagé pour souhaiter que la revue perdure
dans sa structure actuelle et que sa formule originelle reste intacte.

Répondant à vos demandes précises, nous avons donc allégé et simplifié la mise en page, amélioré la lisibilité par des articles
plus courts et des encadrés pour attirer l’attention sur les points importants, et introduit une typographie plus moderne et plus
de couleurs.

Quant au souhait de pérennité exprimé par nos lecteurs, celui-ci vient comme corroborer l’une des valeurs fondamentales de
notre Maison. De fait, Medicographia est un exemple parmi tant d’autres de notre obsession de l’excellence sur le long terme,
qu’il s’agisse de notre recherche, de nos découvertes, ou encore de nos partenariats, nos projets, nos engagements. Soucieux
dès l’origine de notre indépendance, nous avons su éviter les sirènes de la Bourse et la tyrannie des dividendes obligeant
aux résultats à court terme. Ceci nous a assuré une grande liberté en tant qu’entreprise – liberté qui récemment, en ces temps
de crise, a acquis une signification particulière – et qui nous permet depuis les tout débuts de nous engager dans la durée.
Cet engagement est l’une des marques de fabrique du « style Servier », la plus appréciée par ceux qui comptent sur nos pro-
jets, nos médicaments et nos services rendus à la recherche, à la communauté médicale et aux patients qui bénéficient de
nos innovations thérapeutiques.

La principale raison de la longévité de Medicographia réside dans le fait que cette revue propose une forme originale de par-
tenariat entre Servier et la communauté médicale internationale. Medicographia se veut la rencontre de deux excellences :
celle d’auteurs prestigieux, reconnus par leurs pairs, écrivant pour des lecteurs sachant apprécier un panorama faisant un
point complet sur un thème particulier, et celle de l’expertise de notre Maison, toutes deux s’unissant pour proposer une revue
de qualité, un forum privilégié où les auteurs peuvent, en toute indépendance éditoriale, analyser en profondeur les avancées
dans leur spécialité et leurs implications pour le progrès de la médecine. Chaque numéro, quel que soit son thème, s’adresse
aux médecins de toutes spécialités : une exception alors que rares sont les revues qui proposent actuellement des articles
de pointe ne visant pas seulement les spécialistes d’un domaine thérapeutique, mais tous les cliniciens. Medicographia leur
permet ainsi de se tenir au courant des nouveautés dans des secteurs différents du leur et de rester les praticiens d’un tout,
plutôt que d’une partie, que ce soit d’un organe, d’une maladie ou d’une spécialité.

Une autre ambition de cette revue est, à son modeste rang, de représenter la France aux yeux de la communauté médicale
internationale, plutôt habituée à une presse médicale sous dominance anglo-saxonne. Ainsi, les éditoriaux et les résumés de
Medicographia sont systématiquement fournis en français et en anglais, et chaque numéro présente, dans la partie « Touch of
France » (Côté France), deux articles culturels, généreusement illustrés. Un article traite de l’histoire de la médecine, à travers
les grands personnages et courants qui l’ont illustrée, alors que l’autre s’ouvre plus largement au si riche patrimoine culturel
français, pour évoquer l’art, la littérature, l’architecture, les idées...

Fort de ses 30 ans d’existence et rajeuni par sa nouvelle présentation, mais fort surtout du soutien indéfectible de nos lecteurs,
Medicographia continuera, nous l’espérons, à répondre à votre attente pour de nombreuses années encore.

Bien confraternellement,
Docteur Jacques Servier

216 MEDICOGRAPHIA, Vol 31, No. 3, 2009 Medicographia No. 100! – Servier
 EDITORIAL
‘‘ Exciting new analyses have
confirmed that the joint effects of
these two treatments—the fixed
combination of perindopril and in-
dapamide and the gliclazide MR–
based intensive glucose control
regimen—result in very substantial
reductions in mortality and mor-
bidity, reducing all-cause mortality
by one fifth, cardiovascular mor-
tality by one quarter, and new or
worsening nephropathy by one
third. Thus ADVANCE has set the
standard and the pace for the new
century.”
John CHALMERS, FAA,
MD, PhD, FRACP
The George Institute
University of Sydney
Sydney, NSW
AUSTRALIA
Address for correspondence:
Prof John Chalmers, The George
Institute for International Health,
PO Box M201, Missenden Road,
NSW 2050, Australia
(e-mail: jchalmers@george.org.au)
MEDICOGRAPHIA. 2009;31:217-222.
www.medicographia.com
ADVANCE: optimal management of patients with type 2 diabetes – Chalmers
A DVANCE:
setting new standards for
optimal management of
patients with type 2 diabetes
b y J . C h a l m e r s , A u s t ra l i a
W
ith completion of patient follow-up and publication of the main re-
sults of both its blood pressure–lowering arm1 and its intensive
glucose control arm,2 the Action in Diabetes and Vascular disease:
PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) takes
over the mantle as standard bearer for the management of patients with type 2 dia-
betes in the 21st century. The United Kingdom Prospective Diabetes Study (UKPDS)
was clearly the outstanding study on the management of type 2 diabetes in the 20th
century. It established the benefit of blood pressure lowering in hypertensive patients
with type 2 diabetes, demonstrating reductions in mortality and in macrovascular
disease.3 Similar findings were obtained from subgroup analyses in patients with
type 2 diabetes from the HOT trial (Hypertension Optimal Treatment) trial4 and the
MIcroalbuminuria, Cardiovascular, and Renal Outcomes–Heart Outcomes Preven-
tion Evaluation (MICRO-HOPE).5 UKPDS also demonstrated that tighter glucose
control, ie, lowering glycosylated hemoglobin (HbA1c ) by about one percentage
point, reduced the burden of microvascular disease, predominantly through reduc-
tion in retinal disease.6 UKPDS was unable to show any reduction in macrovas-
cular disease during the course of the trial.6
ADVANCE now takes this further, by demonstrating that routine blood pressure
lowering with the fixed combination of perindopril and indapamide in patients with
type 2 diabetes, whether hypertensive or not, reduces mortality and prevents both
coronary disease and diabetic nephropathy.1 ADVANCE has also shown that more
intensive glucose lowering with a regimen based on gliclazide MR (modified release)
reduces major vascular events, predominantly as a result of reduction in microvas-
cular disease, driven by substantial reduction in new or worsening diabetic nephro-
pathy.2 While there was no significant reduction in macrovascular events, all-cause
mortality, or cardiovascular death, the UKPDS confirmation that a sulfonylurea-in-
sulin regimen has a legacy effect with late benefit in these outcomes7 suggests that
the trend towards a benefit seen for these outcomes in ADVANCE, particularly in
the last year of follow-up, should translate into real benefits over time.8
Exciting new analyses have confirmed that the joint effects of these two treat-
ments—the fixed combination of perindopril and indapamide and the gliclazide
MR–based intensive glucose control regimen—result in very substantial reduc-
tions in mortality and morbidity.9 This combined effect reduces all-cause mortality
by one fifth, cardiovascular mortality by one quarter, and new or worsening nephro-
pathy by one third.9 Thus, ADVANCE has set the standard and the pace for the
new century.
MEDICOGRAPHIA, Vol 31, No. 3, 2009 217
EDITORIAL
ADVANCE: design and rationale
ADVANCE was conceived and planned, in 2000, to take us
beyond UKPDS and beyond available evidence, by address-
ing two pressing problems in the management of patients
with type 2 diabetes. The first problem related to the benefits
of blood pressure lowering, since all recommendations and
guidelines went beyond the evidence from UKPDS, to rec-
ommend that the blood pressure thresholds and targets for
treatment should be around 130/80 mm Hg, well below the
range established in UKPDS.3 The second problem con-
cerned the benefits of tighter glucose control, since the ma-
jor international guidelines again went beyond the evidence
from UKPDS, advocating reductions in HbA1c to levels equal
to or less than 6.5% or 7%. ADVANCE was therefore initi-
ated as a randomized 22 factorial study with two arms.10
One arm was established as a double-blind comparison of
the fixed combination of perindopril and indapamide com-
pared with placebo in patients with type 2 diabetes, irrespec-
tive of initial blood pressure, thus enrolling both normoten-
sive and hypertensive patients.1,10 The other arm was estab-
lished as an open, randomized comparison with a prospective,
open, blinded end point (PROBE) design, of an intensive
gliclazide MR–based glucose control regimen, targeting an
HbA1c of 6.5% or less, against standard, guideline-based
glucose control regimens.2,10 For both sets of comparisons,
the primary outcomes were defined as composites of major
macrovascular disease and of major micro-vascular disease,
analyzed jointly and separately.1,2
ADVANCE: lessons and implications from
treatment with the fixed combination of
perindopril and indapamide
The fixed combination of perindopril and indapamide pro-
duced significant reductions in cardiovascular morbidity and
mortality, which translated into substantial absolute bene-
fits. Thus, it can be estimated that 5 years of treatment with
a single tablet of perindopril-indapamide once daily would
prevent 1 death among every 79 patients so treated, 1 ma-
jor vascular event among every 66 patients, 1 coronary event
among every 75 patients, and 1 renal event among every 20
patients so treated.1
Furthermore, these benefits were all obtained in a group of
patients receiving comprehensive cardiovascular care, in-
cluding blood pressure–lowering drugs in over 75% of all
participants, oral hypoglycemic agents in over 90%, and
statins and aspirin in over 50%.1 As a result, the participants
in ADVANCE had much lower risk profiles and event rates
than those in the UKPDS, HOT, and MICRO-HOPE studies.3-5
Importantly, all the benefits observed were consistent,
whether the patients were hypertensive or not, and whatever
concomitant therapies they were receiving, including inhibitors
of the renin-angiotensin system.1 Furthermore, the treatment
was remarkably well tolerated, with adherence to randomized
treatment similar in the active treatment group and the place-
218 MEDICOGRAPHIA, Vol 31, No. 3, 2009 ADVANCE: optimal management of patients with type 2 diabetes – Chalmers
bo-treated group.1 It can be estimated that if all 250 million
people alive with diabetes today were treated with one
tablet of perindopril-indapamide daily, over 3 million lives
would be saved over 5 years. It clearly behoves all physicians
to consider treatment with this fixed-dose combination when-
ever they see a patient with type 2 diabetes.
ADVANCE: lessons and implications from treatment
with the intensive gliclazide MR–based regimen
The gliclazide MR–based intensive glucose control regimen
considerably reduced vascular disease, largely as a result
of great reductions in microvascular and renal disease. These
translated into considerable absolute benefits. It can be
estimated that for every 52 patients undergoing intensive
control with this regimen for 5 years, 1 major macrovascular
or microvascular event would be averted.2 Furthermore, 1 ma-
jor renal event would be averted among every 20 patients
with type 2 diabetes, so treated. These benefits were ob-
tained with very acceptable rates of hypoglycemia—only 7
cases of severe hypoglycemia per 1000 patients per annum,
and without any weight gain, on average, in the intensively
treated group.
One of the most important outcomes, given the early termi-
nation of the intensive glucose control arm of the Action to
Control CardiOvascular Risk in Diabetes (ACCORD) trial on
account of excess mortality,11 was the trend toward a reduc-
tion in both all-cause mortality (7%; nonsignificant) and in car-
diovascular death (12%; nonsignificant). There was no trend
toward an increase in mortality in any subgroup of ADVANCE,
including those most closely resembling the ACCORD cohort.
The much greater safety of the ADVANCE regimen cannot be
attributed to the level of the HbA1c achieved (a mean of 6.5%)
since this was very similar in the two studies.2,11 It must be as-
sociated with the very real differences in the treatment strate-
gies used in these two trials.2,11 The strategy in ADVANCE
started with oral hypoglycemic agents in a progressive and
incremental manner, beginning with gliclazide MR, once daily,
then increasing the dose of gliclazide MR to the point that
70% of patients were receiving the maximum dose of 120 mg
daily. Other hypoglycemic agents were added progressively,
so that by the end of follow-up, 91% were on gliclazide MR,
67% on metformin, and only 17% on thiazolidinediones. In-
sulin was only added if these measures failed, beginning with
basal, nocturnal insulin, and only moving to multiple injection
insulin if really needed further down the track. Only 40% of
patients were on insulin at the end of follow-up in the inten-
sively treated group of ADVANCE, compared with 24% in the
standard treatment group.2 This should be contrasted with
the much more aggressive strategy used in ACCORD, where
the intention was to reduce HbA1c to a target of 6.0% as soon
as possible, with the use of multiple oral hypoglycemic agents
and insulin from the first few months. By the time the intensive
glucose arm of ACCORD was terminated, after an average of
3.5 years of follow-up, over 90% were receiving thiazolidine-

diones, over 90% were receiving metformin, most were on 4
or more agents, and 77% were receiving insulin, most often
multidose.11 Not surprisingly, the annual rate of severe hypo-
glycemia in the ACCORD study was 6 to 7 times greater than
that seen in ADVANCE.2,11
ADVANCE: conclusions
The great benefits observed in the separate and joint ef-
fects of the perindopril-indapamide intervention and the gli-
clazide MR–based regimen are founded on very practical and
pragmatic strategies suited to everyday practice, and on the
particularly appropriate properties of the study drugs for use
in patients with type 2 diabetes.
Patients with diabetes are notorious for not tolerating ele-
vated blood pressure, largely because of progressive stiff-
ening of large arteries coupled with progressive damage to
small vessels, resulting in poor tissue perfusion. The proper-
ties of the fixed combination of perindopril and indapamide
are made to order for this situation, with very effective low-
ering of blood pressure, coupled with a great efficacy in
combating arterial stiffness and in enhancing tissue perfu-
sion through the microcirculation.12-16
Lowering blood glucose is clearly paramount in the treatment
of patients with type 2 diabetes, and the gliclazide MR–based
regimen used in ADVANCE has proved to be remarkably safe
References
1. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril
and indapamide on macrovascular and microvascular outcomes in patients
with type 2 diabetes mellitus (the ADVANCE Trial): a randomised controlled trial.
Lancet. 2007;370:829-840.
2. ADVANCE Collaborative Group. Intensive blood glucose control and vascular
outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.
3. UK Prospective Diabetes Study (UKPDS) Group. Tight blood pressure control
and risk of macrovascular and microvascular complications in type 2 diabetes
(UKPDS 39). BMJ. 1998;317:703-713. (Erratum. BMJ. 1999;318:29.)
4. Hansson L, Zanchetti A, Carruthers S, et al. Effects of intensive blood pres-
sure lowering and low-dose aspirin in patients with hypertension: principal re-
sults of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet.
1998;351:1755-1762.
5. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of
ramipril on cardiovascular and microvascular outcomes in people with diabetes
mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet.
2000;355:253-259.
6. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose con-
trol with sulphonylurea or insulin compared with conventional treatment and
risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;
352:837-853. (Erratum. Lancet. 1999;354:660.)
7. Holman RR, Sanjoy KP, Bethel MA, Matthews DR, Neil HAW. 10-year follow-
up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:
1577-1589.
8. Chalmers J, Cooper M. UKPDS and the Legacy effect. N Engl J Med. 2008;
359:1618-1620.
9. Perkovic V, Ninomiya T, de Galan B, et al. Joint effects of routine blood pressure
lowering and intensive glucose control in the ADVANCE trial. Abstract present-
ed at Renal Week 2008 (American Society of Nephrology). 2008:LB-002.
Keywords: routine blood pressure lowering; intensive glucose control; fixed combination of perindopril and indapamide;
gliclazide MR–based regimen; cardiovascular outcomes; renal outcomes; type 2 diabetes
ADVANCE: optimal management of patients with type 2 diabetes – Chalmers
EDITORIAL
and effective in controlling the metabolic aspects of the dis-
ease as well as the renal and microvascular complications.2
The modified-release formulation of the sulfonylurea gliclazide
MR is at least as effective as other sulfonylureas in lowering
blood sugar, but causes less hypoglycemia than most.17 This
hypoglycemic agent formed an excellent base for a prag-
matic glucose control strategy with progressive intensifica-
tion in a manner well suited to clinical practice worldwide.
The Steno 2 trial has confirmed the great value of a multifac-
torial approach to the control and prevention of the most
serious complications of type 2 diabetes.18 The results of
ADVANCE, the largest ever study of treatment in patients with
diabetes, clearly justify a recommendation that the multifac-
torial regimen used in all patients with type 2 diabetes should
include routine blood pressure lowering, regardless of initial
blood pressure and intensive glucose control targeting an
HbA1c around 6.5%. Furthermore, the outcomes observed
with the two arms of ADVANCE suggest that the two strate-
gies used in ADVANCE—routine blood pressure lowering with
the fixed combination of perindopril and indapamide and
intensive glucose lowering with a gliclazide MR–based reg-
imen—should be considered for all patients with type 2 dia-
betes across the world. This would yield enormous benefits
and avert millions of deaths, major vascular events, and cases
of renal complications of diabetes among the 250 million peo-
ple alive with this disease today. 
10. ADVANCE Management Committee. Study Rationale and Design of ADVANCE:
Action in Diabetes and Vascular disease - Preterax and Diamicron MR con-
trolled evaluation. Diabetologia. 2001;44:1118-1120.
11. ACCORD Study Group. Effects of intensive glucose lowering in type 2 diabetes.
N Engl J Med. 2008;358:2545-2559.
12. London GM, Asmar RG, O’Rourke MF, et al; REASON Project Coordinators
and Investigators. Mechanism(s) of selective systolic blood pressure reduction
after a low-dose combination of perindopril/ indapamide in hypertensive subjects:
comparison with atenolol. J Am Coll Cardiol. 2004;43:92-99.
13. Mogensen CE, Viberti G, Halimi S, et al. Preterax in Albuminuria Regression
(PREMIER) Study Group. Effect of low-dose perindopril/indapamide on albumin-
uria in diabetes. Preterax in Albuminuria Regression: PREMIER. Hypertension.
2003;41:1063-1071.
14. Levy BI, Duriez M, Samuel JL. Coronary microvasculature alteration in hyper-
tensive rats. Effects of treatment with diuretic and an ACE inhibitor. Am J Hy-
pertens. 2001;14:7-13.
15. Mourad JJ, Hanon O, Deverre JR, et al. Improvement of impaired coronary
vasodilator reserve in hypertensive patients by low-dose ACE inhibitor/diuret-
ic therapy: a pilot PET study. J Renin Angiotensin Aldosterone Syst. 2003;4:
94-95.
16. Dahlöf B, Gosse P, Guéret P, et al. Perindopril/indapamide combination more
effective than enalapril in reducing blood pressure and left ventricular mass:
the PICXEL study. J Hypertens. 2005;23:2063-2070.
17. Schernthaner G, Grimaldi A, Di Mario U, et al. GUIDE Study: double-blind com-
parison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients.
Eur J Clin Invest. 2004;34:535-542.
18. Gaede P, Lund-Anderson H, Parving H-H, Pederson O. Effect of a multifac-
torial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:
580-591.
MEDICOGRAPHIA, Vol 31, No. 3, 2009 219
 ÉDITORIAL

‘‘ De nouvelles analyses extrê-

mement intéressantes ont confirmé
que les effets conjoints de l’asso-
ciation fixe perindopril plus inda-
pamide et du contrôle intensif de la
glycémie par le gliclazide MR per-
mettent d’obtenir des réductions
ADVANCE : nouvelles
très substantielles de la mortalité
et de la morbidité, en réduisant la
normes pour la prise en
charge optimale des patients
mortalité de toute cause d’un cin-
quième, la mortalité cardio-vascu-
laire d’un quart et les nouveaux
cas et les aggravations de néphro-
pathie d’un tiers. Par conséquent, atteints de diabète de type 2
l’étude ADVANCE a fixé les normes
ainsi que la marche à suivre pour
ce nouveau siècle.”
p a r J . C h a l m e r s , A u s t ra l i e

L’
achèvement du suivi des patients et la publication des principaux résultats
des deux bras (abaissement de la pression artérielle1 et contrôle intensif
de la glycémie2) de l’étude ADVANCE (Action in Diabetes and Vascular
disease: PreterAx and DiamicroN MR Controlled Evaluation) a permis
d’établir les normes de la prise en charge des diabétiques de type 2 pour le XXI e
siècle. L’étude UKPDS (United Kingdom Prospective Diabetes Study) avait établi
quant à elle les principes de la prise en charge du diabète de type 2 au XX e siècle.
Elle avait démontré le bénéfice d’une réduction de la pression artérielle chez les pa-
tients hypertendus atteints de diabète de type 2, en mettant en évidence des ré-
ductions de la mortalité et des maladies macrovasculaires 3. Des résultats similaires
avaient été obtenus avec des analyses de sous-groupes effectuées chez des pa-
tients diabétiques de type 2 ayant participé à l’étude HOT (Hypertension Optimal
Treatment)4 et à l’étude MICRO-HOPE (MIcroalbuminuria, Cardiovascular, and Re-
nal Outcomes–Heart Outcomes Prevention Evaluation)5. L’étude UKPDS a égale-
ment démontré qu’un contrôle plus étroit de la glycémie, c’est-à-dire une réduction
de l’hémoglobine glycosylée (HbA1c ) d’environ un point de pourcentage, permet-
tait de diminuer l’impact des maladies microvasculaires, principalement par la ré-
duction des pathologies rétiniennes.6 L’étude UKPDS n’a pas été en mesure de
mettre en évidence une réduction des maladies macrovasculaires au cours de
son déroulement 6.

L’étude ADVANCE prend désormais le relais en démontrant qu’une réduction sys-

tématique de la pression artérielle par l’association fixe de perindopril et d’inda-
pamide chez des patients atteints de diabète de type 2, qu’ils soient hypertendus
ou non, permet de réduire la mortalité et de prévenir à la fois les maladies corona-
riennes et la néphropathie diabétique 1. L’étude ADVANCE a également démontré
qu’un abaissement plus intense de la glycémie par un schéma thérapeutique à
base de gliclazide MR (= modified release, à libération modifiée) minorait les évé-
nements vasculaires majeurs, principalement à la suite d’une réduction des patho-
logies microvasculaires, due en particulier à une diminution significative des nouveaux
cas ou à des exacerbations de la néphropathie diabétique 2. Malgré l’absence de ré-
duction significative des événements macrovasculaires, de la mortalité de toute cause
ou de la mortalité cardio-vasculaire, la confirmation apportée par l’étude UKPDS de
l’existence d’un « legacy effect » (bénéfices à très long terme), obtenu grâce à un
schéma thérapeutique associant un sulfamide hypoglycémiant et l’insuline 7, suggère
que la tendance vers l’obtention d’effets positifs observée dans les données de
l’étude ADVANCE, en particulier au cours de la dernière année du suivi, devrait se
traduire par l’obtention de résultats positifs concrets avec le temps 8.

220 MEDICOGRAPHIA, Vol 31, No. 3, 2009 ADVANCE : prise en charge optimale des patients atteints de diabète de type 2 – Chalmers

De nouvelles analyses extrêmement intéressantes ont confir-
mé que les effets conjoints de ces deux traitements – l’asso-
ciation fixe perindopril plus indapamide et le contrôle intensif
de la glycémie reposant sur un traitement à base de glicla-
zide MR – permettent d’obtenir des réductions très substan-
tielles de la mortalité et de la morbidité.9 Cet effet combiné
réduit la mortalité de toute cause d’un cinquième, la morta-
lité cardio-vasculaire d’un quart et les nouveaux cas et les
aggravations de néphropathie d’un tiers 9. Par conséquent,
l’étude ADVANCE a fixé les normes ainsi que la marche à
suivre pour ce nouveau siècle.
ADVANCE : schéma et justificatif
L’étude ADVANCE a été conçue et programmée en 2000,
afin de prendre le relais de l’étude UKPDS et progresser au-
delà des données disponibles, en s’attaquant à deux pro-
blèmes aigus rencontrés dans la prise en charge des diabé-
tiques de type 2. Le premier problème concerne les bénéfices
d’un abaissement de la pression artérielle, dans la mesure
où toutes les recommandations et toutes les directives, dé-
passant les faits recueillis au cours de l’étude UKPDS, ont
recommandé des seuils et des valeurs thérapeutiques cibles
pour la pression artérielle d’environ 130/80 mm Hg, c’est-à-
dire très inférieurs aux chiffres établis dans l’étude UKPDS 3.
Le second problème avait trait au bénéfice d’un contrôle plus
strict de la glycémie, dans la mesure où les principales direc-
tives internationales allaient elles aussi au-delà des conclu-
sions de l’étude UKPDS, recommandant des réductions de
l’HbA1c à des valeurs inférieures ou égales à 6,5 % ou 7 %.
L’étude ADVANCE a par conséquent été mise en œuvre se-
lon un schéma factoriel 2 2 comportant deux bras10. Dans
l’un des bras, une comparaison en double aveugle a été ef-
fectuée entre une association fixe perindopril plus indapamide
et un placebo chez des patients diabétiques de type 2, quelle
que soit leur pression artérielle initiale, incluant par consé-
quent des sujets normotendus et hypertendus 1,10. L’autre bras
a comporté une comparaison ouverte randomisée, reposant
sur un schéma prospectif, ouvert et en aveugle vis-à-vis du cri-
tère, entre un contrôle strict de la glycémie utilisant un schéma
à base de gliclazide MR et visant une valeur d’HbA1c inférieure
ou égale à 6,5 %, et des schémas de contrôle de la glycémie
basés sur les directives standard 2,10. Pour les deux compa-
raisons, les critères primaires ont été des paramètres compo-
sites rassemblant les principales pathologies macrovasculaires
et microvasculaires, analysés simultanément et séparément 1,2.
ADVANCE : enseignements et conséquences
du traitement par l’association fixe perindopril
plus indapamide
L’association fixe de perindopril et d’indapamide a provoqué
des réductions significatives de la morbidité et de la morta-
lité cardio-vasculaires qui se sont traduites par des bénéfi-
ces absolus significatifs. Par conséquent, il peut être estimé
qu’un traitement de 5 ans par un seul comprimé de perindo-
pril-indapamide une fois par jour permet de prévenir un décès
ADVANCE : prise en charge optimale des patients atteints de diabète de type 2 – Chalmers
ÉDITORIAL
pour 79 patients recevant ce type de traitement, un événe-
ment vasculaire majeur pour 66 patients, un événement co-
ronaire pour 75 patients, et un événement rénal pour 20 pa-
tients ainsi traités1.
En outre, ces bénéfices ont tous été obtenus dans un groupe
de patients recevant des soins cardio-vasculaires très sui-
vis, comprenant notamment des antihypertenseurs chez plus
de 75 % des participants, des hypoglycémiants oraux chez
plus de 90 % de ces patients et des statines et de l’aspirine
chez plus de 50 % d’entre eux 1. Par conséquent, les partici-
pants de l’étude ADVANCE présentaient des profils de risque
et des taux d’événements beaucoup plus favorables que
ceux des études UKPDS, HOT et MICRO-HOPE 3-5. Il est im-
portant de souligner que tous les bénéfices observés ont été
constants, que les patients aient été hypertendus ou non, et
quels qu’aient été les traitements concomitants administrés,
notamment des inhibiteurs du système rénine-angiotensine1.
En outre, le traitement a été remarquablement bien toléré, avec
une observance du traitement randomisé similaire dans le
groupe du médicament actif et le groupe placebo1. Par consé-
quent, si les 250 millions de personnes atteintes de diabète
aujourd’hui étaient traitées par un comprimé de perindopril-
indapamide une fois par jour, on estime que plus de 3 mil-
lions de vies pourraient être sauvées sur une période de 5
ans. Ces chiffres doivent inciter tous les médecins à envisager
un traitement par cette association fixe chez tous les patients
atteints de diabète de type 2 venant les consulter.
ADVANCE : enseignements et conséquences
du traitement par le schéma intensif à base
de gliclazide MR
Le schéma de contrôle intense de la glycémie reposant sur
l’administration de gliclazide MR a entraîné des réductions
considérables des maladies vasculaires, principalement à la
suite d’importantes diminutions des pathologies microvas-
culaires et rénales. Ces réductions se sont traduites par des
bénéfices absolus considérables. Il peut être estimé que pour
52 patients soumis à un contrôle intensif par ce schéma
thérapeutique pendant 5 ans, un événement macrovascu-
laire ou microvasculaire majeur peut être prévenu 2. En outre,
un événement rénal majeur peut être évité pour 20 patients
diabétiques de type 2 ainsi traités. Ces bénéfices ont été ob-
tenus avec des taux très acceptables d’hypoglycémie – seu-
lement 7 cas d’hypoglycémie sévère pour 1 000 patients par
an, sans aucun gain de poids, en moyenne, dans le groupe
traité intensivement.
L’un des résultats les plus importants, compte tenu de l’inter-
ruption prématurée du bras de contrôle intensif de la glycé-
mie de l’étude ACCORD (Action to Control CardiOvascular
Risk in Diabetes), due à une mortalité excessive11, a été la ten-
dance vers une réduction de la mortalité de toute cause (7 % ;
non significatif) et de la mortalité cardio-vasculaire (12 % ; non
significatif). Il n’a été observé aucune tendance vers une aug-
MEDICOGRAPHIA, Vol 31, No. 3, 2009 221
ÉDITORIAL
mentation de la mortalité dans aucun des sous-groupes de
l’étude ADVANCE, y compris les plus proches de la cohorte
de l’étude ACCORD. La sécurité d’emploi très supérieure ob-
servée avec le schéma thérapeutique de l’étude ADVANCE
ne peut pas être attribuée au niveau de l’HbA1c atteint (en
moyenne 6,5 %), car il était très similaire dans les deux étu-
des 2,11. Elle doit en revanche être associée aux différences
marquées entre les stratégies thérapeutiques utilisées dans
ces deux essais 2,11. La stratégie de l’étude ADVANCE a débuté
avec des hypoglycémiants oraux administrés de manière pro-
gressive et graduellement croissante, en commençant avec
le gliclazide MR une fois par jour, puis en augmentant la po-
sologie du gliclazide MR jusqu’à ce que 70 % des patients
reçoivent la dose maximale de 120 mg/jour. D’autres hypo-
glycémiants ont été ajoutés progressivement de telle sorte
qu’à la fin du suivi 91 % des patients étaient traités par le
gliclazide MR, 67 % par la metformine, et seulement 17 % par
les thiazolidinediones. L’insuline n’a été ajoutée qu’en cas
d’insuffisance de résultats thérapeutiques, en commençant
par le schéma insulinique de base nocturne, pour ne progres-
ser vers de multiples injections d’insuline qu’en cas de besoin
réel, puis en revenant à la dose initiale. Seulement 40 % des
patients étaient sous insuline à la fin du suivi dans le groupe
recevant le traitement intensif de l’étude ADVANCE, par rap-
port à 24 % dans le groupe du traitement standard 2. Cette
observation doit être mise en perspective avec la stratégie
beaucoup plus agressive utilisée dans l’étude ACCORD, au
cours de laquelle l’objectif était de réduire l’HbA1c à une va-
leur cible de 6,0 % dès que possible, par l’utilisation d’hypo-
glycémiants oraux et d’insuline dès les premiers mois. Lorsque
le bras du contrôle intensif de la glycémie de l’étude ACCORD
a été interrompu, après une moyenne de 3,5 ans de suivi, plus
de 90 % des patients recevaient des thiazolidinediones, plus
de 90 % des patients recevaient de la metformine, la plupart
étaient traitées par au moins 4 médicaments, et 77 % rece-
vaient de l’insuline, souvent en multidoses 9. Il n’est pas sur-
prenant que le taux annuel d’épisodes d’hypoglycémie sévère
dans l’étude ACCORD ait été 6 à 7 fois supérieur à celui ob-
servé dans l’étude ADVANCE 2,11.
ADVANCE : conclusions
Les bénéfices importants obtenus par les effets séparés et si-
multanés de l’association perindopril-indapamide et du schéma
à base de gliclazide MR sont fondés sur des stratégies pra-
tiques et pragmatiques, adaptées à la pratique quotidienne, et
sur les propriétés particulièrement appropriées de ces mé-
dicaments chez les patients atteints de diabète de type 2.
222 MEDICOGRAPHIA, Vol 31, No. 3, 2009 ADVANCE : prise en charge optimale des patients atteints de diabète de type 2 – Chalmers
Les patients diabétiques tolèrent mal l’hypertension artérielle,
principalement à cause de la rigidification progressive des
grandes artères associée à des lésions graduelles des petits
vaisseaux entraînant une altération de la perfusion tissulaire.
Les propriétés de l’association fixe perindopril plus indapamide
sont particulièrement adaptées à cette situation, dans la me-
sure où elle entraîne une réduction efficace de la pression ar-
térielle, tout en luttant efficacement contre la rigidité artérielle
et en favorisant la perfusion tissulaire par la microcirculation12-16.
La réduction de la glycémie est essentielle dans le traitement
des patients atteints de diabète de type 2, et le schéma à base
de gliclazide MR utilisé dans l’étude ADVANCE s’est avéré re-
marquablement sûr et efficace dans le contrôle des aspects
métaboliques de la maladie, ainsi que des complications ré-
nales et microvasculaires2. La formulation à libération modifiée
du gliclazide MR est au moins aussi efficace que les autres
sulfamides hypoglycémiants pour la réduction de la glycémie,
mais elle entraîne moins d’épisodes d’hypoglycémie que la
plupart d’entre eux17. Ce sulfamide hypoglycémiant constitue
une base excellente pour la stratégie pragmatique de contrôle
de la glycémie reposant sur une intensification progressive,
qui peut être instaurée d’une façon parfaitement adaptée à la
pratique clinique à travers le monde.
L’étude Steno 2 a confirmé l’intérêt d’une approche multifac-
torielle pour la lutte contre les complications les plus graves du
diabète de type 2 et leur prévention18. Les résultats de l’étude
ADVANCE, la plus importante étude jamais réalisée sur le
traitement des patients diabétiques, justifient parfaitement d’in-
clure dans le schéma multifactoriel utilisé chez tous les pa-
tients atteints de diabète de type 2 un abaissement systéma-
tique de la pression artérielle, quelle que soit sa valeur initiale,
et un contrôle intensif de la glycémie, avec une valeur cible de
l’HbA1c d’environ 6,5 %. En outre, les résultats observés dans
les deux bras de l’étude ADVANCE suggèrent que les deux
stratégies utilisées dans cet essai – abaissement systéma-
tique de la pression artérielle par l’association fixe perindo-
pril plus indapamide et réduction intensive de la glycémie à
l’aide d’un schéma thérapeutique à base de gliclazide MR
– doivent être envisagées chez tous les patients atteints de
diabète de type 2 à travers le monde. L’utilisation de ce trai-
tement pourrait apporter des bénéfices considérables, em-
pêcher des millions de décès, et prévenir les événements
vasculaires majeurs et les complications rénales du diabète,
chez les 250 millions de personnes aujourd’hui atteintes de
cette maladie. 

‘‘ The BP-lowering arm of the
ADVANCE trial provides the best
evidence to date that modest BP
lowering is beneficial in terms of re-
ducing the risk of critical CV events
and renal end points in a broad
range of patients with established
type 2 diabetes, irrespective of
their baseline BP levels.”
Neil R. POULTER, MBBS,
MSc, FRCP
International Centre for
Circulatory Health (ICCH)
Imperial College London
UNITED KINGDOM
Address for correspondence:
Professor Neil R. Poulter,
ICCH Imperial College London,
59-61 North Wharf Road,
Paddington, London W2 1LA, UK
(e-mail: n.poulter@imperial.ac.uk)
www.medicographia.com
Major findings from ADVANCE: blood pressure–lowering arm – Poulter
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES
Major findings from ADVANCE:
blood pressure–lowering arm
b y N . R . Po u l t e r, U n i t e d K i n g d o m
B
ackground: Although guidelines throughout the world recommend low-
er blood pressure (BP) treatment thresholds and lower BP targets for
patients with type 2 diabetes, the evidence base for so-doing is limited.
Methods: As part of a 22 factorial design, the Action in Diabetes and Vascu-
lar disease: PreterAx and DiamicroN Controlled Evaluation (ADVANCE) trial
randomized 11 140 patients with type 2 diabetes, and at least 1 other prespec-
ified determinant of cardiovascular (CV) risk, to receive perindopril (4 mg)/in-
dapamide (1.25 mg) or placebo, irrespective of whether other antihyperten-
sive medication was being used and irrespective of BP level.
Results: During an average follow-up of 4.3 years, BP was lowered, on aver-
age, by 5.6/2.2 mm Hg among those on perindopril/indapamide compared
with placebo, to a level of 135/75 mm Hg. This BP reduction was associat-
ed with a significant 9% reduction (95% confidence interval [CI], 0.83-1.00;
P=0.04) in the primary end point (major macrovascular or microvascular
events), an 18% (0.68-0.98) reduction in CV mortality and a 14% (0.75-0.98)
reduction in all-cause mortality. New or worsening nephropathy was reduced
by 18% (0.68-1.01), but no effects were apparent on retinopathy. CV benefits
were apparent across all subgroups, and occurred irrespective of baseline
BP and/or background use of angiotensin-converting enzyme inhibition.
Conclusion: Patients with type 2 diabetes should be routinely considered for
the addition of the type of treatment used in the ADVANCE trial, irrespective
of their baseline BP levels.
Medicographia. 2009;31:223-231 (see French abstract on page 231)
Background and rationale
I
ntervention on major cardiovascular (CV) risk factors has traditionally been based
on the absolute levels of the risk factors in question (eg, fasting plasma glucose
>7 mmol/L or systolic blood pressure >140 mm Hg). More recently, the concept
of intervention being based on, or at least influenced by, an estimate of total CV risk
has been introduced into guidelines.1,2
Prior to the conduct and publication of the Action in Diabetes and Vascular disease:
PreterAx and DiamicroN Controlled Evaluation (ADVANCE) trial,3 two things relating
to blood pressure (BP) among people with diabetes were clear. Firstly, there was a
strong dose-response relationship between BP and risk of both macrovascular and
microvascular events across the whole range of BP, irrespective of “hypertensive”
status.4,5 Secondly, findings were consistent from randomized trial data (albeit rel-
MEDICOGRAPHIA, Vol 31, No. 3, 2009 223
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

Registration Figure 1. Trial design for the

6-week run-in phase on active blood pressure–lowering arm
perindopril and indapamide of ADVANCE.
The original power calculations
Randomization were based on a total of 10 000
participants with type 2 diabetes,
with an annual event rate of 3% and
requiring an average follow-up of
4.5 years. All participants entered
Perindopril- Perindopril- Placebo Placebo a preliminary 6-week open run-in
indapamide indapamide phase, during which they received
combination combination + + one tablet daily of perindopril 2 mg –
+ +
indapamide 0.625 mg (Preterax).
intensive standard intensive standard
glucose control glucose control glucose control glucose control Abbreviation: ADVANCE, Action
in Diabetes and Vascular disease:
PreterAx and DiamicroN Controlled
Evaluation.
Modified from reference 12:
End of follow-up (4-5 years) ADVANCE Collaborative Group.
Lancet. 2007;370:829-840.
Copyright © 2007, Elsevier, Ltd.

atively limited in size) that greater BP lowering was superior to
lesser BP lowering in terms of preventing major CV events.6
Interestingly, whilst guidelines among the world vary on sev-
eral key issues relating to optimal BP management, all guide-
lines are consistent in suggesting a lower BP target (<130/80
mm Hg) for patients with type 2 diabetes.1,2 Paradoxically,
there are no good data, based on morbidity and mortality tri-
als, to support these specifically lower BP levels recommend-
ed for diabetic patients and accepted throughout the world!
Prior to the ADVANCE trial, data on BP lowering in diabetes
were available from the results of the United Kingdom Pros-
pective Diabetes Study (UKPDS),7 the Hypertension Optimal
Treatment (HOT) trial,8 and the MIcroalbuminuria, Cardiovas-
cular, and Renal Outcomes in the Heart Outcomes Preven-
tion Evaluation (MICRO-HOPE) trial.9
UKPDS included a small BP-lowering limb comparing more
versus less intensive BP lowering, but only among frankly
hypertensive patients with diabetes. This trial also included a
comparison of two different BP-lowering regimens, but it was
underpowered and totally inadequate, and offered no use-
ful information in this regard. In the small subgroup of diabetic
hypertensive patients in HOT, a comparison of more versus
SELECTED ABBREVIATIONS AND ACRONYMS
ADVANCE Action in Diabetes and Vascular disease
PreterAx and DiamicroN Controlled
Evaluation
CCB calcium channel blocker
CV cardiovascular
HOT Hypertension Optimal Treatment
MICRO-HOPE MIcroalbuminuria, Cardiovascular, and Renal
Outcomes in the Heart Outcomes Prevention
Evaluation
UKPDS United Kingdom Prospective Diabetes Study
less BP lowering (achieved with a regimen based on the di-
hydropyridine calcium channel blocker felodipine) showed a
significant reduction in major CV events, despite only mod-
est differential BP reduction. MICRO-HOPE compared the an-
giotensin-converting enzyme (ACE) inhibitor ramipril with
placebo in a subgroup of about 3300 high-risk patients with
type 2 diabetes.
ADVANCE extended these data in a larger database by
adding additional BP-lowering therapy (with a single-pill com-
bination of perindopril and indapamide) to whatever preven-
tive therapies were being taken (including ACE inhibition).
Other studies have shown that drugs which block the renin-
angiotensin system (RAS)—ACE inhibitors and angiotensin
receptor blockers—appear to have beneficial effects on the
development and progression of renal disease in patients with
diabetes, and that these effects may be superior to those
achieved by other BP-lowering agents for a similar level of BP
reduction.10 These results, based on renal end points, are the
major reason for the recommendation that a RAS-blocker
should probably form part of whatever antihypertensive
“cocktail” is provided for patients with diabetes.11
The ADVANCE trial set out to add to the currently available
data by evaluating whether the addition of further BP low-
ering with perindopril and indapamide would reduce the
risk of major macrovascular and microvascular disease in
patients with type 2 diabetes, irrespective of their baseline BP
or whether they were already taking background ACE inhib-
itor treatment or not.
Design
Details of the design of the ADVANCE trial have been pub-
lished previously.3,12 However, in summary, ADVANCE had a
22 factorial design comparing additional active BP lowering
versus placebo and comparing intensive versus standard glu-
cose control (Figure 1).3

224 MEDICOGRAPHIA, Vol 31, No. 3, 2009 Major findings from ADVANCE: blood pressure–lowering arm – Poulter
 NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

Patients with type 2 diabetes were eligible to join the trial if

they were aged 55 years and had one or more of the fol- Randomized treatment
lowing additional criteria for increased vascular risk—age Active Placebo
65 years, history of major macrovascular disease, history of (n=5569) (n=5571)
major microvascular disease, diabetes diagnosed >10 years Age (years) 66 66
ago, or any other major risk factor (eg, current smoker, to- Female (%) 43 43
tal cholesterol > 6.0 mmol/L, high-density lipoprotein [HDL] Age at diabetes diagnosis (years) 58 58
cholesterol <1.0 mmol/L). Following registration with the tri- Systolic blood pressure (mm Hg) 145 145
al, potentially eligible participants underwent a 6-week run- Diastolic blood pressure (mm Hg) 81 81
in treatment period with a single daily pill combination of History of treated hypertension (%) 68 69
perindopril 2 mg and indapamide 0.625 mg, which was History of macrovascular disease (%) 32 32
added to whatever previous therapy was being taken. Pa- History of microvascular disease (%) 10 10
tients with a compelling indication for an ACE inhibitor other Microalbuminuria (%) 26 26
than perindopril or for a thiazide/thiazide-like diuretic were Hemoglobin A1c (%) 7.5 7.5
ineligible. During the run-in period, these diuretics were with- Current smokers (%) 14 16
drawn and ACE inhibitors other than perindopril were re- Body mass index (kg/m 2) 28 28
placed by perindopril (up to 4 mg daily). Total cholesterol (mmol/L) 5.2 5.2
Oral hypoglycemic drugs (%) 91 91
After the run-in period, those who had tolerated and ad- Insulin (%) 1 1
hered to trial therapy were randomized double-blind to re- Statins (%) 28 29
ceive either placebo or a single pill combination of perindopril Other lipid-modifying drugs (%) 9 8
2 mg/indapamide 0.625 mg daily for 3 months, after which Aspirin (%) 44 44
active therapy was doubled to perindopril 4mg/indapamide Other antiplatelet drugs (%) 4 5
1.25 mg daily. If, during the trial, a compelling indication to use
a different ACE inhibitor and/or a thiazide/thiazide-like diuret- Table I. Baseline characteristics of randomized patients in
ic was found, open-label therapy was substituted for study ADVANCE.
treatment. Patients were seen at 3, 4, and 6 months after Modified from reference 12: ADVANCE Collaborative Group. Lancet.
2007;370:829-840. Copyright © 2007, Elsevier, Ltd.
randomization and 6-monthly thereafter.
BP was lowered, on average, by 5.6/2.2 mm Hg with perin-
At each study visit, BP was recorded using standardized dopril/indapamide, compared with placebo. The combined
conditions and recording devices,3 and details of all/any primary outcome was significantly reduced by 9% (95% con-
end points were recorded. The primary outcome was major fidence interval [CI], 0% to 17%) in favor of active BP lowering
macrovascular disease (nonfatal stroke, nonfatal myocar- (Figure 2).12 Major macrovascular and microvascular events
dial infarction [MI], or CV death) and/or major microvascu- were nonsignificantly reduced by 8% (-4% to 19%) and 9%
lar disease (new or worsening nephropathy or diabetic eye
disease). Secondary outcomes included all those expected
in a major trial of CV outcomes in diabetic patients.3 At 2 and Placebo
4 years of follow-up, a quality of life assessment, a mini men- 20% Perindopril-indapamide
tal state examination, and a retinal examination were made,
and a urinary albumin-creatinine ratio was measured.

The trial was originally designed to detect a 16% greater

reduction in macrovascular and in microvascular events, with 10%
90% power at the “5% level,” between the active BP low-
ering and placebo groups. However, due to lower than ex- Hazard ratio=0.91
95% CI: 0.83-1.00
pected event rates after approximately half the expected fol-
P=0.041
low-up period had elapsed, it was agreed to extend the
BP-lowering arm by an extra year and to evaluate macrovas- 0
cular and microvascular events both jointly and separately. 0 6 12 18 24 30 36 42 48 54 60
Follow-up (months)

Results
Of the 12 877 men and women from Europe, Canada, Asia,
the Indian Subcontinent, and Australasia registered for the
trial, 11 140 were randomized into the main trial. Baseline
characteristics of those randomized are shown in Table I.
Figure 2. Results on the combined primary outcome in ADVANCE
(major macro- or microvascular events) for perindopril/indapamide
versus placebo.
Modified from reference 12: ADVANCE Collaborative Group. Lancet.
2007;370:829-840. Copyright © 2007, Elsevier, Ltd.

Major findings from ADVANCE: blood pressure–lowering arm – Poulter MEDICOGRAPHIA, Vol 31, No. 3, 2009 225
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

(--4% to 20%), respectively. The biggest single contributor to
the beneficial effect of perindopril/indapamide on the primary
outcome was a significant 18% (2% to 32%) reduction in car-
diovascular death, which when allied to an absence of ad-
verse effect on noncardiovascular death generated a 14%
(2% to 25%) significant reduction in all-cause mortality.
Interestingly, nonfatal stroke and MI were unaffected by ad-
ditional BP lowering as was new or worsening eye disease,
whilst new or worsening nephropathy showed an 18% (--1%
to 32%) reduction.
A summary of the outcomes is shown in Figure 312 and the
use of concomitant medications at baseline and by the end
of follow-up are shown in Table II. When subgroups of pa-
tients were considered in relationship to the primary com-
posite outcome (Figure 4, page 228)12 or the development
of microalbuminuria (Figure 5, page 229), no sign of hetero-
geneity was apparent.
Two critical findings among these subgroup analyses were
that the benefits of perindopril/indapamide were equally
large whether patients were receiving background ACE in-

Number (%) of patients

with event

Perindopril- Placebo Favors Favors Relative risk

indapamide (n=5571) perindopril- placebo reduction
(n=5569) indapamide (95% CI)

Combined macro+micro 861 (15.5%) 938 (16.8%) 9% (0 to 17)

Macrovascular 480 (8.6%) 520 (9.3%) 8% (–4 to 19)

Microvascular 439 (7.9%) 477 (8.6%) 9% (–4 to 20)

All deaths 408 (7.3%) 471 (8.5%) 14% (2 to 25)

Cardiovascular death 211 (3.8%) 257 (4.6%) 18% (2 to 32)

Noncardiovascular disease death 197 (3.5%) 212 (3.8%) 8% (–12 to 24)

Total coronary events 468 (8.4%) 535 (9.6%) 14% (2 to 24)

Major coronary events 265 (4.8%) 294 (5.3%) 11% (–6 to 24)

Other coronary events* 283 (5.1%) 324 (5.8%) 14% (–1 to 27)

Total cerebrovascular events 286 (5.1%) 303 (5.4%) 6% (–10 to 20)

Major cerebrovascular events 215 (3.9%) 218 (3.9%) 2% (–18 to 19)

Other cerebrovascular events† 79 (1.4%) 99 (1.8%) 21% (–6 to 41)

Total renal events 1243 (22.3%) 1500 (26.9%) 21% (15 to 27)

New or worsening nephropathy 181 (3.3%) 216 (3.9%) 18% (–1 to 32)

New microalbuminuria 1094 (19.6%) 1317 (23.6%) 21% (14 to 27)

Total eye events 2531 (45.4%) 2611 (46.9%) 5% (–1 to 10)

New or worsening retinopathy 289 (5.2%) 286 (5.1%) –1% (–18 to 15)

Visual deterioration 2446 (43.9%) 2514 (45.1%) 5% (–1 to 10)

0.5 1.0 2.0

Hazard ratio

* Other coronary events = unstable angina requiring hospitalization, coronary revascularization, or silent myocardial infarction.
† Other cerebrovascular events = transient ischemic attack (including amaurosis fugax) or subarachnoid hemorrhage.
Red squares = point estimates (with area proportional to number of events); horizontal lines = 95% CI.
Diamonds = point estimate and 95% CI for overall effects.
Vertical broken lines = point estimates for overall effect, within categories.

Figure 3. Efficacy of perindopril/indapamide versus placebo on primary and secondary end points in ADVANCE.
Modified from reference 12: ADVANCE Collaborative Group. Lancet. 2007;370:829-840. Copyright © 2007, Elsevier, Ltd.

226 MEDICOGRAPHIA, Vol 31, No. 3, 2009 Major findings from ADVANCE: blood pressure–lowering arm – Poulter
 NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

Registration visit End of follow-up

Active Placebo Active Placebo
Blood pressure–lowering drugs
Perindopril, n (%) 490 (9%)† 449 (8%)† 2128 (45%) 2591 (55%)
Other ACE inhibitor, n (%) 1914 (34%) 1969 (35%) 232 (5%) 213 (5%)
ARB, n (%) 289 (5%) 320 (6%) 453 (10%) 618 (13%)
β-Blockers, n (%) 1344 (24%) 1385 (25%) 1492 (31%) 1671 (35%)
Calcium antagonists, n (%) 1669 (30%) 1758 (32%) 1531 (32%) 2040 (43%)
Thiazides, n (%) 786 (14%) 808 (15%) 158 (3%) 217 (5%)
Other diuretics, n (%) 596 (11%) 577 (10%) 673 (14%) 749 (16%)
Other BP-lowering drug, n (%) 700 (13%) 683 (12%) 463 (10%) 638 (14%)
Any BP-lowering drug, n (%) 4166 (75%) 4200 (75%) 3634 (74%) 4024 (83)%

Other drugs
Aspirin, n (%) 2445 (44%) 2449 (44%) 2680 (56%) 2574 (55%)
Other antiplatelets, n (%) 236 (4%) 269 (5%) 292 (6%) 269 (6%)
Statins, n (%) 1538 (28%) 1608 (29%) 2126 (44%) 2132 (45%)
Other lipid-modifying drugs, n (%) 472 (9%) 464 (8%) 394 (8%) 309 (7%)
Gliclazide MR, n (%) 433 (8%)‡ 432 (8%)‡ 2228 (47%) 2189 (46%)
Other sulfonylurea, n (%) 3570 (64%) 3520 (63%) 1467 (31%) 1491 (32%)
Metformin, n (%) 3399 (61%) 3352 (60%) 3321 (69%) 3390 (72%)
Any oral hypoglycemic drug (%) 5082 (91%) 5047 (91%) 4438 (90%) 4422 (91%)
Insulin, n (%) 80 (1%) 79 (1%) 1581 (33%) 1431 (30%)
* Treatments at the first (registration) visit; participants entered the active run-in phase after this visit.
† Percentage taking perindopril at the first (registration) visit; by the randomization visit, 47% were taking open-label perindopril in both groups.
‡ Percentage taking gliclazide MR at the first (registration) visit; by the randomization visit, 49% were taking gliclazide MR in both groups.

Table II. Drug treatment being received by patients at registration visit* and end of follow-up in ADVANCE.
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure; MR, modified release.
Modified from reference 12: ADVANCE Collaborative Group. Lancet. 2007;370:829-840. Copyright © 2007, Elsevier, Ltd.

hibition or not, and that the benefits of BP lowering were “the lower, the better” approach for BP in patients with dia-
equally large whether “hypertensive” or not and regardless of betes seems appropriate, it must be acknowledged that cur-
whether initial systolic BP was above or below 140 mm Hg. rent recommendations are not truly evidence-based.
Indeed, the impact of baseline BP level, considered as a con-
tinuous variable, on the beneficial effects of perindopril/inda-
UKPDS MICRO-HOPE ADVANCE
pamide, was further and more robustly evaluated, and no n=1148 n=3577 n=11 140
sign of any interaction was apparent. That is to say, that right
across the BP range, additional BP lowering generated simi- BP levels (mm Hg) 145/82 139/77 136/73
Active treatment
lar relative benefits. at end of follow-up
Use of background No No Yes
 ADVANCE in the context of previous trials ACE inhibitors
Table III shows that ADVANCE was larger than all previous
Use of statins No + ++
relevant trials. In addition, by virtue of the inclusion criteria
and, to a larger extent, the greater use of in-trial concomi- HbA1c at end 8.3% 9.5% 6.9%
of follow-up
tant medications, the CV event rates experienced were
much lower in ADVANCE than in UKPDS and MICRO- Event rate
HOPE. This reflects the fact that current management of Total and CV mortality +++ +++ +
high-risk diabetic patients currently usually involves the use Stroke ++ +++ +
of ACE inhibition, statins, and aspirin—a situation which
Table III. ADVANCE in context: comparative patient profiles for
did not prevail at the time UKPDS or MICRO-HOPE were UKPDS, MICRO-HOPE, and ADVANCE.
conducted. Importantly, the BP level achieved (136/73 mm Abbreviations: ACE, angiotensin-converting enzyme; BP, blood pressure; CV,
Hg) is the lowest level achieved in any of the relevant tri- cardiovascular; MICRO-HOPE, MIcroalbuminuria, Cardiovascular, and Renal
Outcomes in the Heart Outcomes Prevention Evaluation; UKPDS, United King-
als—though some way short of the target level of <130/80 dom Prospective Diabetes Study.
mm Hg recommended in all the world’s guidelines! While a Based on data from references 3, 7, 9, and 12.

Major findings from ADVANCE: blood pressure–lowering arm – Poulter MEDICOGRAPHIA, Vol 31, No. 3, 2009 227
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

Number (%) of patients

with event

Perindopril- Placebo Favors Favors Relative risk

indapamide (n=5571) perindopril- placebo reduction
(n=5569) indapamide (95% CI)

Age (years)
<65 325 (14.4%) 346 (15.2%) 6% (–10 to 19)
65 536 (16.2%) 592 (18.0%) 11% (0 to 21)
Sex
Men 546 (17.0%) 594 (18.6%) 10% (–1 to 20)
Women 315 (13.3%) 344 (14.5%) 8% (–7 to 21)
SBP (mm Hg)
<140 309 (13.1%) 341 (14.5%) 10% (–5 to 23)
140 552 (17.2%) 597 (18.6%) 9% (–2 to 19)
History of hypertension*
No 121 (12.7%) 136 (13.8%) 9% (–17 to 29)
Yes 740 (16.0%) 802 (17.5%) 9% (0 to 18)
HbA 1c (%)
7.5 406 (12.4%) 456 (13.5%) 9% (–4 to 20)
>7.5 451 (19.9%) 481 (22.0%) 11% (–1 to 22)
History of macrovascular disease
No 498 (13.2%) 559 (14.8%) 12% (1 to 22)
Yes 363 (20.2%) 379 (21.1%) 5% (–10 to 18)
History of microvascular disease
No 670 (13.4%) 744 (14.9%) 11% (1 to 20)
Yes 191 (33.6%) 194 (33.2%) –1% (–23 to 18)
Treatment with any BP-lowering drugs
No 177 (12.6%) 183 (13.3%) 6% (–15 to 24)
Yes 684 (16.4%) 755 (18.0%) 10% (0 to 19)
Treatment with open-label perindopril
No 417 (14.1%) 455 (15.6%) 10% (–3 to 21)
Yes 444 (17.0%) 483 (18.3%) 8% (–4 to 20)
Treatment with statins
No 638 (15.8%) 687 (17.3%) 10% (0 to 19)
Yes 223 (14.5%) 251 (15.6%) 8% (–10 to 23)
Treatment with antiplatelet drugs
No 408 (13.7%) 454 (15.3%) 11% (–2 to 22)
Yes 453 (17.4%) 484 (18.6%) 7% (–5 to 18)

Combined macro+micro 861 (15.5%) 938 (16.8%) 9% (0 to 17)

0.5 1.0 2.0

Hazard ratio

* History of hypertension = blood pressure–lowering drugs used at baseline, systolic pressure >140 mm Hg,
or diastolic blood pressure >90 mm Hg at study entry.
Vertical broken line = point estimate for overall effect.

Figure 4. Subgroup efficacy analysis on the primary composite end point in ADVANCE.
Modified from reference 12: ADVANCE Collaborative Group. Lancet. 2007;370:829-840. Copyright © 2007, Elsevier, Ltd.

228 MEDICOGRAPHIA, Vol 31, No. 3, 2009 Major findings from ADVANCE: blood pressure–lowering arm – Poulter
 NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

Number (%) of events

Perindopril- Placebo Favors Favors Relative risk

indapamide (n=5571) perindopril- placebo reduction
(n=5569) indapamide (95% CI)

Age (years)
<65 448 522 16% (5 to 26)
65 646 795 24% (15 to 31)
Sex
Men 601 724 21% (12 to 29)
Women 493 593 20% (9 to 29)
SBP (mm Hg)
<140 465 535 16% (4 to 25)
140 629 782 24% (16 to 32)
History of hypertension
No 178 218 19% (1 to 34)
Yes 916 1099 21% (14 to 28)
HbA 1c (%)
7.5 640 795 20% (11 to 28)
>7.5 444 517 22% (11 to 31)

All participants 1094 1317 21% (14 to 27)

0.5 1.0 2.0

Hazard ratio
Phomogeneity all>0.1

Figure 5. Subgroup analysis of microalbuminuria events by age, sex, blood pressure, and HbA1c in ADVANCE.
Modified from reference 12: ADVANCE Collaborative Group. Lancet. 2007;370:829-840. Copyright © 2007, Elsevier, Ltd.

If the results of the effect of BP lowering on the individual
macrovascular components evaluated in ADVANCE are
compared with those predicted by the Blood Pressure
Lowering Treatment Trialists’ Collaboration,13 some effects (eg,
on stroke) are apparently rather smaller than what might be
expected whilst others (CV mortality and total mortality), are
larger than expected. Nevertheless, the observed effect sizes
are all essentially compatible with those predicted. The small
effect on fatal and nonfatal stokes (2% [--17% to 20%]) is, at
first sight, surprising. It may be that the significantly greater
in-trial use of calcium channel blockers (CCBs) in the place-
bo group—which was 10% higher—may have contributed to
the relatively greater stroke protection in this group, which is
in keeping with previous analyses that suggest CCBs may
provide stroke protection beyond that expected by BP re-
duction alone.14 However, it should be remembered that in
the Perindopril pROtection aGainst REcurrent Stroke Study
(PROGRESS)15 and Poststroke Antihypertensive Treatment
Study (PATS)16 trials, perindopril/indapamide and indapa-
mide, respectively, have been shown to prevent stroke sig-
nificantly, and hence chance along with differential CCB use
may have contributed to the apparently small effect size in
ADVANCE.
The lack of impact on the hard end points relating to new or
worsening nephropathy (development of proliferative retino-
pathy, macular edema, retinal photocoagulation therapy, or
diabetes-related blindness) is in sharp contrast to the re-
sults of UKPDS,7 in which large benefits of BP lowering were
apparent (mainly regarding retinal photocoagulation). These
disparities may reflect differences in terms of duration of the
diabetes diagnosis (new-onset in UKPDS) or, more likely, the
much lower BP levels at play in the 2 trials, and the much
greater use of other CV protective agents in ADVANCE
(Table III).
 Implications of the ADVANCE results
The number needed to treat (NNT) for 5 years associated
with the use of perindopril/indapamide in the context of the
ADVANCE population was 66 to prevent 1 major macro- or
microvascular event and 79 to prevent 1 death. Allied with
the fact that the active BP-lowering therapy was tolerated as
well as the placebo (adherence rates were 73% and 74%,
respectively), a blanket policy to apply additional BP lower-
ing to all patients with type 2 diabetes, irrespective of their
BP level, seems reasonable. Two critical caveats need to be
considered first, however.

Major findings from ADVANCE: blood pressure–lowering arm – Poulter MEDICOGRAPHIA, Vol 31, No. 3, 2009 229
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE
Firstly, is it affordable? Cost-benefit analyses are in the
process of being published, but given the massive health
burden associated with the CV sequelae of type 2 diabetes,
it is likely that the approach practiced in ADVANCE is cost-
effective.
Secondly, were the beneficial effects observed due to BP
lowering alone, to the use of an ACE inhibitor plus a diuretic,
or to the specific combination used? Prior prejudice deter-
mines the answers given by individuals to this question,
and there is no definitive “true” answer. However, evidence is
mounting that not all hypertensive agents are equal in terms
of associated outcomes for any level of BP reduction,14,17 and,
pending evidence to the contrary, we should try to stick
with the evidence base arising from relevant trials.
Clinicians and research workers are variably influenced by
the effect of interventions on various surrogate renal end
points, such as microalbuminuria. However, most diabetol-
ogists and renal physicians will be suitably impressed by the
large benefits of perindopril/indapamide on microalbuminuria
observed in ADVANCE. Various measures of proteinuria are
undoubtedly associated with CV events (as was the case in
ADVANCE), presumably reflecting generalized endothelial
dysfunction and increased cardiovascular risk. The greater
effect on these end points observed in ADVANCE compared
with the size of effect on individual macrovascular events (ex-
cept CV mortality) may well reflect a time lag which prevents
References
1. Wood D, Poulter NR, Williams B, et al. JBS2: Joint British Societies’ Guidelines
on Prevention of Cardiovascular Disease in Clinical Practice. Heart. 2005;91
(suppl V):1-52.
2. Mancia G, De Backer G, Dominiczak A, et al. 2007 ESH-ESC Practice Guide-
lines for the Management of Arterial Hypertension. ESH-ESC Task Force on
the Management of Arterial Hypertension. J Hypertens. 2007;25:1751-1762.
3. ADVANCE Collaborative Group. Rationale and design of the ADVANCE study:
a randomised trial of blood pressure lowering and intensive glucose control in
high-risk individuals with type 2 diabetes mellitus. J Hypertens. 2001;19:S21-S28.
4. Asia Pacific Cohort Studies Collaboration. Systolic blood pressure, diabetes
and the risk of cardiovascular diseases in the Asia-Pacific region. J Hypertens.
2007;25:1205-1213.
5. Adler AI, Stratton IM, Neil HA, et al; UK Prospective Diabetes Study Group.
Association of systolic blood pressure with macrovascular and microvascu-
lar complications of type 2 diabetes (UKPDS 36): prospective observational
study. BMJ. 2000;321:412-419.
6. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different
blood pressure-lowering regimens on major cardiovascular events in individuals
with and without diabetes mellitus. Arch Intern Med. 2005;165:1410-1419.
7. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of
macrovascular and microvascular complications in type 2 diabetes: UKPDS 38.
BMJ. 1998;317:703-713.
8. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood pres-
sure lowering and low dose aspirin in patients with hypertension: principal re-
sults of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet.
1998;351:1755-1762.
9. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of
ramipril on cardiovascular and microvascular outcomes in people with diabetes
Keywords: hypertension; type 2 diabetes; therapeutic trial; macrovascular event; microvascular event; angiotensin-con-
verting enzyme inhibition; perindopril; indapamide
230 MEDICOGRAPHIA, Vol 31, No. 3, 2009
2 DIABETES
the realization of CV benefits in the relatively short follow-up
period of less than 5 years.
Conclusions
The BP-lowering arm of the ADVANCE trial provides the best
evidence to date that modest BP lowering is beneficial in
terms of reducing the risk of critical CV events and renal end
points in a broad range of patients with established type 2
diabetes, irrespective of their baseline BP levels. The signifi-
cant 9% reduction in major vascular events and 18% reduc-
tion in CV mortality, plus an 18% reduction in new or worsen-
ing nephropathy and a 14% reduction in coronary events,
were apparent in all major subgroups of patients, whether al-
ready taking ACE inhibitors or not, and irrespective of being
hypertensive or not. Critically, for a potentially generalizable
recommendation, the agents used to lower BP in ADVANCE
were very well tolerated and NNTs to prevent major CV events
or deaths were modest.
It therefore seems reasonable to conclude that all patients
with type 2 diabetes should be considered for treatment with
the type of intervention used in ADVANCE, ie, the combina-
tion of perindopril and indapamide, in addition to whatever
other agents are already being taken and irrespective of the
patient’s BP level. 
Neil Poulter was the North European Regional Principal Investigator of
the ADVANCE trial.
mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;
355:253-258.
10. Strippoli GF, Bonifati C, Craig M, Navaneethan SD, Craig JC. Angiotensin con-
verting enzyme inhibitors and angiotensin II receptor antagonists for prevent-
ing the progression of diabetic kidney disease. Cochrane Database Syst Rev.
2006;CD006257.
11. Williams B, Poulter N, Brown M, et al. Guidelines for management of hyper-
tension: report of the fourth working party of the British Hypertension Society
2004-BHS IV. J Human Hypertens. 2004;18:139-185.
12. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and
Indapamide on macrovascular outcomes in patients with type 2 diabetes mel-
litus: results of the blood pressure lowering arm of the ADVANCE trial. Lancet.
2007;370:829-840.
13. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different
blood-pressure-lowering regimens on major cardiovascular events: results of
prospectively-designed overviews of randomised trials. Lancet. 2003;362:
1527-1535.
14. Verdecchia P, Reboldi G, Angeli F, et al. Angiotensin-converting enzyme inhibitors
and calcium channel blockers for coronary heart disease and stroke prevention.
Hypertension. 2005;46:386-392.
15. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-
pressure-lowering regimen among 6105 individuals with previous stroke or
transient ischaemic attack. Lancet. 2001;358:1033-1041.
16. PATS Collaborative Group. Post-stroke antihypertensive treatment study. A pre-
liminary result. Chin Med J. 1995;108:710-717.
17. Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs:
a network meta-analysis. Lancet. 2007;369:201-207. [Erratum. Lancet. 2007;
369:1518.]
Major findings from ADVANCE: blood pressure–lowering arm – Poulter
 NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

PRINCIPAUX RÉSULTATS DE L’ÉTUDE ADVANCE :

BRAS « CONTRÔLE INTENSIF DE LA PRESSION ARTÉRIELLE »
Contexte : Bien que les recommandations mondiales préconisent, pour les diabétiques de type 2, des seuils et des
valeurs cibles plus bas de pression artérielle (PA), l’efficacité de cette mesure est encore insuffisamment démontrée.
Méthodes : 11 140 patients diabétiques de type 2, ayant au moins un autre facteur préspécifié de risque cardio-
vasculaire (CV), ont été randomisés dans l’étude ADVANCE (Action in Diabetes and Vascular disease : PreterAx
and DiamicroN Controlled Evaluation), contrôlée en plan factoriel 22, pour recevoir l’association fixe perindopril
(4 mg)/indapamide (1,25 mg) ou un placebo, quels que soient les autres traitements antihypertenseurs utilisés ou
le niveau de PA des patients.
Résultats : Au cours d’un suivi moyen de 4,3 ans, la PA a été abaissée à un niveau de 135/75 mmHg, soit d’environ
5,6/2,2 mmHg en moyenne dans le groupe traité par perindopril/indapamide comparé au placebo. Cette diminution
de la PA a été associée à une réduction significative de 9 % (intervalle de confiance [IC] 95 %, 0,83-1,00 ; p = 0,04)
du critère primaire (événements macrovasculaires ou microvasculaires majeurs), de 18 % (0,68-0,98) de la mortalité
CV, et de 14 % (0,75-0,98) de la mortalité toutes causes. L’apparition ou l’aggravation d’une néphropathie a été ré-
duite de 18 % (0,68-1,01), mais la rétinopathie est restée en apparence inchangée. Des bénéfices CV ont été ob-
servés dans tous les sous-groupes, indépendamment de la PA initiale et/ou de l’utilisation antérieure d’inhibiteurs
de l’enzyme de conversion.
Conclusion : Le traitement de l’étude ADVANCE devrait être ajouté en routine aux diabétiques de type 2, quelle que
soit leur PA initiale.

Major findings from ADVANCE: blood pressure–lowering arm – Poulter MEDICOGRAPHIA, Vol 31, No. 3, 2009 231

‘‘ The glucose arm of ADVANCE
achieved its primary end point,
a statistically significant 10%
decrease in a composite of micro-
and macrovascular complica-
tions…. This effect on the primary
end point appeared to be related
predominantly to the 14% de-
crease in microvascular complica-
tions and, in particular, to the 21%
reduction in renal, rather than the
nonsignificant 5% decrease in
retinal, events.”
Mark E. COOPER, MB, BS,
PhD, FRACP
Diabetes Division, Baker IDI
Heart and Diabetes Institute
Melbourne, Victoria
AUSTRALIA
Address for correspondence:
Prof Mark E. Cooper, Diabetes Division,
Baker IDI Heart and Diabetes Institute,
75 Commercial Rd, Melbourne,
Victoria 3004, Australia
(e-mail: mark.cooper@bakeridi.edu.au)
www.medicographia.com
232 MEDICOGRAPHIA, Vol 31, No. 3, 2009
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES
Major findings from the
ADVANCE study:
glucose-lowering arm
b y M . E . C o o p e r, A u s t ra l i a
I
n the glucose arm of the Action in Diabetes and Vascular disease: PreterAx
and DiamicroN Controlled Evaluation (ADVANCE) study, subjects were
randomized to either intensified glycemic control (n=5571) involving the
use of gliclazide modified release (MR) and other drugs, as required, or to
standard management (n=5569). In the intensified glycemic control arm, the
strategy was to reduce glucose levels with the aim of reaching a glycated
hemoglobin 6.5%. In this group, after maximizing the dose of gliclazide MR,
there was sequential addition and/or an increase in the dose of metformin,
thiazolidinediones, acarbose, or insulin. At the end of the follow-up, mean
HbA1c was 6.5% and 7.3% in the intensive and standard groups, respective-
ly. There was a statistically significant 10% decrease in the primary end point,
a composite of micro- and macrovascular complications. This effect on the
primary end point appeared to be related predominantly to the 14% decrease
in microvascular complications and, in particular, to the reduction in renal,
rather than retinal, events. These findings emphasize the role of intensified
glycemic control in reducing the major burden of diabetes, its vascular com-
plications. It is anticipated that further follow-up of these subjects over the
next few years will allow us to determine if the beneficial effects seen with re-
spect to renal disease ultimately translate into reduced cardiovascular events
and a decrease in overall mortality.
Medicographia. 2009;31:232-237 (see French abstract on page 237)
Rationale of the ADVANCE study
A
lthough the link between hyperglycemia and complications has been clear-
ly demonstrated in type 1 diabetes, primarily from the findings of the Dia-
betes Control and Complications Trial (DCCT) and its follow-up study, the
Epidemiology of Diabetes Interventions and Complications (EDIC) trial,1 the issue
has remained unresolved with respect to type 2 diabetes. At the time of the design
and commencement of the Action in Diabetes and Vascular disease: PreterAx and
DiamicroN Controlled Evaluation (ADVANCE) study, the best data available came
from the United Kingdom Prospective Diabetes Study (UKPDS), which demon-
strated that intensified glycemic control with various drugs, including sulphonylureas
and insulin (achieving a reduction in HbA1c of 0.9% when compared with conven-
tional treatment in newly diagnosed type 2 diabetic subjects), led to reduced micro-
vascular complications.2 With an achieved average HbA1c of 7% in UKPDS, there
was a tendency towards, but neither a statistically significant decrease in macro-
vascular events nor a decrease in mortality. These findings led to most, but not
Major findings from the ADVANCE study: glucose-lowering arm – Cooper
 NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

all, international guidelines to suggest an HbA1c of 6.5% or

7% as the appropriate target for glucose-lowering treat- 10.0
ment in type 2 diabetes.3,4 9.5

Mean glycated hemoglobin (%)

9.0
Design of the ADVANCE study 8.5
The ADVANCE study has made great progress in helping us
8.0
to determine what is the right approach for managing hyper- P<0.001 Standard control
7.5
glycemia in type 2 diabetes. The ADVANCE study was an in-
7.0
vestigator-initiated multinational trial. Within the glucose arm
6.5
of the study, subjects were randomized to either intensified Intensive control
6.0
glycemic control (n=5571) involving the use of gliclazide mod-
ified release (MR) and other drugs, as required, or to standard 5.5

management (n=5569). In the intensified glycemic control 5.0

arm, the strategy was to reduce glucose levels with the aim
of reaching a glycated hemoglobin 6.5%. In this group, af-
ter maximizing the dose of gliclazide MR, there was sequen-
tial addition and/or an increase in the dose of metformin, thi-
azolidinediones, acarbose, or insulin. The intensified glycemic
control group also had more frequent follow-up visits and
were encouraged to be more active with respect to home
blood-glucose monitoring. All analyses in this trial were based
on the intention to treat principle.
Results of the ADVANCE study
The median duration of follow-up was 5 years, and, at base-
line, both groups had similar characteristics, including a
baseline HbA1c of 7.5%. At the end of the follow-up, mean
HbA1c was 6.5% and 7.3% in the intensive and standard
groups, respectively (Figure 1). In terms of the various glu-
cose-lowering treatments, the intensive group were taking
more drugs, and, in particular in this group, insulin was pre-
scribed in over 40% of subjects versus 24% in the standard
group. The glucose arm of the study achieved its primary
end point, a statistically significant 10% decrease in a com-
posite of micro- and macrovascular complications.5 There
was no evidence of an interaction between the blood pres-
sure and glucose interventions for this primary outcome.
This effect on the primary end point appeared to be related
predominantly to the 14% decrease in microvascular com-
SELECTED ABBREVIATIONS AND ACRONYMS
ACCORD Action to Control CardiOvascular Risk in
Diabetes
ADVANCE Action in Diabetes and Vascular disease PreterAx
and DiamicroN Controlled Evaluation
AGE advanced glycation end product
BMI body mass index
DCCT Diabetes Control and Complications Trial
EDIC Epidemiology of Diabetes Interventions and
Complications
ESRD end-stage renal disease
RAGE receptor for advanced glycation end products
UKPDS United Kingdom Prospective Diabetes Study
0.0
0 6 12 18 24 30 36 42 48 54 60 66
Months of follow-up
Value
Standard 7.32 7.30 7.29 7.29 7.31 7.33 7.29
Intensive 7.01 6.93 6.70 6.53 6.50 6.52 6.53
Figure 1. Glucose control at baseline and during follow-up, accord-
ing to glucose-control strategy.
Data are shown for mean glycated hemoglobin. The average difference between
the intensive-control group and the standard-control group for the follow-up
period was 0.67 percentage points (95% confidence interval [CI], 0.64 to 0.70)
for glycated hemoglobin.
Reproduced from reference 5: Patel A, MacMahon S, Chalmers J, et al. N Engl J
Med. 2008;358:2560-2572. Copyright © 2008, Massachusetts Medical Society.
plications and, in particular, to the 21% reduction in renal,
rather than the nonsignificant 5% decrease in retinal, events.
There was no significant effect on major macrovascular
events, including no statistical decrease in cardiovascular
mortality. Importantly, there was no evidence of an increase
in total mortality. Indeed, there was a nonstatistical 7% de-
crease in mortality. No effects were seen on nonfatal myocar-
dial infarction or stroke.
 Clinical relevance of the findings of the ADVANCE study
The major issue is the clinical relevance of these findings and
how these will translate into routine care of type 2 diabetes.
The population studied came from 20 different countries of
diverse ethnic backgrounds, with a significant proportion of
subjects from Asia. Furthermore, when one looks at the de-
mographic characteristics of the individuals in this study, these
reflect the clinical features of type 2 diabetic subjects current-
ly managed throughout the world. Indeed, if one compares
the age, gender, glycemic control, and blood pressure of the
subjects in the ADVANCE study, their clinical characteristics
are almost identical to those from recently reported studies of
the French and Australian type 2 diabetic populations.6,7 Thus,
the conclusions from the ADVANCE study should be con-
sidered highly relevant for both specialists and family prac-
titioners who treat type 2 diabetes.
 Renal events in the glucose arm of the ADVANCE study
One of the most important findings from the ADVANCE study
was the demonstration of reduced renal events in the inten-

Major findings from the ADVANCE study: glucose-lowering arm – Cooper MEDICOGRAPHIA, Vol 31, No. 3, 2009 233
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

sified glucose control arm (Figure 2).5 Renal disease is itself a
major cause of morbidity and mortality in the diabetic pop-
ulation. Furthermore, in Western countries, diabetic nephro-
pathy remains the major cause of end-stage renal disease
(ESRD), with diabetes being the primary cause of renal failure
in over 50% of individuals currently entering renal replacement
programs.8 There was also a reduction in new-onset micro-
and macroalbuminuria with intensified glycemic control. This
will clearly ultimately translate into reduced ESRD, and al-
though in the ADVANCE study there was a greater than 30%
decrease in the development of ESRD, this did not reach sta-
tistical significance since only a small number of subjects de-
veloped this very serious diabetic complication.
 Renal and cardiovascular end points in the
ADVANCE study
It is well known that there is a close association between
renal and cardiovascular disease in diabetes and that both
micro- and macroalbuminuria have been reported to be linked
to the subsequent development of macrovascular disease.
Indeed, this association was also observed in the ADVANCE
study population when assessing the link between micro-
and macroalbuminuria at baseline and in the subsequent de-
velopment not only of renal, but also of cardiovascular events.
Thus, although the ADVANCE study did not demonstrate a
decrease in cardiovascular mortality or events over the rela-
tively short period of 5 years, one cannot exclude the pos-

Number of patients (%)

Relative risk
Intensive control Standard control Hazard ratio reduction (%)
Subgroup (n=5571) (n=5569) (95% CI) (95% CI)

Primary end points

Combined major macrovascular 1009 (18.1) 1116 (20.0) 10 (2 to 18)
and microvascular events
Major macrovascular events 557 (10.0) 590 (10.6) 6 (−6 to 16)
Nonfatal MI 153 (2.7) 156 (2.8) 2 (−23 to 22)
Nonfatal stroke 214 (3.8) 209 (3.8) −2 (−24 to 15)
Death from cardiovascular causes 253 (4.5) 289 (5.2) 12 (−4 to 26)
Major microvascular events 526 (9.4) 605 (10.9) 14 (3 to 23)
New or worsening nephropathy 230 (4.1) 292 (5.2) 21 (7 to 34)
New or worsening retinopathy 332 (6.0) 349 (6.3) 5 (−10 to 18)
Secondary end points
Death from any cause 498 (8.9) 533 (9.6) 7 (−6 to 17)
Major coronary events 310 (5.6) 337 (6.1) 8 (−7 to 21)
All coronary events 560 (10.1) 572 (10.3) 2 (−10 to 13)
Major cerebrovascular events 238 (4.3) 246 (4.4) 3 (−16 to 19)
All cerebrovascular events 352 (6.3) 327 (5.9) −8 (−26 to 7)
Heart failure 220 (3.9) 231 (4.1) 5 (−14 to 21)
Peripheral vascular events 343 (6.2) 366 (6.6) 6 (−9 to 19)
All cardiovascular events 1232 (22.1) 1249 (22.4) 1 (−7 to 9)
New-onset microalbuminuria 1318 (23.7) 1434 (25.7) 9 (2 to 5)
Visual deterioration 3033 (54.4) 3015 (54.1) 0 (−5 to 5)
New or worsening neuropathy 2353 (42.2) 2311 (41.5) −4 (−10 to 2)
Cognitive decline 895 (16.1) 911 (16.4) 2 (−7 to 11)
Dementia 61 (1.1) 48 (0.9) −27 (−86 to 13)
Hospitalization 2501 (44.9) 2381 (42.8) −7 (−13 to −1)

0.5 1.0 2.0

Intensive better Standard better

Figure 2. Relative effects of glucose-control strategy on all prespecified primary and secondary outcomes.
The diamonds incorporate the point estimates, represented by the vertical dashed lines, and the 95% confidence intervals of the overall effects within categories; for
subcategories, black squares represent point estimates (with the area of the square proportional to the number of events), and horizontal lines represent 95% confidence
intervals. The hazard ratios and relative risk reductions are given for intensive glucose control as compared with standard glucose control.
Reproduced from reference 5: Patel A, MacMahon S, Chalmers J, et al. N Engl J Med. 2008;358:2560-2572. Copyright © 2008, Massachusetts Medical Society.

234 MEDICOGRAPHIA, Vol 31, No. 3, 2009 Major findings from the ADVANCE study: glucose-lowering arm – Cooper
 NEW A D VA N C E S
sibility that longer follow-up would demonstrate a benefit on
macrovascular disease. There are such precedents in the
literature, including, firstly, the recent report on the longer fol-
low-up of the UKPDS cohort, where the initial borderline ben-
efit seen with intensified glycemic control on cardiovascular
disease has now been shown to be very clear after a much
longer period of follow-up, despite subjects returning back
to usual care without ongoing, intensified, glucose-lowering
management.9 Secondly, in the Steno 2 study, where multi-
factorial intervention with not only intensified glycemic con-
trol, but also active treatment with antihypertensive and lipid-
lowering therapy was included, the initial evaluation after 4
years of active treatment revealed no evidence of a decrease
in macrovascular, but a reduction in microvascular, events.10
However, at the 8-year time point, there was a decrease in
macrovascular disease11 that, interestingly, translated into a
decrease in mortality 5 years later, despite subjects returning
to usual care after 8 years in the study.12 These findings em-
phasize the importance of either ongoing follow-up of sub-
jects in these relatively short duration clinical trials involving
cardiovascular end points or considering trials which involve
active interventions for more than 5 years. Thus, it is critical
to continue to monitor cardiovascular events and mortality in
the subjects from the ADVANCE study, as is planned.
 ADVANCE findings with respect to those from the
ACCORD study
The findings of the ADVANCE study need to be considered in
the light of the results of the Action to Control CardiOvascular
Risk in Diabetes (ACCORD) study,13 published at the same
time, as well as the as the more recently reported findings of
the smaller Veterans Affairs Diabetes Trial (VADT) study.14,15 The
ACCORD study also included more than 10 000 type 2 diabet-
ic subjects, although all subjects in that study were recruited
from the US and Canada.13 The glucose arm of that trial was
prematurely terminated due to an unexpected 22% increase
in total mortality, primarily reflecting the reported increase in
cardiovascular mortality in that study. This increase in mor-
tality remains unexplained, but was clearly not observed in the
ADVANCE study. Furthermore, as yet, the results on microvas-
cular events have not been reported from the ACCORD trial.
There are a number of key differences between the ACCORD
and ADVANCE studies. In the ACCORD study, subjects had
a higher baseline HbA 1c, a higher body mass index (BMI), and
lower blood pressure than in the ADVANCE study. Thus, the
investigators from the ADVANCE study have explored whether
subjects with higher baseline HbA 1c , BMI >30, and lower
blood pressure behaved differently to the other subjects in
terms of response to intensified glycemic control. However,
even in the subjects from the ADVANCE trial that matched the
ACCORD cohort more closely, no evidence of increased car-
diovascular or total mortality was observed, nor did these in-
dividuals behave differently in terms of their clinical response
to more intensive glucose-lowering management.5
Major findings from the ADVANCE study: glucose-lowering arm – Cooper
IN THE T R E AT M E N T OF TYPE 2 DIABETES
In the ACCORD study, the intensive glucose-lowering strat-
egy was a much more aggressive approach with reductions
in HbA1c of between 1% and 1.5% achieved within 6 months
of starting active treatment.13 Multiple drugs were used with
many subjects on up to 4 glucose-lowering drugs within the
first year of the study. Indeed, a very high proportion of the
intensified glucose control group in that study ended up on
treatment with the thiazolidinedione rosiglitazone and/or in-
sulin. This approach clearly comes at a price—increased hy-
poglycemia and weight gain. In the ADVANCE study, the glu-
cose-lowering strategy was much more gradual than in the
ACCORD trial, with the maximal HbA1c reduction not seen
till at least 2 to 3 years after the commencement of the
ADVANCE study. This approach was not associated with sig-
nificant weight gain, and the rates of hypoglycemia were
much lower than observed in the ACCORD study. Although
the ACCORD investigators have suggested that the marked
increase in hypoglycemia does not explain the increase in
mortality seen with aggressive glucose-lowering in that
study,13 one cannot be sure as to the impact of intermittent,
often unrecognized hypoglycemia in diabetic subjects with
silent cardiovascular disease. Clearly, this is a potential area
of exciting research, and, in particular, the link between hypo-
glycemia (including asymptomatic episodes), the sympathet-
ic nervous system, and cardiovascular events needs further
examination.16
 Tissue remodeling in diabetes
As outlined previously, the ADVANCE study did not demon-
strate a decrease in cardiovascular disease, although there
appears to be a trend, albeit modest and not statistically sig-
nificant after 5 years of treatment.5 It remains unexplained
as to why no statistically significant beneficial effect was ob-
served on macrovascular disease in this study. This may not
only relate to the short duration of the study, but could reflect
underlying pathological processes within the diabetic vascu-
lature. Indeed, in the seminal studies involving pancreatic
transplantation in type 1 diabetes, renal morphological injury
took up to 10 years to reverse, despite a decade of normo-
glycemia.17 The rates of remodeling within organs, such as
the kidney, and within blood vessels may be rather slow and,
thus, take many years of improved glycemic control for end-
organ injury to be reversed.
 Advanced glycation
One of the key biochemical mechanisms implicated in dia-
betic complications, a result of chronic hyperglycemia, is
known as advanced glycation.18 In blood vessels, these ad-
vanced glycation end products (AGEs) accumulate and may
persist, despite improved glycemic control. These chemical
moieties interact with specific receptors, such as the receptor
for advanced glycation end products (RAGE), to induce vascu-
lar inflammation and promote atherosclerosis.19 Thus, it may
be necessary to not only reduce glucose levels, but to direct-
ly inhibit the advanced glycation pathway. Such an approach
MEDICOGRAPHIA, Vol 31, No. 3, 2009 235
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE
is currently under active clinical investigation, with preclinical
studies in models of diabetic complications providing prom-
ising results.20,21 It should also be noted that angiotensin-con-
verting enzyme inhibitors, such as perindopril, can directly in-
fluence various components of the AGE/RAGE pathway 22 and
could explain the added benefits seen in the subjects from
the intensive glycemic control group in ADVANCE, who also
had more aggressive antihypertensive treatment with a perin-
dopril-based regimen.
 Hyperglycemic memory
Another possibility for the lack of dramatic effect of glucose
lowering on macrovascular disease may relate to a phe-
nomenon known as “hyperglycemic memory”. It has previ-
ously been reported in type 1 diabetes in the DCCT/EDIC
studies and more recently in type 2 diabetes in the longer
term follow-up of UKPDS that there are sustained effects on
the vasculature as a result of prior levels of metabolic con-
trol.1,9 For example, in both the DCCT/EDIC and UKPDS stud-
ies, despite subjects returning to usual management of their
hyperglycemia, these individuals continued to benefit from
their previous period of better metabolic control.1,9 The un-
derlying explanation for this phenomenon, known as either
“hyperglycemic memory” or the “legacy effect,” remains un-
explained,23 but recently it has been suggested that epige-
netic mechanisms may be involved,24,25 possibly with reac-
References
1. Epidemiology of Diabetes Interventions and Complications (EDIC) study: Sus-
tained effect of intensive treatment of type 1 diabetes mellitus on development
and progression of diabetic nephropathy. JAMA. 2003;290:2159-2167.
2. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose con-
trol with sulphonylureas or insulin compared with conventional treatment and
risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;
352:837-853.
3. American Diabetes Association. Standards of medical care in diabetes - 2007.
Diabetes Care. 2007;30(suppl 1):S4-S41.
4. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular
diseases in people with diabetes mellitus: a scientific statement from the Amer-
ican Heart Association and the American Diabetes Association. Circulation.
2007;115:114-126.
5. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and
vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:
2560-2572.
6. Marant C, Romon I, Fosse S, et al. French medical practice in type 2 diabetes:
the need for better control of cardiovascular risk factors. Diabetes Metab. 2008;
34:38-45.
7. Thomas MC, Weekes AJ, Broadley OJ, Cooper ME, Mathew TH. The burden of
chronic kidney disease in Australian patients with type 2 diabetes (the NEFRON
study). Med J Aust. 2006;185:140-144.
8. U.S. Renal Data System. Atlas of End-Stage Renal Disease in the United States.
In: USRDS 2004 Annual Data Report. Bethesda, Md: National Institutes of
Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2004.
9. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-Year Follow-up of
Intensive Glucose Control in Type 2 Diabetes. N Engl J Med. 2008;359:1577-
1589.
10. Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial intervention
in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2
randomised study. Lancet. 1999;353:617-622.
11. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactor-
ial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl
J Med. 2003;348:383-393.
12. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial
intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580-591.
236 MEDICOGRAPHIA, Vol 31, No. 3, 2009
2 DIABETES
tive oxygen species acting as key intermediates.24,26 This is
likely to be an active area of ongoing research with the mo-
lecular mechanisms responsible for conferring hyperglycemic
memory being increasingly delineated.
Summary
ADVANCE provides us with new evidence emphasizing the
role of intensive glucose control in reducing diabetic compli-
cations, in particular, nephropathy. Thus, the current guide-
lines suggesting that clinicians should aim to achieve an
HbA1c of 6.5% or 7% appear sensible and can be justified
by the more recent data obtained from trials like ADVANCE5
and the recent long-term follow-up from UKPDS.9 The prac-
tical and gentle strategy of reducing glucose levels in order
to achieve, on average, an HbA1c of 6.5%, using regimens in-
volving agents such as gliclazide as first-line therapy with sub-
sequent use of other oral agents and, ultimately, often insulin,
appears to be feasible, as has been demonstrated in a typi-
cal group of type 2 diabetic subjects in ADVANCE. This strat-
egy, of course, must be considered in conjunction with impor-
tant lifestyle measures, including diet (often with an emphasis
on weight loss) as well as increased exercise. Such individ-
uals could be managed in general or specialist practice,
and it is likely that this strategy will not be associated with
major side effects, such as severe hypoglycemia or exces-
sive weight gain. 
13. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lower-
ing in type 2 diabetes. N Engl J Med. 2008;358:2545-2559.
14. Abraira C, Duckworth WC, Moritz T. Glycaemic separation and risk factor
control in the Veterans Affairs Diabetes Trial: an interim report. Diabetes Obes
Metab. 2009;11:150-156.
15. Duckworth W, Abraira C, Moritz T, et al; VADT Investigators. Glucose control
and vascular complications in veterans with type 2 diabetes. N Engl J Med.
2009;360:129-139.
16. Goldstein DS. Stress-induced activation of the sympathetic nervous system.
Baillieres Clin Endocrinol Metab. 1987;1:253-278.
17. Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer M. Reversal of lesions
of diabetic nephropathy after pancreas transplantation. N Engl J Med. 1998;
339:69-75.
18. Goh SY, Cooper ME. Clinical review: The role of advanced glycation end prod-
ucts in progression and complications of diabetes. J Clin Endocrinol Metab.
2008;93:1143-1152.
19. Soro-Paavonen A, Watson AM, Li J, et al. Receptor for advanced glycation end
products (RAGE) deficiency attenuates the development of atherosclerosis in
diabetes. Diabetes. 2008;57:2461-2469.
20. Oldfield MD, Bach LA, Forbes JM, et al. Advanced glycation end products cause
epithelial-myofibroblast transdifferentiation via the receptor for advanced gly-
cation end products (RAGE). J Clin Invest. 2001;108:1853-1863.
21. Forbes JM, Yee LT, Thallas V, et al. Advanced glycation end product interventions
reduce diabetes-accelerated atherosclerosis. Diabetes. 2004;53:1813-1823.
22. Forbes JM, Thorpe SR, Thallas-Bonke V, et al. Modulation of soluble receptor
for advanced glycation end products by angiotensin-converting enzyme-1 in-
hibition in diabetic nephropathy. J Am Soc Nephrol. 2005;16:2363-2372.
23. Chalmers J, Cooper ME. UKPDS and the Legacy Effect. N Engl J Med. 2008;
359:1618-1620.
24. El-Osta A, Brasacchio D, Yao D, et al. Transient high glucose causes persistent
epigenetic changes and altered gene expression during subsequent normo-
glycemia. J Exp Med. 2008;205:2409-2417.
25. Mack CP. An epigenetic clue to diabetic vascular disease. Circ Res. 2008;103:
568-570.
26. Ihnat MA, Thorpe JE, Kamat CD, et al. Reactive oxygen species mediate a cellu-
lar 'memory' of high glucose stress signalling. Diabetologia. 2007;50:1523-1531.
Major findings from the ADVANCE study: glucose-lowering arm – Cooper
 NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

Keywords: gliclazide; diabetes; glycemic control; vascular disease; glucose-lowering arm

PRINCIPAUX RÉSULTATS DE L’ ÉTUDE ADVANCE : BRAS « CONTRÔLE INTENSIF DE LA GLYCÉMIE »

Dans le bras « contrôle intensif de la glycémie » de l’étude ADVANCE (Action in Diabetes and Vascular disease :
PreterAx and DiamicroN Controlled Evaluation), des patients ont été randomisés pour recevoir soit un contrôle gly-
cémique intensif (n = 5 571) au moyen du gliclazide à libération modifiée (LM) et d’autres traitements médicamenteux,
conformément aux recommandations en vigueur, soit un traitement standard (n = 5 569). Dans le bras contrôle gly-
cémique intensif, la stratégie avait pour but de réduire la glycémie pour atteindre des taux d’hémoglobine glyquée
6,5 %. Dans ce groupe, une fois la posologie maximale de gliclazide LM atteinte, il était possible d’ajouter et/ou
d’augmenter la dose de metformine, de thiazolidinediones, d’acarbose ou d’insuline de façon séquentielle. À la fin
du suivi, l’HbA1c moyenne était respectivement de 6,5 % et 7,3 % dans les groupes intensif et standard. Le cri-
tère primaire, un composite de complications micro- et macrovasculaires, a diminué de façon statistiquement signi-
ficative de 10 %. Cet effet sur le critère primaire semblait être lié principalement à une diminution de 14 % des com-
plications microvasculaires, en particulier des événements rénaux, plutôt que rétiniens. Ces résultats soulignent le
rôle du contrôle intensif de la glycémie dans la réduction du principal fardeau du diabète que sont les complications
vasculaires. Le suivi ultérieur de ces patients dans les années à venir nous permettra de déterminer si les effets bé-
néfiques enregistrés pour la maladie rénale se traduisent finalement en réduction des événements cardio-vascu-
laires et de la mortalité globale.

Major findings from the ADVANCE study: glucose-lowering arm – Cooper MEDICOGRAPHIA, Vol 31, No. 3, 2009 237

‘‘ The modern treatment goal
for hypertension in people with di-
abetes should be “the lowest pres-
sure the patient will tolerate with-
out an adverse impact on func-
tion.” Of course, this conclusion
does warrant confirmation, and
further information of the impact
of a more intensive BP-lowering
strategy will come from ACCORD
in the US. ACCORD is testing
whether lowering BP to normal
(<120 mm Hg systolic) reduces
stroke and heart disease risk com-
pared with the level usually target-
ed in current clinical practice.”
Bryan WILLIAMS, MD,
FRCP, FAHA
Leicester Royal Infirmary
Leicester
UNITED KINGDOM
Address for correspondence:
Prof Bryan Williams, Clinical Sciences
Building, PO Box 65, Leicester Royal
Infirmary, Leicester LE2 7LX, UK
(e-mail: bw17@le.ac.uk)
www.medicographia.com
238 MEDICOGRAPHIA, Vol 31, No. 3, 2009
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES
Implications of ADVANCE
in the management of blood
pressure in diabetic patients
by B. Williams, United Kingdom
E
pidemiological studies in the 1970s established that high blood pressure
(BP) is both common and a major risk factor for macrovascular and mi-
crovascular disease in people with type 2 diabetes. However, uncertainty
remained about the benefits and safety of BP lowering in people with dia-
betes. Previous studies, such as the United Kingdom Prospective Diabetes
Study (UKPDS) in the late 1990s, demonstrated that lowering BP is very ef-
fective at reducing cardiovascular disease (CVD) and microvascular disease
risk and, as a consequence, mortality. Questions remained, however, about
whether there was a specific threshold below which BP lowering would be
ineffective at reducing risk. The Action in Diabetes and Vascular disease:
PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) study was de-
signed with this key question in mind and set about lowering BP in people with
diabetes, irrespective of their baseline BP, to determine whether this strategy
would safely further reduce risk. The strategy employed was the addition of
a combination of perindopril/indapamide, added to usual care, as part of a
factorial study design that also examined the impact of “more versus less”
glucose lowering. The BP-lowering arm of the ADVANCE study demonstrated
that further BP lowering with perindopril/indapamide significantly reduced
the risk of a combined end point of macrovascular and microvascular events
and total mortality. This is a significant advance as it suggests that this treat-
ment strategy will further reduce the risk for people with type 2 diabetes, ir-
respective of their prior treatment or baseline BP. This finding has important
implications for people with type 2 diabetes and is a further step forward in
improving treatment strategies for these patients beyond existing therapies
to reduce their CVD and microvascular risk.
Medicographia. 2009;31:238-244 (see French abstract on page 244)
S
ome 25 years ago as a young doctor, I became interested in blood pressure
(BP) in people with diabetes when I noted three things that intrigued me. First-
ly, that the pathology associated with diabetes seemed to be primarily a vas-
cular problem, and that the pathology looked remarkably similar to that seen in
nondiabetic people with severe hypertension. Secondly, that people with diabetes
invariably seemed to be hypertensive, often severely so. And, thirdly, that the doc-
tors caring for patients with type 2 diabetes seemed less concerned about
measuring and treating their blood pressure than I was! We now know much more,
and the approach to detection and treatment of blood pressure has changed dra-
matically.
Implications of ADVANCE in the management of blood pressure in diabetic patients – Williams
 NEW
People with diabetes often develop hypertension. In younger
people with type 1 diabetes, an increase in BP often signals
the early development of diabetic nephropathy. In older pa-
tients with type 2 diabetes, hypertension—defined as a BP
140/90 mm Hg—is at least twice as common as in an age-
matched nondiabetic population, affecting approximately 80%
of people with type 2 diabetes. It is also important to note that
the characteristics of hypertension are very different in people
with type 2 diabetes. In these patients, the progressive age-
related rise in systolic BP occurs earlier. This means that many
people with type 2 diabetes develop systolic hypertension at
least 10 years earlier than the general population, and there
is an associated early widening of pulse pressure indicative
of accelerated aging and stiffening of the large arteries. This
arterial stiffening is important because it renders BP more re-
sistant to treatment. Furthermore, subtle autonomic dysfunc-
tion occurs in the majority of these patients that disturbs the
normal circadian rhythm of BP regulation. In particular, there
is a blunting of the usual nocturnal dip in BP during sleep.
This means that, for any given level of office BP, people with
type 2 diabetes invariably have a higher 24-hour BP load. To
compound matters, blood flow autoregulation is also impaired
in people with diabetes. This means that any increase in cir-
culatory pressures is more readily transferred to the delicate
microcirculation, which thereby explains, in large part, the de-
velopment of devastating microvascular disease in these pa-
tients. These observations are fundamental because they un-
derscore why the detection and treatment of hypertension
in people with diabetes is especially important in protecting
both the macro- and microvasculature. Mindful of the fact
that the BP load is elevated and the microcirculatory de-
fenses are impaired, it also provides a rationale for advocating
more aggressive BP lowering.
Importance of diabetes and hypertension
as cardiovascular disease risk factors
We now recognize that an elevated BP is a major risk fac-
tor for macrovascular and microvascular complications in
people with diabetes and a major contributor to associated
SELECTED ABBREVIATIONS AND ACRONYMS
ACCORD Action to Control CardiOvascular Risk in
Diabetes
ADVANCE Action in Diabetes and Vascular disease PreterAx
and DiamicroN Controlled Evaluation
ALLHAT Antihypertensive and Lipid-Lowering treatment to
prevent Heart Attack Trial
CVD cardiovascular disease
HDS Hypertension in Diabetes Study
NNT number needed to treat
RAS renin-angiotensin system
SHEP Systolic Hypertension in the Elderly Programme
UKPDS United Kingdom Prospective Diabetes Study
Implications of ADVANCE in the management of blood pressure in diabetic patients – Williams
A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES
premature morbidity and mortality. In 1974, the Framingham
study was the first major study to highlight the fact that car-
diovascular disease (CVD) risk was elevated in people with
diabetes.1 This was the result of two important factors: (i)
people with diabetes had a greater likelihood of abnormali-
ties in major risk factors, such as lipids and blood pressure;
and (ii) that, even when these risk factors were accounted
for, their risk was magnified. Since then, there has been some
controversy as to the magnitude of the excess CVD risk as-
sociated with type 2 diabetes, but no dispute about the fact
that it is elevated when compared to the nondiabetic pop-
ulation. Moreover, elevation in CVD risk occurs at levels of
glycemia below that required for the diagnosis of diabetes,
suggesting that control of glycemia per se is unlikely to be a
very effective strategy in reducing CVD risk. Another important
observation from early epidemiological studies noted that
when people with type 2 diabetes develop coronary heart dis-
ease, heart failure, or stroke, their prognosis was worse than
that of the nondiabetic population. This latter point is espe-
cially important because it highlights the special importance
of primary prevention in people with type 2 diabetes.
With regard to BP, it was recognized in the Framingham study
that the prevalence of hypertension was higher in people with
type 2 diabetes. However, hypertension at the time was de-
fined at a higher threshold (160/90 mm Hg). There was also
a much greater focus on diastolic pressure at the time, and
even though systolic pressure was commonly elevated, it was
often ignored in BP classification. This means that the true
prevalence of hypertension was often underestimated in the
early surveys. In 1993, data from the United Kingdom Prospec-
tive Diabetes Study (UKPDS) reported a strikingly high preva-
lence of hypertension—defined as a systolic BP 160 mm Hg
and/or a diastolic BP 90 mm Hg—in patients (40%) at the
time of diagnosis of type 2 diabetes, with a higher prevalence
among women and increasing prevalence with age.2-4 The
thresholds for the diagnosis of hypertension used in UKPDS
were much higher than current thresholds. Consequently, by
modern criteria (BP 140/90 mm Hg), almost 80% would
have been designated hypertensive. They also noted that hy-
pertensive patients were more likely to be obese and that
they already had almost double the risk of established car-
diovascular complications at the time of diagnosis of type 2
diabetes when compared with those without hypertension.
Alarmingly, most of the hypertension was unrecognized and
untreated.3 This hypertensive cohort within UKPDS became
the basis of a key substudy: the Hypertension in Diabetes
Study (HDS). HDS was one of the first prospective evaluations
of the association between BP and clinical outcomes within
a major clinical outcomes trial. Within 5 years of commencing
HDS, the strong association between BP and clinical out-
comes was reported by the group for patients with type 2
diabetes.3 After a median follow-up of only 4.6 years, it had
become clear that hypertension was a major risk factor for
MEDICOGRAPHIA, Vol 31, No. 3, 2009 239
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

cardiovascular morbidity and mortality in this population. The a diabetes-related death was only 15 patients. The treatment
authors speculated that “antihypertensive therapy may pro- strategy was safe and well tolerated, and the result was un-
vide greater benefit in this high risk group than in the gener- equivocal. Moreover, the treatment benefit from BP lower-
al population.”3 ing was greater than anticipated from the epidemiological as-
sociation between BP and risk in people with type 2 diabetes
One of the problems bedeviling treatment was a lack of clin- (Table I). This, perhaps, reflects the enhanced vulnerability of
ical trial data demonstrating the safety and efficacy of BP low- patients with diabetes to pressure-mediated cardiovascular
ering in people with diabetes. This was a key question. Today, disease (see below).
many would regard the answer as obvious, but at the time
there was concern that BP lowering might be poorly tolerat- Risk reduction (%) per 10 mm Hg
ed by people with diabetes and that it could lead to critical BP reduction and P value
ischemia in vital organs, compounded by autonomic dys-
UKPDS UKPDS BP-lowering
function. Moreover, the “presence of diabetes” was often an observational intervention
exclusion criteria for early BP-lowering trials, thus little data
existed upon which to base treatment recommendations. All-cause 13 P<0.0001 21 P<0.0001
Consequently, the detection and treatment of hypertension mortality
was often poor in people with diabetes and considered less Diabetes 9 P<0.001 24 P<0.0001
end point
important than glucose control.
Microvascular 10 P<0.001 37 P<0.009
disease
The emergence of blood pressure–lowering trials Heart failure 14 P<0.002 56 P<0.004
in people with diabetes Stroke 13 P<0.0002 44 P<0.013
The UKPDS study had originally been established to study
the impact of improved glycemic control on clinical outcomes Table I. Relationship between predicted benefit of BP lowering
in people with type 2 diabetes. The investigators, recognizing and actual benefit of BP lowering in the UKPDS. Based on data
the high prevalence of hypertension in their patients, embed- from reference 5.
Abbreviations: BP, blood pressure; UKPDS, United Kingdom Prospective Dia-
ded HDS within UKPDS. I recently reviewed the impact of this betes Study.
study on the treatment of hypertension in people with dia-
betes, in some detail.4 HDS addressed a key question: would Just prior to publication of UKPDS and HDS in 1998, the dia-
more intensive versus less intensive blood pressure lowering betes subgroup (n=583) from the Systolic Hypertension in the
improve clinical outcomes in people with type 2 diabetes?5 Elderly Programme (SHEP) had reported a reduction in half of
HDS started in 1987 and recruited 1148 hypertensive type 2 cardiovascular events in an elderly population experiencing a
diabetic patients from the 4297 patients recruited into UKPDS. similar improvement in BP control over 5 years of treatment.6
Of note was the fact that these patients were newly diag- However, this had less impact than the UKPDS data that iden-
nosed and had not previously had BP treatment. The patients tified that hypertension was the norm and almost invariably
were allocated to treatment with either “less tight control of present in these patients, rather than the exception. UKPDS
BP,” aiming for a BP <180/105 mm Hg, or “tight control of demonstrated that hypertension was dangerous and marked-
BP,” aiming for a BP of <150/85 mm Hg. The very fact that, ly increased the risk of the premature development of diabet-
in the early 1990s, it was considered reasonable to random- ic complications and that, left untreated, ultimately contributed
ize people with diabetes to what is now considered grade III to premature mortality. It not only showed for the first time
hypertension, is testimony to the lack of evidence that existed that, for BP, “lower was better” in improving the outcomes
and, consequently, the low profile of BP control in the routine in people with type 2 diabetes, but that lower was safe. The
care of people with type 2 diabetes, at the time. study also showed that almost all patients require multiple
drugs in combination to achieve improved BP control and
After a median of 8.4 years of follow-up, the mean blood pres- better clinical outcomes.
sure during follow-up was significantly reduced in the group
assigned tight blood pressure control (144/82 mm Hg) com- Early indicators of the relative importance
pared with the group assigned to less tight control (154/87 of blood pressure versus glycemic control in
mm Hg).5 This 10/5 mm Hg difference in BP was associated type 2 diabetes
with a reduction in diabetes-related end points of a quarter, Glycemic control has for many years been the main focus of
reductions in deaths related to diabetes of almost a third, a treatment for people with type 2 diabetes. UKPDS allowed the
reduction in stroke of almost a half and in heart failure of more relative impact of BP lowering versus intensified glycemic con-
than a half, and a reduction in microvascular disease of about trol on clinical outcomes to be compared prospectively. As
a third (mainly delayed progression of retinopathy). The num- indicated above, intensified BP control was impressive at
ber needed to treat (NNT) to prevent one major complication reducing major diabetes end points, including significant re-
over 10 years was only 6 patients, while the NNT to prevent duction in diabetes-related death, stroke, and microvascular

240 MEDICOGRAPHIA, Vol 31, No. 3, 2009 Implications of ADVANCE in the management of blood pressure in diabetic patients – Williams
 NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

disease, and tends to be of benefit in all end points. This is de-
spite the small size of the BP-lowering study. The benefits of
BP lowering appeared more impressive than those resulting
from the intensified glycemic control strategy in UKPDS, even
on microvascular end points, for which the latter had been
strongly advocated. I highlight this comparison not to sug-
gest that glycemic control is unimportant, but, rather, because
of its importance in changing perceptions about the impor-
tance of BP control in protecting people with type 2 diabetes
from microvascular and macrovascular damage.
The ADVANCE of knowledge regarding
blood pressure lowering in people with diabetes
Many questions remained after the emergence of the early
evidence that BP lowering was both safe and very efficacious
at reducing CVD events and microvascular disease in people
with diabetes. Should BP be lowered even further than the
average of 144/82 mm Hg achieved in the tight control group
of HDS in UKPDS? Is the definition of hypertension, in any
case, arbitrary, and would people with diabetes benefit from
BP lowering, whatever their baseline BP? Moreover, does it
matter what drug we use to lower BP in people with type 2
diabetes? A meta-analysis of trials that followed UKPDS
concluded that BP lowering per se is the dominant means
of achieving macro- and microvascular benefits, and that
achieving a lower BP does appear to be better—even more
so than in the nondiabetic hypertensive population.7 This, in
part, relates to the fact that people with diabetes are at much
higher cardiovascular risk and, thus, stand to gain more ab-
solute benefit from BP lowering. It may also relate to the fact
that people with diabetes are especially vulnerable to hyper-
tensive injury.8 Data also suggest that blockade of the renin-
angiotensin system (RAS) “adds value,” over and above the
BP lowering they produce, in preventing cardiovascular events
in people with diabetes,9,10 although this has not been con-
firmed by all studies.11 One important clinical outcome where

Randomized treatment

Active (n=5569) Placebo (n=5571)

Age (years), mean (SD) 66 (6) 66 (7)

Female, n (%) 2366 (43%) 2369 (43%)
Age when diabetes first diagnosed (years), mean (SD) 58 (9) 58 (9)

Previous vascular disease

History of major macrovascular disease, n (%) 1798 (32%) 1792 (32%)
History of myocardial infarction, n (%) 678 (12%) 656 (12%)
History of stroke, n (%) 502 (9%) 520 (9%)
History of major microvascular disease, n (%) 568 (10%) 584 (10%)
History of macroalbuminuria,† n (%) 197 (4%) 204 (4%)
History of microvascular eye disease,‡ n (%) 389 (7%) 404 (7%)

Blood pressure control

Systolic blood pressure (mm Hg), mean (SD) 145 (22) 145 (21)
Diastolic blood pressure (mm Hg), mean (SD) 81 (11) 81 (11)
History of currently treated hypertension, n (%) 3802 (68%) 3853 (69%)

Other major risk factors

Current smokers, n (%) 804 (14%) 878 (16%)
Serum total cholesterol (mmol/L), mean (SD) 5.2 (1.2) 5.2 (1.2)
Serum HDL cholesterol (mmol/L), mean (SD) 1.3 (0.3) 1.3 (0.4)
Urinary albumin:creatinine ratio (μg/mg), median (IQR) 15 (7 to 40) 15 (7 to 40)
Microalbuminuria, n (%) 1441 (26%) 1421 (26%)
Serum creatinine (μmol/L), mean (SD) 87 (23) 87 (26)
Serum hemoglobin A 1c concentration (%), mean (SD) 7.5 (1.6) 7.5 (1.6)
Body mass index (kg/m 2 ), mean (SD) 28 (5) 28 (5)
* Characteristics of participants recorded at the first (registration) visit, before active run-in.
† Urinary albumin-creatinine ratio >300 μg/mg.
‡ Proliferative diabetic retinopathy, retinal photocoagulation therapy, macular edema, or blindness in one eye thought to be caused by diabetes.

Table II. Patient characteristics at baseline* in the ADVANCE study.

Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; HDL, high-density lipoprotein.
Reproduced from reference 15: ADVANCE Collaborative Group. Lancet. 2007;370:829–840. Copyright © 2007, Elsevier Ltd.

Implications of ADVANCE in the management of blood pressure in diabetic patients – Williams MEDICOGRAPHIA, Vol 31, No. 3, 2009 241
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

there appears to be a clear advantage of RAS blockade in

people with type 2 diabetes is on renal end points (albumin- Placebo
20
uria and progression of renal disease).12-14 This has prompt- Perindopril-
ed international guidelines to conclude that RAS blockade indapamide
should be part of the cocktail of treatments used to lower

Cumulative incidence (%)

HR 0.91 (95% CI 0.81-1.00)
BP in people with type 2 diabetes. Thus, modern treatment P=0.041
strategies usually include RAS blockade, along with a calci-
um channel blocker and/or a thiazide-type diuretic. 10

However, uncertainty has remained about “how low to go?”

Guidelines were making recommendations to aim for lower
BP targets in people with diabetes, but evidence to support
these recommendations was lacking. There was a clear need 0
to push the boundaries beyond those explored by UKPDS 0 6 12 18 24 30 36 42 48 64 60
Follow-up (months)
and to take BP into uncharted territories and evaluate the
Number at risk
“lower is better” hypothesis. This was the purpose of the re-
Placebo 5571 5558 5362 5253 5078 4909 4805 4703 4383 1854
cent Action in Diabetes and Vascular disease: PreterAx and Per-ind 5568 5448 5361 5260 5122 4986 4906 4806 4466 1895
DiamicroN MR Controlled Evaluation (ADVANCE) trial that
tested the “lower is better” hypothesis by measuring the effect Figure 1. Primary outcome in the ADVANCE trial: reduction in
of further BP reductions (achieved with an angiotensin-con- combined primary end point of macrovascular and microvascular
verting enzyme [ACE] inhibitor [perindopril]/thiazide-type di- events.
uretic [indapamide] combination versus placebo, on top of The vertical lines indicate the 2- and 4-year time points in the trial at which data
were collected for microvascular end points (albuminuria and retinal photography).
conventional therapy) on vascular events in 11 140 people with Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx
type 2 diabetes.15 An important aspect of this study was that and DiamicroN MR Controlled Evaluation.
Reproduced from reference 15: ADVANCE Collaborative Group. Lancet. 2007;
the BP-lowering combination therapy (perindopril/indapamide) 370:829–840. Copyright © 2007, Elsevier Ltd.
was added: (i) irrespective of baseline blood pressure lev-
els—that is, it was added even if patients would have been of additional BP-lowering therapy differed according to initial
considered “normotensive” by conventional criteria; and (ii) blood pressure level—in other words, even those within the
irrespective of whether the patients were already receiving lowest BP strata at baseline experienced a similar relative risk
other BP-lowering drugs, including ACE inhibitors. reduction to those in the highest BP strata. Moreover, the low-
est BP strata included patients whose BP was already be-
The mean age of the ADVANCE population was 66 years, of low the currently recommended treatment target for type 2
whom 57% were male. About a third had a prior history of ma- diabetes (<130/80 mm Hg). It is also noteworthy that the
jor macrovascular disease and a tenth had microvascular dis-
ease. The patient profile in ADVANCE is shown in Table II
(page 243). In addition, glycemic control was excellent through- Placebo
out the study. A large proportion (68%) were being treated Perindopril-indapamide
Cumulative incidence (%)

for hypertension at the time, with a baseline BP of approxi-

mately 145/81 mm Hg. Importantly, the standard deviation 10
around this mean baseline was approximately 22/11 mm Hg, HR 0.86 (95% CI 0.75-0.98)
P=0.025
indicating that many patients had substantially lower baseline
BPs. Over a mean follow-up of 4.3 years, additional perindo-
pril/indapamide therapy was associated with a lower BP
(–5.6/–2.2 mm Hg) versus placebo treatment. This modest BP
reduction reflects that fact that patients in the placebo group 0
received additional add-on therapy for their BP (83% received 0 6 12 18 24 30 36 42 48 64 60
additional BP-lowering drugs in the placebo group, versus Follow-up (months)
Number at risk
74% in the perindopril/indapamide group), as often happens
Placebo 5571 5535 5493 5433 5397 5340 5282 5211 4955 2126
in clinical trials when active BP-lowering therapy is compared Per-ind 5568 5533 5500 5455 5416 5377 5334 5277 5014 2165
to placebo treatment. The additional BP lowering associated
with perindopril/indapamide was associated with a significant Figure 2. Prespecified outcome of “all-cause mortality” in the
9% risk reduction in major macrovascular and microvascular ADVANCE trial.
events (Figure 1), a significant 18% reduction in cardiovas- Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx
and DiamicroN MR Controlled Evaluation.
cular death, and a 14% reduction in all cause mortality (Fig- Reproduced from reference 15: ADVANCE Collaborative Group. Lancet. 2007;
ure 2). Importantly, there was no evidence that the benefits 370:829–840. Copyright © 2007, Elsevier Ltd.

242 MEDICOGRAPHIA, Vol 31, No. 3, 2009 Implications of ADVANCE in the management of blood pressure in diabetic patients – Williams
 NEW A D VA N C E S
ADVANCE result was achieved in a population with high con-
comitant use of statins (almost half of patients by study end),
antiplatelet drugs (more than half of patients by study end), and
background ACE inhibition, and with good glycemic control,
in both arms of the trial. With regard to background ACE in-
hibition, those already receiving ACE inhibition at baseline were
standardized to treatment with perindopril, thus, by the study
end, about half of all patients were receiving perindopril in ad-
dition to placebo or additional perindopril/indapamide.
It is also worth noting that because the background use of
perindopril was so extensive, one of the major differences be-
tween the treatment arms was the use of indapamide, a thia-
zide-like diuretic. This is important when one considers the re-
sistance to using diuretics in people with diabetes in the past.
The data from SHEP,6 the Antihypertensive and Lipid-Low-
ering treatment to prevent Heart Attack Trial (ALLHAT),11 and
now ADVANCE15 attest to the effectiveness of thiazide-type
diuretics at reducing BP and major CVD and microvascular
events in people with diabetes. In modern therapy for BP low-
ering in type 2 diabetes, thiazide-type diuretics are usually
used alongside RAS blockade, as in the ADVANCE study.
The ADVANCE trial is very important because it extends our
understanding of the importance of further BP lowering in
patients with type 2 diabetes. The findings extend the orig-
inal findings of UKPDS into new territories and provide strong
evidence to support the safety, tolerability, and efficacy of a
“lower is better” philosophy for BP control in people with di-
abetes. Indeed, in my recent review of key trials in hyperten-
sion, which considered the ADVANCE trial, I suggested that
the modern treatment goal for hypertension in people with
diabetes should be “the lowest pressure the patient will tol-
erate without an adverse impact on function”.16 Of course,
this conclusion does warrant confirmation, and further infor-
mation of the impact of a more intensive BP-lowering strat-
References
1. Garcia MJ, McNamara PM, Gordon T, Kannel WP. Morbidity and mortality in
diabetics in the Framingham population. Sixteen year follow-up study. Diabetes.
1974;23:105-111.
2. Hypertension in Diabetes Study Group. HDS 1: Prevalence of hypertension in
newly presenting type 2 diabetic patients and the association with risk factors
for cardiovascular and diabetic complications. J Hypertens. 1993;11:309-317.
3. Hypertension in Diabetes Study Group. HDS 2: Increased risk of cardiovascu-
lar complications in hypertensive type 2 diabetic patients. J Hypertens. 1993;11:
319-325.
4. Williams B. The hypertension in diabetes study (HDS); a catalyst for change.
Diabet Med. 2008;25(suppl 2):13-19.
5. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of
macrovascular and microvascular complications in type 2 diabetes: UKPDS 38.
BMJ. 1998;317:703-713.
6. Curb JD, Pressel SL, Cutler JA, et al. Effect of diuretic-based antihypertensive
treatment on cardiovascular disease risk in older diabetic patients with isolat-
ed systolic hypertension. Systolic Hypertension in the Elderly Program Coop-
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7. Turnbull F, Neal B, Algert C, et al. Effects of different blood pressure-lowering
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Implications of ADVANCE in the management of blood pressure in diabetic patients – Williams
IN THE T R E AT M E N T OF TYPE 2 DIABETES
egy will come from the ACCORD study (the Action to Control
Cardiovascular Risk in Diabetes) in the US.17 ACCORD is test-
ing whether lowering BP to normal (<120 mm Hg systolic) re-
duces stroke and heart disease risk compared with the level
usually targeted in current clinical practice, ie, one below the
current definition of hypertension (<140 mm Hg systolic) in
people with type 2 diabetes.
Conclusions
The story of hypertension in diabetes is a young one. The first
substantive epidemiological clues to its high prevalence and
clinical importance first emerged less than 40 years ago.
Since then, we have learned much about the pathophysiology
of qualitative and quantitative BP disturbances that charac-
terize people with type 2 diabetes. Changes in clinical practice
have been driven by evidence from clinical trials, which be-
gan with UKPDS and which have continued (see the studies
highlighted above) up until ADVANCE, from which the latest
data come. In addition to BP, it is also clear that the high CVD
risk and microvascular disease burden experienced by people
with type 2 diabetes is best addressed by multifactorial inter-
vention based on improved BP control, on better lipid man-
agement with statins, on antiplatelet drugs, and on improved
glycemic control, which is best highlighted by studies from
the Steno centre.18,19 Mindful of the almost obsessive focus of
diabetes care on glucose control over the years, it is some-
what ironic that it is this aspect of intervention which has the
less convincing evidence base and which remains the most
controversial with regard to clinical outcomes. It is also clear
that following the spectacular pace of change in the treatment
of people with type 2 diabetes and, especially, the overall im-
provement in their CVD risk management, future trials will be
more challenging. In this context, the data from the ADVANCE
BP study are all the more remarkable in showing that we can
still do more to improve the survival of an otherwise well-
treated population. 
8. Williams B. The unique vulnerability of diabetic subjects to hypertensive in-
jury. In: Williams B, ed. Hypertension in Diabetes. London, UK: Martin Dunitz
Ltd; 2003:99-108.
9. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril
on cardiovascular and microvascular outcomes in people with diabetes melli-
tus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:
253-259.
10. Lindholm LH, Ibsen H, Dahlöf B, et al; LIFE Study Group. Cardiovascular mor-
bidity and mortality in patients with diabetes in the Losartan Intervention For
Endpoint reduction in hypertension study (LIFE): A randomised trial against
atenolol. Lancet. 2002;359:1004-1010.
11. Whelton PK, Barzilay J, Cushman WC, et al; ALLHAT Collaborative Research
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2005;165:1401–1409.
12. Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner
P; Irbesartan in Patients with type 2 Diabetes and Microalbuminuria Study
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protective effect of the angiotensin-receptor antagonist irbesartan in patients
with nephropathy due to type 2 diabetes. N Engl J Med. 2001,345:851-860.
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14. Brenner BM, Cooper ME, de Zeeuw D, et al; RENAAL Study Investigators.
Effects of Losartan on renal and cardiovascular outcomes in patients with
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15. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril
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with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled tri-
al. Lancet. 2007;370:829–840.
16. Williams B. The Year in hypertension. J Am Coll Cardiol. 2008;51:1803-1817.
17. Buse J; ACCORD Study Group. Action to Control Cardiovascular Risk in Di-
abetes (ACCORD) trial: design and methods. Am J Cardiol. 2007;99(supple-
ment 1):S21-S33.
18. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pederson O. Multifac-
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Keywords: blood pressure; microvascular disease; macrovascular disease; diabetes; blood glucose control; epidemiological
study; Preterax; Diamicron

IMPLICATIONS DE L’ ÉTUDE ADVANCE DANS LA PRISE EN CHARGE

DE LA PRESSION ARTÉRIELLE CHEZ LES DIABÉTIQUES
Dans les années 70, des études épidémiologiques ont montré qu’une pression artérielle (PA) élevée était à la fois
fréquente et un facteur de risque majeur des maladies macro- et microvasculaires chez les diabétiques de type 2.
Des doutes persistaient néanmoins quant aux bénéfices et à l’innocuité de la baisse de PA dans une telle population.
Dans les années 90, des études comme l’UKPDS (United Kingdom Prospective Diabetes Study) ont montré que la
baisse de la PA était très efficace dans la réduction de la maladie cardio-vasculaire (MCV) et du risque de maladie
microvasculaire et donc, de la mortalité. Restait à savoir s’il existait un seuil spécifique en-deçà duquel la baisse de
la PA ne réduisait pas le risque. L’étude ADVANCE (Action in Diabetes and Vascular disease : PreterAx and Diami-
croN MR Controlled Evaluation) a été conçue pour répondre à cette question clé et a entrepris de baisser la PA chez
des diabétiques, indépendamment de leur PA initiale, pour savoir si cette stratégie pourrait davantage réduire le
risque en toute sécurité. Pour ce faire, une association de perindopril/indapamide a donc été ajoutée au traitement
habituel dans le cadre d’une étude factorielle dans laquelle était également évaluée l’effet d’une baisse « plus » en
comparaison avec une baisse « moins » de la glycémie. Le bras « PA » de l’étude ADVANCE a montré qu’une dimi-
nution supplémentaire de la PA par l’association perindopril/indapamide réduisait significativement le risque du cri-
tère combiné événements macro- et microvasculaires et mortalité totale. Il s’agit donc d’une avancée significative
puisqu’elle suggère que cette stratégie thérapeutique diminuera encore le risque pour les diabétiques de type 2,
indépendamment de leur traitement antérieur ou de leur PA initiale. Pour cette population, il s’agit donc une avancée
supplémentaire vers l’amélioration des stratégies thérapeutiques pour réduire la MCV et le risque microvasculaire.

244 MEDICOGRAPHIA, Vol 31, No. 3, 2009 Implications of ADVANCE in the management of blood pressure in diabetic patients – Williams

‘‘ Recent trials of glycemic con-
trol in type 2 diabetes have given
new insights into the benefits
and risks of tight glycemic con-
trol. Overall, the trial data sug-
gest that lowering glucose is
beneficial, especially early in the
disease process. A more cautious
approach may be needed late in
the disease, especially to avoid
hypoglycemia.”
David R. MATTHEWS, MA,
DPhil, BM, BCh, FRCP
Oxford Centre for Diabetes,
Endocrinology and Metabolism
National Institute for Health
Research, Oxford Biomedical
Research Centre, Oxford
UNITED KINGDOM
Address for correspondence:
Prof David R. Matthews, Oxford
Centre for Diabetes, Endocrinology
and Metabolism, Churchill Hospital,
Oxford OX3 7LJ, UK
(e-mail: david.matthews@
ocdem.ox.ac.uk)
www.medicographia.com
ADVANCE and the management of glucose lowering in diabetic patients – Matthews
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES
Implications of ADVANCE
in the management of glucose
lowering in diabetic patients
by D. R. Matthews, United Kingdom
M
ajor studies have addressed the problem of whether improved
glycemic control would improve the outcome in type 2 diabetes.
Two large studies from the 20th century caused controversy: the
Universities Group Diabetes Program (UGDP) raised a suggestion that tolbu-
tamide might not be efficacious, and the United Kingdom Prospective Dia-
betes Study (UKPDS) had an equivocal outcome for myocardial infarction. In
recent years, a number of landmark studies, including PROspective pioglitA-
zone Clinical Trial In macroVascular Events (PROACTIVE), Action in Diabetes
and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation
(ADVANCE), Action to Control CardiOvascular Risk in Diabetes (ACCORD),
Veterans Affairs Diabetes Trial (VADT), Steno 2, and the United Kingdom Pros-
pective Diabetes Study-PostTrial Monitoring (UKPDS-PTM) have all reported.
Ongoing trials, such as Rosiglitazone Evaluated for Cardiac Outcomes and
Regulation of glycemia in Diabetes (RECORD) and Outcome Reduction with
an Initial Glargine Intervention (ORIGIN), may add to our knowledge. The out-
comes from these trials have given some answers. We are now convinced
that early intervention and intensive control is worthwhile. However, there are
still unanswered questions, including questions of interpretation and uncer-
tainties about the choice of agents.
Medicographia. 2009;31:245-250 (see French abstract on page 250)
Background
T
ype 2 diabetes is now pandemic. In the World Health Organization report
of 1997 the world estimate for diabetes was 140 million people. The esti-
mates from current epidemiology suggest that this number will increase to
200 million people by the year 2010, and to 300 million by 2025. The problem is not
one confined to country, race, or geographical location. Type 2 diabetes pervades
societies in countries as diverse as Mexico, China, Japan, and the Ukraine.
The challenge for health care in the 21st century is one of provision of appropriate
health care and establishing therapeutic regimes which optimize the outcome of
metabolic control in the short term and minimize tissue damage, including retino-
pathy, neuropathy, nephropathy, stroke, and heart disease, in the longer term. Epi-
demiological studies from a wide range of data sources suggest that relative risks
for ischemic heart disease are probably 3 times those of nondiabetic individuals,
and that overall all-cause morbidity from diabetes-associated pathology is twice
that of the nondiabetic age-matched population.
MEDICOGRAPHIA, Vol 31, No. 3, 2009 245
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE
SELECTED ABBREVIATIONS AND ACRONYMS
ACCORD Action to Control CardiOvascular Risk in
Diabetes
ADVANCE Action in Diabetes and Vascular disease
PreterAx and DiamicroN Controlled Evaluation
ORIGIN Outcome Reduction with an Initial Glargine
Intervention
PROACTIVE PROspective pioglitAzone Clinical Trial In macro-
Vascular Events
RECORD Rosiglitazone Evaluated for Cardiac Outcomes
and Regulation of glycemia in Diabetes
UGDP Universities Group Diabetes Program
UKPDS United Kingdom Prospective Diabetes Study
UKPDS-PTM United Kingdom Prospective Diabetes Study-
PostTrial Monitoring
VADT Veterans Affairs Diabetes Trial
What is appropriate treatment for type 2 diabetes? What
should our goals and targets be? How aggressively should
we be treating hyperglycemia? Are there targets and goals
to which we should adhere or simply aspire?
Trials of glycemic control
Throughout the 1950s and 1960s there had been a growing
awareness that diabetes complications—both of microvas-
cular and macrovascular origin—were presenting the great-
est challenge to quality of life and to longevity in type 2 dia-
betes. Clinical acumen and observation had demonstrated
that allowing glycosuria and very high blood glucose levels
led to poor quality of life, but some physicians, up until late
into the 20th century, were still thinking that perhaps poor
control had an advantage in terms of weight loss. It was cer-
tainly cheaper than intensive therapy.
The Universities Group Diabetes Program (UGDP)1 was the
first to attempt to answer the question using a controlled tri-
al approach: launched in 1960, this placebo-controlled, mul-
ti-center clinical trial aimed to determine which, if any, of the
treatments for type 2 diabetes was efficacious. Although the
differences seen in the cumulative total mortality were not sta-
tistically significant, a subgroup analysis suggested that car-
diac deaths occurred more frequently in the tolbutamide group.
The investigators terminated this limb of the study. However,
the randomization was significantly skewed in that, at base-
line, there were 30% more ECG abnormalities, 40% more
angina, and 90% more hypercholesterolemia in the tolbuta-
mide group.2 So, randomization had failed to deliver equipoise
in the outcome.
The United Kingdom Prospective Diabetes Study (UKPDS)
was established to give a definitive answer to the glycemic
control controversy as well as an attempt to answer impor-
tant questions about class of agents used to achieve control.3
The UKPDS had stringent aims for glycemia, but allowed for
246 MEDICOGRAPHIA, Vol 31, No. 3, 2009 ADVANCE and the management of glucose lowering in diabetic patients – Matthews
2 DIABETES
fasting glucose to rise to 15 mmol/L before adding new thera-
pies. Because it aimed to address the questions about which
therapy should be used, the glycemia rose progressively
throughout the trial. At the closeout, the results showed that
intensive glucose control was efficacious in reducing many
complications, but the results for myocardial infarction were
borderline with a statistical value for efficacy of P=0.052.4,5
The world divided into the statistical fundamentalists, who
used this as evidence against the hypothesis that macrovas-
cular disease could be prevented by good glycemic control,
and into those who pointed out that the odds of glycemic con-
trol not being important were 1 in 19.2 as opposed to 1 in 20.
The UKPDS used an intensive versus conventional treat-
ment for blood-glucose control and achieved HbA1c in the
study population of 7% in the intensive groups compared
with 7.9% HbA1c in the conventional group. The totality of di-
abetes related end points was reduced by 12% (relative risk
[RR], 0.88; 95% confidence interval [CI], 0.79-0.99).5 The con-
tribution to the risk reduction was both from microvascular
complications (RR, 0.75; 95% CI, 0.60-0.93) and myocardial
infarction (RR, 0.84; 95% CI, 0.71-1.0).6 So questions re-
mained—especially the question of how low should one aim
in glycemic control. We did not know the extent to which more
aggressive glucose control would decrease macrovascular or
microvascular disease in conventionally normotensive diabet-
ic patients. Nor did we understand the extent to which there
might be differences in the outcomes between different racial
groups. So, the question remained open. With new agents and
new enthusiasm to demonstrate how diabetes should best be
treated, a series of trials were initiated.
In 2005, PROspective pioglitAzone Clinical Trial In macro-
Vascular Events (PROACTIVE)7 reported its results: it was a
prospective, randomized controlled trial of 5238 patients with
type 2 diabetes who had evidence of macrovascular disease.
The median follow-up was just under 3 years. Patients were
assigned to pioglitazone or placebo taken in addition to their
glucose-lowering drugs and other medications. The primary
end point was a composite of cardiovascular disease, includ-
ing surgical intervention in the coronary or leg arteries and am-
putation above the ankle. The outcome of this was not signif-
icant (P=0.095). However, the “main secondary end point” was
the composite of all-cause mortality, nonfatal myocardial in-
farction, and stroke: this showed a significant favorable re-
sponse to pioglitazone (P=0.027).
So, the trial was marred by the known problem of selecting a
primary combined outcome which involved not only the on-
set of new pathology, but the surgical interventions relating
to pathology. Combining outcomes may increase the event
count, but can do so at the expense of specificity.
Then, in 2007, Nissen et al8 produced a meta-analysis which
seemed to demonstrate that rosiglitazone might have an ad-
 NEW A D VA N C E S
verse effect on cardiovascular outcome. That meta-analysis
has been criticized,9 especially on the basis that the meta-
analysis was not a comprehensive search for all studies that
might yield evidence about rosiglitazone’s cardiovascular ef-
fects and that studies were combined on the basis of a lack
of statistical heterogeneity, despite variability in study design
and outcome assessment. Diamond et al9 concluded that the
risk for myocardial infarction and death from cardiovascular
disease for diabetic patients taking rosiglitazone was uncer-
tain, and stated that “neither increased nor decreased risk is
established”. One should certainly not regard such combina-
torial analysis as being evidentially as good as a random-
ized trial.
At this point, Rosiglitazone Evaluated for Cardiac Outcomes
and Regulation of glycemia in Diabetes (RECORD), an inter-
vention trial using rosiglitazone, was under pressure to pro-
duce an early interim analysis,10 and this reported that, in a
total of 217 patients in the rosiglitazone group and 202 pa-
tients in the control group, the hazard ratio for hospitalization
or death from cardiovascular cause was 1.11 (95% CI, 0.93-
1.32) and there were more patients with heart failure in the
rosiglitazone group than in the control group (hazard ratio [HR],
2.15; 95% CI, 1.30-3.57). So, it remains to be demonstrated
that the use of rosiglitazone is not associated with cardiovas-
cular risk.
Then, in the summer of 2008, 3 cardiovascular disease (CVD)
trials reported at the American Diabetes Association. These
were the Action in Diabetes and Vascular disease: PreterAx
and DiamicroN MR Controlled Evaluation (ADVANCE),11 the Ac-
tion to Control CardiOvascular Risk in Diabetes (ACCORD),12
and the Veterans Affairs Diabetes Trial (VADT)13 trials. ACCORD
produced a startling headline result that mortality was worse
in the group that was intensively treated to lower HbA1c to-
ward 6%. At 1 year, stable median glycated hemoglobin lev-
els of 6.4% and 7.5% were achieved in the intensive-therapy
group and the standard-therapy group, respectively. During
follow-up, the primary outcome occurred in 352 patients in
the intensive-therapy group, compared with 371 in the stan-
dard-therapy group (HR, 0.90; 95% CI, 0.78-1.04; P=0.16).
However, 257 patients in the intensive-therapy group died,
compared with 203 patients in the standard-therapy group
(HR, 1.22; 95% CI, 1.01-1.46; P=0.04).12 This then raised the
question again about the main result from UKPDS. Is intensive
glucose lowering actually harmful? Nevertheless, one can-
not compare the patients in ACCORD directly with those re-
cruited into UKPDS (Figure 1). UKPDS recruited “healthy” new-
onset type 2 diabetes patients (serious disease of any kind
was a contraindication). In ACCORD, patients were 10 years
into established diabetes and were selected for preexisting
cardiovascular disease or specific risk factors. Making sud-
den changes in glycemia in such patients may not be a smart
therapeutic idea. In fact, in this trial, the reports show that the
majority of the glucose-lowering effect was already achieved
ADVANCE and the management of glucose lowering in diabetic patients – Matthews
IN THE T R E AT M E N T OF TYPE 2 DIABETES
within the first 4 months, by which time the median HbA1c was
6.6%. Although there was no explicit evidence that hypogly-
cemia was the precipitating cause of death, it remains the
highest suspect for the increased death rate. Hypoglycemia
rates were 3 times higher in the intensively treated group, and
death precludes a contemporaneous measurement of blood
glucose. Many of the patients were receiving rosiglitazone
(91% in the intensive and 57% in the standard therapy arm,
respectively). The excess mortality was not simply cardiovas-
cular, but hypoglycemia can cause falls or aspiration at night,
leading to pneumonia. In the elderly, any significant medical
event may be seriously life-threatening.
ADVANCE11 was the largest trial of cardiovascular disease in
type 2 diabetes to date, recruiting 11 140 patients with type 2
diabetes randomized to standard or intensive glucose con-
trol, with the aim of using gliclazide modified release (MR) plus
other drugs, as required, to achieve an HbA1c value of 6.5% or
less. After a median of 5 years of follow-up, the mean HbA1c
HbA1c
9% UKPDS
ACCORD
8%
7%
6%
ADVANCE
0 2 4 6 8 10 12 14
Years from diagnosis
Figure 1. Schematic of HbA1c in the study populations of UKPDS,
ACCORD, and ADVANCE.
The schematic shows how these studies are not directly comparable in terms of
their populations, especially with regard to duration of diabetes at recruitment.
Grey lines are the control groups. Left group of four lines all relate to UKPDS:
grey = conventional treatment; green = glibenclamide; blue = chlorpropamide;
and red = insulin. Right group of lines relate to: ACCORD, solid lines (——); and
ADVANCE, dashed lines (----) [red = intensive group for both studies].
Abbreviations: ACCORD, Action to Control CardiOvascular Risk in Diabetes;
ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR
Controlled Evaluation; UKPDS, United Kingdom Prospective Diabetes Study.
in the intensive-control group had achieved 6.5% compared
with 7.3% in the control group. In the intensive group, there
was a reduced incidence in the combined end point of major
macrovascular and microvascular events (HR, 0.90; 95%
CI, 0.82-0.98; P=0.01) as well as that of major microvascu-
lar events (9.4% vs 10.9%; HR, 0.86; 95% CI, 0.77-0.97;
P=0.01), primarily because of a reduction in the incidence of
nephropathy (HR, 0.79; 95% CI, 0.66-0.93; P=0.006). How-
ever, there were no significant effects of the type of glucose
control on major macrovascular events (HR with intensive con-
MEDICOGRAPHIA, Vol 31, No. 3, 2009 247
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE
trol, 0.94; 95% CI, 0.84-1.06; P=0.32), death from cardiovas-
cular causes (HR with intensive control, 0.88; 95% CI, 0.74-
1.04; P=0.12), or death from any cause (HR with intensive
control, 0.93; 95% CI, 0.83-1.06; P=0.28).
 Comparisons between the trials
The effects shown in the ADVANCE trial were mainly attrib-
utable to a 21% relative reduction in nephropathy, but un-
like in the ACCORD trial, there was no signal that achieving
the target of 6.5% gradually over 4 years had any detrimen-
tal cardiovascular effects nor any increased mortality. How
can one explain the differences between these outcomes?
Good evidence Fair evidence Fair evidence
that glycemic that aggressive, that slow, late
HbA1c control is beneficial late glycemic glycemic control
UKPDS and control is harmful is beneficial
8.5% UKPDS-PTM ACCORD ADVANCE
7.5%
6.5%
0 10 Time (years)
Good evidence for metformin (UKPDS)
Fair evidence for gliclazide and pioglitazone
(ADVANCE and PROACTIVE)
Poor evidence for rosiglitazone (ACCORD and RECORD)
Figure 2. Summary of the evidence for glycemia trials in type 2
diabetes.
The lines show the stylized glycemia over time, and the boxes summarize the
evidence from the trials.
Abbreviations: ACCORD, Action to Control CardiOvascular Risk in Diabetes;
ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR
Controlled Evaluation; PROACTIVE, PROspective pioglitAzone Clinical Trial In
macroVascular Events; RECORD, Rosiglitazone Evaluated for Cardiac Outcomes
and Regulation of glycemia in Diabetes; UKPDS, United Kingdom Prospective
Diabetes Study. UKPDS-PTM, United Kingdom Prospective Diabetes Study-
PostTrial Monitoring.
ADVANCE used gliclazide (mainly gliclazide modified release)
to achieve a lower glycemia in the intensive control group, and
this contrasts with ACCORD where there was a high usage
of rosiglitazone (in both arms) and insulin and sulphonylurea, in
combination. In ACCORD, the glycemic targets were aggres-
sively pursued, and the control of glycemia over time did not
deteriorate (Figure 2). By contrast in ADVANCE, the target
of HbA1c below 6.5% was achieved only progressively over
a period of 4 years—a much slower rate than that of the
ACCORD patients, and the totality of the updated mean dif-
ference was much less. On the other hand, the duration of
diabetes was similar (8 years). So, the differences between the
2 trials was a marked difference in rate of achievement of tar-
get glycemia, a very high hypoglycemia rate in ACCORD (a
nearly 4 times greater rate than in ADVANCE), and a clear dif-
ference in the choice of agents for the 2 trials. ACCORD sug-
248 MEDICOGRAPHIA, Vol 31, No. 3, 2009 ADVANCE and the management of glucose lowering in diabetic patients – Matthews
2 DIABETES
gests that intensive glycemic control achieved fast and late in
diabetes using multiple agents might not be wise. ADVANCE
suggests that achieving such targets over several years is
not contraindicated, and there may be gains to be achieved
in the prevention of renal disease.
The VADT trial also presented its results at the American Dia-
betes Association meeting, though they were not then avail-
able in print. The trial ran for about 6 years, but the numbers
of patients were few, and it was not surprising that there was
no differential in the cardiovascular outcome. Essentially, the
trial was under powered—1792 subjects14 followed for “5 to
7” years.13 This was a strange error to make in view of the
known longevity of UKPDS in terms of patient years required
to produce a meaningful answer. A subgroup analysis of cal-
cification in VADT15 suggested that this was a clear marker of
CVD risk—though these data do not help us decide on the
generality of CVD risk reduction.
 UKPDS long-term follow-up
In 2008, the glycemic control debate was galvanized not only
by the presentation of the outcomes of seminal trials, but also
by the publication and simultaneous presentation of the Unit-
ed Kingdom Prospective Diabetes Study-PostTrial Monitoring
(UKPDS-PTM).16 This examined the outcome of the patients
in UKPDS 10 years after the trial had finished. It examined
the question of whether the effects of being in the intensive-
ly controlled group would dissipate with time. After the trial,
everyone was given advice about intensive control. The 3277
patients remaining in the trial were asked to attend annual
UKPDS clinics for 5 years, but no attempts were made to
maintain their previously assigned therapies. Annual ques-
tionnaires were used to follow patients who were unable to
attend the clinics, and all patients in years 6 to 10 were as-
sessed through questionnaires. For the years that followed
their inclusion in the trial, no glycemic differences were strived
for, nor seen. The null hypothesis was that with no differences
in treatment, the differences in outcome would be lost. But,
far from there being a diminution of the glycemic trial effect
over the 10 years, the effects of lower incidence of pathology
were maintained, and with the advent of more events, the sta-
tistical probabilities of error declined. In the sulfonylurea-in-
sulin group, relative reductions in risk persisted at 10 years
for any diabetes-related end point (9%, P=0.04) and micro-
vascular disease (24%, P=0.001), and risk reductions for my-
ocardial infarction (15%, P=0.01) and death from any cause
(13%, P=0.007) emerged over time, as more events occurred
(Figure 3). In the metformin group, significant risk reductions
persisted for any diabetes-related end point (21%, P=0.01),
myocardial infarction (33%, P=0.005), and death from any
cause (27%, P=0.002). So, despite an early loss of glycemic
differences, a continued reduction in microvascular risk and
emergent risk reductions for myocardial infarction and death
from any cause were observed during 10 years of posttrial
follow-up.
 NEW
1.2 HR=0.88 HR=0.91
Hazard ratio
P=0.029 Any diabetes-related end point P=0.039
1.0
0.8
1.0
Hazard ratio
0.8
0.6 HR=0.84 Myocardial infarction HR=0.85
P=0.052 P=0.014
1997 1999 2001 2003 2005 2007
Year
Figure 3. Hazard ratios (intensive vs conventional treatment) for
poststudy monitoring in UKPDS.
During this period, the glycemic control of the two groups converged, so that
there was no significant difference in glycemic exposure. Upper panel shows data
for any diabetes-related end point and lower panel for myocardial infarction.
Abbreviations: UKPDS, United Kingdom Prospective Diabetes Study.
Clinical implementation
How do these data help in making decisions about what we
should do in clinical practice? It is paradoxical that it has tak-
en the UKPDS-PTM 20-year duration trial and a 10-year post-
trial follow-up to establish that early intervention in glycemic
control is worthwhile. Is it worth intervening after 8 or 10 years
of indifferent control? The answer seems to be “yes,” but we
need to add particular caveats. ACCORD teaches us that very
sudden changes in glycemia in the elderly may do more harm
than good, while ADVANCE suggests that even if cardiovas-
cular disease cannot be diminished in the short term, then one
can at least get gains from less renal pathology.
What agents should one use? The peroxisome proliferator-
activated receptor γ (PPARγ) agonist pioglitazone has emerged
as efficacious in the light of the PROACTIVE trial, but rosigli-
tazone still has to be proved to be effective in cardiovascular
outcomes. The evidence tends to point in the other direction.
References
1. Meinert CL, Knatterud GL, Prout TE, Klimt CR. A study of the effects of hypo-
glycemic agents on vascular complications in patients with adult-onset dia-
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2. Leibel B. An analysis of the University Group Diabetes Study Program: data re-
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3. UKPDS Group. UK Prospective Diabetes Study VIII: Study design, progress
and performance. Diabetologia. 1991;34:877-890.
4. UKPDS Group. Effect of intensive blood-glucose control with metformin on
complications in overweight patients with type 2 diabetes (UKPDS 34). UK Pros-
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A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES
What about sulphonylureas? Despite the debates dating back
to the UGDP, and the fear that β-cell failure might be affect-
ed, the sulfonylureas have continued to stand the test of time.
There was no detrimental signal from UKPDS or from UKPDS-
PTM,16 and ADVANCE shows that gliclazide modified release
can be an effective late intervention. And what about insulin?
UKPDS used insulin as one of its randomized interventions,
and there was no suggestion that this policy was unsafe or
had detrimental outcomes. What about the new analogue
insulins? The Outcome Reduction with an Initial Glargine In-
tervention (ORIGIN) trial 17 will report soon on CV outcome in
a trial of people aged over 50 years with evidence of cardio-
vascular disease and with impaired fasting glucose, impaired
glucose tolerance, or newly detected or established diabetes
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cose of 5.3 mmol/L or less in the intensive group.
What about hypoglycemia? Here, I think we are closer to real
answers. ACCORD had a very high rate of hypoglycemia, and
there are many rational reasons to suppose this to be dan-
gerous in the elderly. So, we need to take new stock of this as
a real risk to life as well as to quality of life. Hypoglycemia in
the elderly may lead to internal pathology (the myocardium is
unlikely to function well) and will certainly cause threatening
events related to falls, aspiration pneumonia, accidents, for-
getfulness, and other significant risks.
Conclusions
All the trial data suggest that hyperglycemia is a risk for car-
diovascular disease and should be lowered if possible. The
targets for glycemia are for HbA1c lower than 7.5%, and may
be nearer 6.5%, if achieved slowly and without dangerous
hypoglycemia.
Finally, one should remember that diabetes cannot be treat-
ed simply as a disease of abnormal glucose. The trial data are
strongly indicative that lipids and blood pressure18 should
be treated in parallel, and the Steno 219,20 trial—a trial of mul-
tiple intervention care-packages—suggests real benefits from
this approach. 
tive observational study. BMJ. 2000;321:405-412.
7. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of
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(PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised
controlled trial. Lancet. 2005;366:1279-1289.
8. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction
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myocardial infarction and cardiovascular death. Ann Intern Med. 2007;147:
578-581.
10. Yamasaki Y, Kawamori R, Wasada T, et al; AD-4833 Glucose Clamp Study
Group. Pioglitazone (AD-4833) ameliorates insulin resistance in patients with
NIDDM. Tohoku J Exp Med. 1997;183:173-183.
11. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and
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12. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose low-
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on glycemic control and complications in diabetes mellitus type 2: Veterans Af-
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15. Reaven PD, Emanuele N, Moritz T, et al. Proliferative diabetic retinopathy in
type 2 diabetes is related to coronary artery calcium in the Veterans Affairs Dia-
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16. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up
of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-
1589.
17. Gerstein H, Yusuf S, Riddle MC, Ryden L, Bosch J; Origin Trial Investigators. Ra-
tionale, design, and baseline characteristics for a large international trial of car-
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26-32.
18. UKPDS Group. Effect of intensive blood-glucose control with metformin on
complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet.
1998; 352:854-865.
19. Gaede P, Valentine WJ, Palmer AJ, et al. Cost-effectiveness of intensified versus
conventional multifactorial intervention in type 2 diabetes: Results and projec-
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37(suppl 1):76-82.

Keywords: trial; type 2 diabetes; cardiovascular disease; gliclazide; insulin; rosiglitazone; pioglitazone; ADVANCE

PRISE EN CHARGE DE LA BAISSE DE LA GLYCÉMIE CHEZ LES DIABÉTIQUES :

IMPLICATIONS DE L’ ÉTUDE ADVANCE
Des études à grande échelle ont cherché à savoir si l’optimisation du contrôle glycémique pouvait améliorer l’évo-
lution du diabète de type 2. Deux grandes études du XX e siècle ont été à l’origine de controverses: l’étude UGDP
(Universities Group Diabetes Program) émit des doutes sur l’efficacité du tolbutamide, tandis que l’étude UKPDS
(United Kingdom Prospective Diabetes Study) rapportait des résultats équivoques sur l’infarctus du myocarde. Ces
dernières années, de nombreuses études reconnues ont donné leurs conclusions, comme l’étude PROACTIVE
(PROspective pioglitAzone Clinical Trial In macroVascular Events), l’étude ADVANCE (Action in Diabetes and Vascular
disease : PreterAx and DiamicroN MR Controlled Evaluation), l’étude ACCORD (Action to Control CardiOvascular
Risk in Diabetes), l’étude VADT (Veterans Affairs Diabetes Trial), l’étude Steno 2 et l’étude UKPDS-PTM (United King-
dom Prospective Diabetes Study-Post Trial Monitoring). Des études en cours comme l’étude RECORD (Rosiglitazone
Evaluated for Cardiac Outcomes and Regulation of glycemia in Diabetes) et l’étude ORIGIN (Outcome Reduction
with an Initial Glargine Intervention), devraient nous apporter des réponses supplémentaires. Certaines questions ont
d’ores et déjà trouvé réponse. Ainsi, nous sommes désormais convaincus de l’intérêt d’un contrôle précoce et in-
tensif de la glycémie. Toutefois certaines questions restent encore à éclaircir concernant des divergences d’inter-
prétation ainsi que quelques incertitudes sur le choix des produits.

250 MEDICOGRAPHIA, Vol 31, No. 3, 2009 ADVANCE and the management of glucose lowering in diabetic patients – Matthews

‘‘ Target organ damage in hy-
pertension and diabetes is most-
ly due to an effect on the arterial
tree. The major arterial changes
are increased stiffness of large ar-
teries, endothelial dysfunction, and
remodeling of small arteries and
capillaries. Together, this vascular
syndrome causes cardiovascular
morbidity and mortality.”
Harry A. J. STRUIJKER-
BOUDIER, PhD
Dept of Pharmacology
and Toxicology
Maastricht University
Maastricht
THE NETHERLANDS
Address for correspondence:
Prof Harry A. J. Struijker-Boudier,
Dept of Pharmacology and
Toxicology, Maastricht University,
PO Box 616, 6200 MD, Maastricht,
The Netherlands
(e-mail: h.struijkerboudier@
farmaco.unimaas.nl)
www.medicographia.com
Micro- and macrocirculation in diabetes and hypertension – Struijker-Boudier
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES
The burden of vascular disease
in diabetes and hypertension:
from micro- to macrovascular
disease–the “bad loop”
b y H . A . J . S t r u ij ke r- B o u d i e r,
The Netherlands
H
ypertension and diabetes often coexist in the elderly population. Both
are risk factors for atherosclerotic disease. Furthermore, they affect
the same target organs—heart, brain, and kidney—causing subse-
quent cardiovascular morbidity and mortality. Target organ damage is mostly
due to an effect on the arterial tree. The arterial tree consists of three com-
partments with important structural and functional differences. The most prox-
imal part contains elastic arteries with a diameter >2 mm. The more distal ar-
terial compartment contains muscular arteries with a diameter of 150 µm to
2 mm. The third compartment is the microcirculation, with arterioles ranging
from 8 to 150 µm. Both hypertensive and diabetic patients have increased
large artery stiffness. In hypertension, increased blood pressure per se increas-
es arterial stiffness. Moreover, changes in the extracellular matrix contribute
to the increased stiffness. In diabetics, endothelial dysfunction is an important
pathogenic mechanism and vascular effects of advanced glycation end prod-
ucts (AGEs) also contribute. Remodeling of the structure of the small arteries
is a common feature of hypertension and diabetes. In hypertension, eutroph-
ic inward remodeling is the major change, in contrast with hypertrophic remod-
eling in diabetes. With regard to microcirculation, microvascular rarefaction
is the major vascular event in hypertension and diabetes. Hypertension and
diabetes are characterized by a vascular syndrome that can be described as
a “bad loop.” This “bad loop” starts with microvascular damage, which caus-
es capillary and small arteriolar rarefaction. This leads to increased arterial
wave reflections in the macrocirculation, which cause increased large artery
stiffness and increased pulse pressure. The latter causes further damage to
the microcirculation, thus reinforcing the “bad loop.”
Medicographia. 2009;31:251-256 (see French abstract on page 256)
H
ypertension and diabetes are well-defined risk factors for atherosclerosis.
Furthermore, both hypertension and diabetes affect the same target or-
gans—heart, brain, and kidney—with subsequent cardiovascular morbidity
and mortality. Clinically, hypertension and diabetes often occur together, with ap-
proximately 80% of diabetics also being hypertensive.1 A common denominator of
the pathogenic mechanisms in hypertension and diabetes is the vascular tree. Both
hypertension and diabetes affect the vascular tree at various levels. The aim of this
contribution is to review the major changes in vascular function and structure in hy-
pertensive and diabetic patients and to provide a hypothesis on the common caus-
es of both diseases.
MEDICOGRAPHIA, Vol 31, No. 3, 2009 251
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE
The various segments of the vascular tree
Although the veins are an important site for the control of
body fluid volumes and cardiac output, the major focus of
this contribution is on the arterial and capillary segments of
the vascular tree. The arterial tree consists of three segments
(Figure 1). The most proximal part contains elastic arteries with
a diameter >2 mm. The more distal arterial compartment con-
tains muscular arteries with a diameter of 150 μm to 2 mm.
The third compartment is the microcirculation, with arterioles
ranging from 8 to 150 μm.
The basic architecture of arteries is usually described in terms
of the cross-sectional arrangement of cells and extracellu-
lar matrix. The latter consists, within the media, of lamellae
of elastic material with intervening layers of vascular smooth
Macro- and microvessels
Proximal arterial compartment Distal arterial compartment
Elastic arteries
Diameter >2 mm
Endothelium + ++
Medial layer ++
Function Conduit; compliance
Figure 1. The three segments of the arterial tree.
muscle (VSM) cells, collagen fibers, and ground substance.2
However, the distribution of elastin and collagen varies marked-
ly along the longitudinal aortic axis.3 In the proximal part of the
aorta, elastin is the predominant component, whereas in the
distal aorta and its side branches, the collagen-to-elastin ratio is
reversed, with a predominance of collagen in peripheral mus-
cular arteries. The transition occurs rapidly over the distal 5 cm
of the thoracic aorta above the diaphragm and over a similar
distance in the branches leaving the arch of the aorta. There-
after, VSM cells largely predominate. In the microcirculation,
one or more layers of VSM cells and an endothelial cell lay-
er form the arteriolar wall. Thus, it is anatomically justified to
divide the arterial tree into three compartments. During devel-
opment, VSM cell layers of different embryonic origin clearly
reflect the differences in anatomic location.4 In the avian ab-
dominal aorta and small muscular arteries, the smooth mus-
cle cells are of mesodermal origin, whereas those of the aortic
SELECTED ABBREVIATIONS AND ACRONYMS
AGE advanced glycation end product
Cx connexin
NO nitric oxide
PP pulse pressure
VSM vascular smooth muscle
252 MEDICOGRAPHIA, Vol 31, No. 3, 2009
2 DIABETES
arch and thoracic aorta are mainly derived from the ecto-
dermal cardiac neural crest.5 The participation of VSM cells
of ectodermal origin is essential in the formation and organ-
ization of elastic laminae and tensoreceptors in the great ves-
sels.5 These changes in VSM cells as a function of distance
from the heart have been further confirmed by studies of the
chemical properties, pharmacological sensitivities, and gene
expression patterns of elastin and collagen along the aorta.6,7
VSM cells in the microcirculation have a different origin. The
formation of microvascular networks is the result of a com-
plex process of angiogenesis which takes place during em-
bryogenesis, but also, thereafter, under circumstances of hy-
poxia, viz, tissue ischemia.8 Furthermore, recent data indicate
that newborn sympathetic neurons distinguish and choose be-
tween distinct vascular trajectories to innervate their appropri-
Arterioles + Capillaries
Muscular arteries Arterioles Capillaries
150 µm-2 mm 8-150 µm <8 µm
+++ ++++
++ + 0
Compliance; resistance Resistance Exchange
ate end organs.9 Differences in origin may explain why certain
classes of vasodilators (for instance, calcium channel block-
ers or α-adrenoceptor antagonists) act differently on proximal
VSM cells compared to more distally located VSM cells.
The characteristics and amounts of elastin and collagen are
to a large degree determined at a very young developmental
stage and, thereafter, remain quite stable because of a very
low turnover. Nevertheless, the proportion of elastin and of
collagen type I and type III differs markedly between various
species and has a substantially differential mechanical ef-
fect on stiffness and distensibility of the vessel wall.10 In addi-
tion, several neurohormonal factors, particularly those related
to the angiotensin II and aldosterone systems, may modulate
collagen accumulation.11 Collagen may also be subjected to
important chemical modifications, such as breakdown, cross-
linking or glycation, resulting in marked changes in stiffness.12
Finally, in central conduit arteries, large amounts of collagen
are observed in the adventitia, thus contributing to altered ar-
terial mechanical properties. Collagen is principally responsi-
ble for the discontinuities of the vessel wall, mainly at vessel
bifurcations. It greatly modifies arterial rigidity and the transit
of wave reflections, thereby increasing thoracic aorta pulse
pressure (PP). In turn, the increased cyclic stress causes frag-
mentation and fracture of elastin and also causes calcifica-
tion, particularly in the elderly.
Micro- and macrocirculation in diabetes and hypertension – Struijker-Boudier
 NEW A D VA N C E S
Extracellular matrix is responsible for the passive mechani-
cal properties of the arteries, particularly in the aorta and its
main branches. In a cylindrical vessel, when the transmural
pressure rises, a curvilinear pressure-diameter curve ensues,
primarily caused by the effects of elastin at low pressure and
recruitment of collagen fibers at high pressure.3,13 Neverthe-
less, other molecules, through their role in cell-cell and cell-
matrix attachments, may contribute to the three-dimensional
repartition of mechanical forces within the arterial wall.14-18 An
illustrative example is given by the role of the different connex-
in (Cx) isotypes along the aortic axis. In rat proximal elastic
arteries, the main smooth muscle cell type consists of desmin-
negative cells with high levels of Cx43, whereas in small to
medium muscular arteries, the main cell type is desmin-pos-
itive cells, with low levels of Cx43.15 In mice lacking desmin,
isobaric carotid stiffness is increased in association with en-
hanced vessel wall viscosity.16 In rat models, an increased
sodium diet is associated with increased isobaric systemic
stiffness and reduced aortic proteoglycans.17 On the other
hand, chronic aldosterone excess produces increased iso-
baric carotid stiffness and arterial fibronectin, a process re-
versed by the aldosterone antagonist eplerenone.18
Finally, VSM cells do not represent a homogenous popula-
tion. For the same genomic background, they may have dif-
ferent mixtures of phenotypes, not only with contractile and
synthetic, but also with proliferative and apoptotic behav-
ior.12,19 The relative occurrence of each of the phenotypes de-
pends not only on age, but also on location in the vascular
tree and prevailing (pathological) conditions. Contractile prop-
erties, which are mainly expressed in the distal arterial com-
partment, are responsible for the active mechanical properties
of conduit vessels.3 Changes in VSM tone may occur either
directly or through signals arising from endothelial cells. The
endothelium is a source of substances, particularly nitric ox-
ide (NO), and of signal transduction mechanisms that influ-
ence the biophysical properties of conduit arteries. NO is the
principal mediator, dilating larger arteries more than smaller
arteries.3,13 Whereas the role of flow- and endothelium-de-
pendent dilation is not restricted to a particular vessel cate-
gory, the role of mediators arising from the endothelium pre-
dominates in muscular distal arteries.20,21 In such vessels, the
site and the pattern of wave reflections22 are influenced by
the local differential effects of NO and vasoconstrictive (ie, nor-
adrenaline, angiotensin, and endothelin) compounds.21 Re-
search that relates arterial stiffness, the reflectance properties
of the arterial system, and VSM tone is just emerging and may
greatly contribute to our knowledge on the mechanisms of
(systolic) hypertension.
Large arteries in hypertension and diabetes
Both hypertensive and diabetic patients have an increased
stiffness of their large arteries. There is abundant evidence
for increased arterial stiffness in hypertension. The reader is
referred to a recent excellent volume of the Handbook of Hy-
Micro- and macrocirculation in diabetes and hypertension – Struijker-Boudier
IN THE T R E AT M E N T OF TYPE 2 DIABETES
pertension 23 for a detailed discussion of many studies that
have been performed in this field. Even in the early stage of
hypertension, there is evidence for reduced large artery com-
pliance.24-27 In children, this hemodynamic pattern is frequent-
ly associated with being overweight and changes in wave
reflections.28,29 Reduced arterial compliance in established
hypertension cannot be attributed entirely to elevated blood
pressure. Both increased smooth muscle tone and a changed
wave reflection have been held responsible for reduced ar-
terial compliance.23 Using local echotracking techniques, sev-
eral authors have shown that reduced compliance is con-
fined to central arteries (thoracic and abdominal aorta and
carotid artery). In muscular arteries (brachial, radial, and femoral
arteries), normal values were observed.30,31 With aging, the in-
crease in systolic blood pressure is more pronounced than
in diastolic pressure. This is caused by a reduction of arterial
compliance in older hypertensive subjects.
Changes of arterial stiffness in diabetes have been reviewed
by Stehouwer and Ferreira.32 Recent studies investigating the
association between both type 1 and type 2 diabetes and
arterial stiffness have consistently shown that these patients
have stiffer arteries than nondiabetic subjects. In both groups
of patients, arterial stiffness precedes clinical cardiovascular
disease. In type 1 diabetes, increased pulse pressure, a com-
mon marker of arterial stiffness and determinant of cardiovas-
cular complications in adults older than 50 years, is already
present in patients in their early thirties.32 In type 2 diabetes,
macrovascular changes also begin at the prediabetic stage.32
These data support the concept that diabetes, in part, has a
vascular etiology.
Several mechanisms have been implicated in the diabetes-as-
sociated increase in arterial stiffness. A recent study showed
that glycemia was the major determinant of arterial stiffness
in diabetic patients.33 Hyperglycemia is a notorious cause of
endothelial dysfunction. Many studies have consistently shown
impaired dilatation in response to endothelium-dependent ag-
onists in diabetics.34,35 It has been suggested that the mech-
anism of endothelial dysfunction is based on increased inac-
tivation of nitric oxide by either oxygen-derived free radicals
or advanced glycation end products (AGEs).
An alternative or additional mechanism of large artery stiff-
ness in diabetes is the AGE-related stiffening of collagen in the
vessel wall. Evidence for such a mechanism has been de-
rived from studies with drugs that interfere with the forma-
tion of these glycosylated vessel wall molecules.23
Microcirculation in hypertension and diabetes
At the level of small arteries, there are similarities, but also
differences between hypertensive and diabetic subjects. In
both pathologies, small arteries remodel. The majority of avail-
able data indicate that, in patients with essential hypertension,
small arteries show a greater media thickness and a reduced
MEDICOGRAPHIA, Vol 31, No. 3, 2009 253
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE
lumen and external diameter (with an increased media-to-lu-
men ratio), without any significant change in the total amount
of wall tissue.36 Therefore, the major part of the structural
changes observed in these patients is the consequence of
inward eutrophic remodeling without net cell growth. Recent
data suggest that chronic vasoconstriction may lead to eu-
trophic remodeling.37,38 In addition, it has been suggested that
vascular wall components move relative to each other through
a process which may be integrin-mediated.39,40
In diabetic patients, a clear increase in the media cross-sec-
tional area in small vessels has been observed, suggesting the
presence of hypertrophic remodeling.41,42 This hypertrophy
may be related to a cellular growth response to increased
levels of insulin or insulin-like growth factor 1.41 An alternative
explanation has been put forward by Schofield et al.43 These
authors propose increased wall stress resulting from impaired
myogenic response of the small arteries in diabetes as a pos-
sible stimulus for hypertrophic remodeling. Finally, diabetic
patients show alterations of the vascular extracellular matrix,
as suggested by the observation of an increased collagen-
to-elastin ratio in their small arteries. The increased collagen
deposition in the vessel wall may be due to the inflammatory
and profibrotic properties of several hormones that are ac-
tive in diabetics.
A final vascular site of damage in hypertension and diabetes
are the small arterioles and capillaries. Vascular resistance is
not only determined by the arteriolar diameter, but also by the
number of perfused vessels. Microvascular rarefaction may
be the result of closure of the small arterioles (functional rar-
efaction) or structural rarefaction, where the vessels are ac-
tually missing. Microvascular rarefaction has been a consis-
tent observation over many years in hypertensive patients
and animal models.44 In most vascular beds, not all microves-
sels are perfused at any one time; the fraction of nonperfused
vessels constitutes a reserve that may be called upon un-
der conditions of high metabolic demand. Progressive non-
perfusion can lead to structural loss of vessels, analogous to
the progression of active vasoconstriction in structural remod-
eling of small arteries, as discussed before.
Histological analysis of skeletal muscle biopsy samples re-
veals capillary rarefaction in subjects with type 2 diabetes.45
Histological capillary density is inversely related to fasting
plasma glucose and fasting insulin levels and is positively re-
254 MEDICOGRAPHIA, Vol 31, No. 3, 2009
2 DIABETES
lated to insulin sensitivity in nondiabetic individuals.46 Micro-
vascular permeability to large molecules, such as albumin, is
increased in diabetes, a process that is linked to hypergly-
cemia and oxidative stress.47
Microvascular rarefaction has been consistently reported in
the myocardium of hypertensives and diabetics. The func-
tional consequence is a reduced coronary flow reserve. Re-
duced maximal blood flow is probably related to structural
abnormalities in the coronary microcirculation, although func-
tional factors, including endothelial dysfunction, may also con-
tribute.48
The bad loop
The evidence discussed above suggests that hypertension
and diabetes share at least two pathogenic mechanisms: de-
creased microcirculatory tissue perfusion and increased large
artery stiffness. We recently proposed that impaired tissue
perfusion underlies much of the tissue and organ dysfunction
associated with chronic conditions, including hypertension,
diabetes, and obesity.44 Figure 2 summarizes how the various
Increased
wave reflection
Large artery Capillary
stiffness rarefaction
Increased Microvascular
pulse pressure damage
Figure 2. The “bad loop” vascular changes in hypertension and
diabetes.
segments of the vascular system interact to create a vicious
cycle. In healthy individuals, this loop is not active. During ag-
ing, the loop may become progressively active, thus explain-
ing the high incidence of hypertension and diabetes in the
elderly. Once the loop becomes active, it slowly progresses,
unless drugs or diets are given to interfere. The ideal drug or
diet should target both the macro- and microvascular abnor-
malities in this vascular syndrome. 
Micro- and macrocirculation in diabetes and hypertension – Struijker-Boudier
 NEW A D VA N C E S
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hypertension; diabetes
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IN THE T R E AT M E N T OF TYPE 2 DIABETES
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terminant of albumin permeability in diabetic microcirculation: the role of mu-
calpain. Diabetes. 2007;56:1842-1849.
48. Buus NH, Bottcher M, Jorgensen CG, et al. Myocardial perfusion during long-
term angiotensin-converting enzyme inhibition of beta-blockade in patients with
essential hypertension. Hypertension. 2004;44:465-470.
MEDICOGRAPHIA, Vol 31, No. 3, 2009 255
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

LE FARDEAU DE LA MALADIE VASCULAIRE DANS LE DIABÈTE ET L’HYPERTENSION :

LE « CERCLE VICIEUX » DE LA PATHOLOGIE MICROVASCULAIRE À MACROVASCULAIRE
Diabète et hypertension, facteurs de risque de maladie athéroscléreuse, coexistent souvent chez les personnes
âgées, touchant en outre les mêmes organes cibles (cœur, cerveau, rein), et provoquant ainsi morbidité et mortalité
cardio-vasculaires. La lésion des organes cibles est due principalement à un effet sur l’arbre artériel, composé de
trois compartiments aux différences fonctionnelles et structurales importantes. La partie la plus proximale renferme
des artères élastiques d’un diamètre supérieur à 2 mm. Le compartiment artériel le plus distal renferme des artères
musculaires de 150 μm à 2 mm de diamètre. La microcirculation constitue le troisième compartiment avec des ar-
térioles de 8 à 150 μm. Les patients diabétiques et hypertendus présentent tous deux une augmentation de la rigi-
dité des grosses artères. Dans l’hypertension, c’est l’augmentation de la pression artérielle elle-même qui augmente
la rigidité artérielle, majorée de plus par des modifications de la matrice extracellulaire. Chez les diabétiques, la dys-
fonction endothéliale est un important mécanisme pathogène, auquel contribuent également les effets vasculaires
des produits de glycation avancée (AGE). Le remodelage de la structure des petites artères est un phénomène cou-
ramment observé dans l’hypertension et le diabète. Dans l’hypertension, le remodelage eutrophique profond est le
changement principal, contrairement au remodelage hypertrophique du diabète. Au niveau de la microcirculation, la
raréfaction microvasculaire est l’événement vasculaire majeur chez les patients atteints d’hypertension et de dia-
bète, ces deux affections étant caractérisées par un syndrome vasculaire pouvant être décrit comme un « cercle
vicieux ». Ce « cercle vicieux » commence avec des lésions microvasculaires qui provoquent une raréfaction des ca-
pillaires et des petites artérioles. Il en résulte une majoration de la réflexion de l’onde artérielle dans la macrocircu-
lation, induisant une augmentation de la rigidité des grosses artères et de la pression pulsée. Cette dernière en-
traîne finalement des lésions supplémentaires de la microcirculation. Ainsi est entretenu le « cercle vicieux ».

256 MEDICOGRAPHIA, Vol 31, No. 3, 2009 Micro- and macrocirculation in diabetes and hypertension – Struijker-Boudier

‘‘ The interaction of AGEs and
their receptors (RAGEs) plays a
major role in the development
and progression of diabetic CVD
through deleterious effects in-
cluding oxidative stress and in-
flammatory responses. Prevention
of AGE formation is feasible, in
particular by optimizing glycemic
control. In addition, some oral
antidiabetic agents may directly
counteract AGE-induced cellular
damage. Drug treatments reduc-
ing the deleterious effects of the
AGE-RAGE interaction are being
developed and hold promise.”
Piero MARCHETTI, MD, PhD
Department of Endocrinology
and Metabolism
University of Pisa
Pisa, ITALY
Address for correspondence:
Department of Endocrinology and
Metabolism, Cisanello Hospital,
via Paradisa 2, 56124 Pisa, Italy
(e-mail: marchant@immr.med.unipi.it)
www.medicographia.com
AGEs and RAGEs in diabetic vascular disease – Marchetti
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES
Advanced glycation
end products (AGEs) and
their receptors (RAGEs)
in diabetic vascular disease
b y P. M a rc h e t t i , I t a l y
I
ncreasing evidence demonstrates that advanced glycation end products
(AGEs) play a pivotal role in the development and progression of diabetic
vascular damage. AGEs are generated as a result of chronic hyperglyce-
mia. Then, following the interaction with receptors for advanced glycation end
products (RAGEs), a series of events leading to vessel damage are elicited and
perpetuated, which include oxidative stress, increased inflammation, and en-
hanced extracellular matrix accumulation. Whereas targeting glycemic con-
trol and treating additional risk factors, such as obesity, dyslipidemia, and hy-
pertension, are mandatory to reduce chronic complications and prolong life
expectancy in diabetic patients, drug therapy tailored to reducing the delete-
rious effects of the AGE-RAGE interaction is being actively investigated and
showing signs of promise.
Medicographia. 2009;31:257-265 (see French abstract on page 265)
A
ccelerated atherosclerosis is the leading cause of morbidity and mortality in
patients with diabetes.1 Several mechanisms, including endothelial cell dam-
age, platelet activation and aggregation, hypercoagulability, and impaired
fibrinolysis, are involved in the pathogenesis of a thrombogenic diathesis in diabetes.1
Among various biochemical pathways implicated in diabetic vascular complications,
the process of formation and accumulation of advanced glycation end products
(AGEs) and their mode of action play a major role.2-4 AGEs are generated in the di-
abetic milieu as a result of chronic hyperglycemia and enhanced oxidative stress.
Then, via pathways also involving receptor-dependent signals, they promote the de-
velopment and progression of cardiovascular disease. These compounds interact
with receptors, such as RAGEs (receptors for advanced glycation end products),
to induce oxidative stress, increase inflammation by promoting nuclear factor-κB
(NFκB) activation, and enhance extracellular matrix accumulation.5-7 These biolog-
ical effects translate into accelerated plaque formation and increased cardiac fibro-
sis, with consequent effects on cardiac function. In this article, we will deal with the
biology of AGEs and RAGEs, with particular emphasis on their role in diabetes. Strate-
gies to reduce the deleterious effects of the AGE-RAGE interaction will also be dis-
cussed.
Advanced glycation end products (AGEs)
Advanced glycation end products (AGEs) are modifications of proteins or lipids that
become nonenzymatically glycated and oxidized after contact with aldose sugars.
In other words, they are the result of a chain of chemical reactions which follow an
MEDICOGRAPHIA, Vol 31, No. 3, 2009 257
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

initial glycation reaction. The interme-

diate products are known as Schiff
base, Amadori, and Maillard prod-
ucts, after the researchers who first
described them. Initially, glycation in-
volves covalent reactions between
free amino groups of amino acids,
such as lysine, arginine, or protein ter-
minal amino acids and sugars (glu-
cose, fructose, ribose, etc), to create,
first, the Schiff base and then Ama-
dori products, of which the best
known are HbA1c (Figure 1) and fruc-
tosamine (fructoselysine). Addition-
al reactions occur successively.

AGE formation from fructoselysine

involves the nonoxidative dissocia-
tion of fructoselysine to form new re-
active intermediates that again mod-
ify proteins to form AGEs of various
Figure 1. Formation of glycated hemoglobin A1c (HbA1c ).
different chemical structures (Fig-
HbA1c is an Amadori product and is formed through the intermediate Schiff base step.
ure 2). Alternatively, fructoselysine
decays and releases its carbohydrate moiety either as glu- Accumulation of AGEs in the ECM occurs on proteins with a
cose or as the more reactive hexoses, such as 3-deoxyglu- slow turnover rate, with the formation of cross-links that can
cosone, which themselves may modify proteins. In addition, trap other local macromolecules. In this way, AGEs alter the
it has recently been found that glucose can auto-oxidize to properties of the large matrix proteins collagen, vitronectin,
form reactive carbonyl compounds (glyoxal and methylgly- and laminin. AGE cross-linking on type I collagen and elastin
oxal) which can react with proteins to form glycoxidation causes an increase in the area of ECM, resulting in increased
products (Figure 2). In addition to this, products of oxidative stiffness of the vasculature. Glycation results in increased syn-
stress, such as peroxynitrite, can also induce the formation of thesis of type III collagen, type V collagen, type VI collagen,
carboxymethyl lysine by oxidative cleavage of Amadori prod- laminin, and fibronectin in the ECM, most likely via upregula-
ucts and/or the generation of reactive dicarbonyl compounds tion of transforming growth factor-β pathways. Formation of
from glucose (Figure 2). Thus, AGEs can arise from glucose AGEs on laminin results in reduced binding to type IV collagen,
and lipids through several, partially intermingling reactions. reduced polymer elongation, and lower binding of heparan sul-
Once formed, they may damage cellular structures via a num- fate proteoglycan. Glycation of laminin and type I and type IV
ber of mechanisms, including the formation of cross-links be- collagens, key molecules in the basement membrane, causes
tween key molecules in the basement membrane of the extra- inhibited adhesion to endothelial cells for both matrix glyco-
cellular matrix (ECM) and the interaction of AGEs with RAGEs proteins. In addition, it has been suggested that AGE forma-
on cell surfaces, thus altering cellular functions.2-7 tion leads to a reduction in the binding of collagen and heparan
to the adhesive matrix molecule vitronectin. AGE-induced al-
terations of vitronectin and laminin may explain the reduction
SELECTED ABBREVIATIONS AND ACRONYMS
in binding of heparan sulfate proteoglycan, a stimulant of oth-
AGE advanced glycation end product er matrix molecules in the vessel wall, to the diabetic base-
DCCT Diabetes Control and Complications Trial ment membrane. As for the role of lipids, glycated low-den-
ECM extracellular matrix sity lipoprotein (LDL) reduces nitric oxide (NO) production and
LDL low-density lipoprotein suppresses uptake and clearance of LDL through its recep-
MAPK mitogen-activated protein kinase tor on endothelial cells.
NFκB nuclear factor-κB
NO nitric oxide It must also be kept in mind that AGEs can be absorbed
PKC protein kinase C through diet.8 In this regard, foods high in protein and fat,
RAGE receptor for advanced glycation end products such as meat, cheese, and egg yolk, are rich in AGEs, where-
ROS reactive oxygen species as those high in carbohydrates have the lowest amount of
sRAGE soluble receptor for advanced glycation end products AGEs. In addition, increased cooking temperatures, through
broiling and frying, and increased cooking times lead to an

258 MEDICOGRAPHIA, Vol 31, No. 3, 2009 AGEs and RAGEs in diabetic vascular disease – Marchetti
 NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

AGEs
Carboxymethyl lysine
Glycolysis Methylglyoxal Methylglyoxal lysine dimer
Hydroimidazolone

Schiff Amadori 3-Deoxyglucosone lysine dimer

Glucose base product
1-Deoxyglucosone
Glucospane

Fragmentation
Oxidative stress Pentosidine

Glyoxal Carboxymethyl lysine

Lipids Glycolaldehyde Glyoxal lysine dimer
Hydroimidazolone

Figure 2. Schematic representation of the formation of some common advanced glycation end products (AGEs).

increased amount of AGEs. A diet heavy in AGEs results in
proportional elevations in serum AGE levels and increased
cross-linking in patients with diabetes, whereas, conversely,
dietary AGE restriction causes a marked reduction in serum
AGEs in healthy subjects.9-11
ing. In addition to full-length RAGE, truncated forms have also
been described (due to mRNA splice variants). In particular,
one variant protein (N-truncated type) lacks the V-type im-
munoglobulin domain, but it is otherwise identical to full-length
RAGE and is retained in the plasma membrane.

Receptor for AGEs (RAGE)

RAGE is a member of the immunoglobulin superfamily of re-
ceptors. The human RAGE gene is on chromosome 6 in the
major histocompatibility complex between genes for class II
and class III. It is composed of 11 exons and a 3UTR region,
and common variants have been described.12 For example,
the Gly82Ser polymorphism in exon 3 is located in the lig-
and-binding V-domain of RAGE (see below), and has been
studied to assess its role in subjects with vascular disease.
It was found that cells bearing the Ser82 isoform displayed
higher ligand affinity resulting in increased activation of the
proinflammatory proteins TNF-α, IL-6, and MMP-9.13 In con-
trast, the –374T/A polymorphism in the promoter region of
the RAGE gene has been shown to exert protective effects.
In diabetic patients with the mutation, there was a lower in-
cidence of coronary heart disease, acute myocardial infarc-
tion, and peripheral vascular disease, and, in nondiabetic in-
dividuals, the presence of the polymorphism was associated
with a reduced risk of coronary artery disease.6,14

At the protein level, RAGE is an approximately 45-kDa pro-

tein. It has an extracellular component, consisting of two C-
type (constant) domains preceded by one V-type (variable)
immunoglobulin-like domain (Figure 3). RAGE has a single
Figure 3. Structure of the receptor for advanced glycation end
transmembrane domain followed by a cytosolic tail. The V do-
products (RAGE).
main in the N-terminus is important in ligand binding, and the Adapted from reference 6: Basta G. Atherosclerosis. 2008;196:9-21. Copy-
cytosolic tail is critical for RAGE-induced intracellular signal- right © 2008, Elsevier, Ltd.

AGEs and RAGEs in diabetic vascular disease – Marchetti MEDICOGRAPHIA, Vol 31, No. 3, 2009 259
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

However, since the V-type immunoglobulin domain is delet- Intriguingly, it has been demonstrated that activation of RAGE
ed, this RAGE form shows impaired ability to bind ligands. can promote cell survival through increased expression of the
In addition, forms of RAGE lacking both the cytosolic and antiapoptotic protein Bcl-2.15 However, whereas nanomolar
the transmembrane domains have been described. These concentrations of ligand induced trophic effects in RAGE-ex-
forms of RAGE are, therefore, secreted extracellularly, can be pressing cells, micromolar concentrations caused apoptosis in
detected in circulating blood, and are called soluble recep- a manner that appeared to depend on oxidative stress.15 For
tors for advanced glycation end products (sRAGEs).5-7 This both of these outcomes, the cytoplasmic domain of RAGE was
is of importance since sRAGEs can
bind their ligands in the circulation,
thus preventing the adverse intracel-
lular events of the AGE-RAGE axis
(see below).

It has to be kept in mind, however,

that RAGEs also bind ligands other
than AGEs.5-7 Shortly after its dis-
covery, structural analysis of the lig-
and-RAGE interaction revealed that
the receptor recognized three-dimen-
sional structures, such as β sheets
and fibrils, rather than specific amino
acid sequences (ie, primary struc-
tures). As a matter of fact, RAGEs bind
amyloid-β peptide (which accumu-
lates in Alzheimer’s disease) and amy-
loid A (which accumulates in systemic
amyloidosis). Further ligands of RAGE
are S100/calgranulins, a family of
Figure 4. Schematic representation of some of the intracellular events following the AGE-
closely related calcium-binding poly- RAGE interaction.
peptides that accumulate extracel- Abbreviations: AGE, advanced glycation end product; IL-6, interleukin 6; MAPK, mitogen-activated protein kinase;
lularly at sites of chronic inflamma- NADPH, reduced nicotinamide adenine dinucleotide phosphate; NFκ B, nuclear factor-κ B; TNF-α , tumor necrosis
factor α ; RAGE, receptor for advanced glycation end products, ROS, reactive oxygen species; VCAM-1, vascular
tion. An additional proinflammatory cell adhesion molecule 1; VEGF, vascular endothelial growth factor.
ligand of RAGE is the DNA-binding
protein HMGB1 (amphoterin), which is released by cells un- required, as cells lacking the cytosolic tail were unresponsive.
dergoing necrosis. Finally, RAGEs also interact with surface After being highly expressed during embryonic development,
molecules on bacteria and leukocytes. Thus, RAGEs have RAGE is downregulated in most organs during normal life.
a large repertoire of ligands, making this receptor crucial at With aging, RAGE expression increases again, possibly due
the crossroad between diabetes, inflammation, and vascular to the accumulation of RAGE ligands, which upregulate re-
disease. ceptor expression. In the cases of diabetes, inflammation,
and atherosclerosis, there is marked induction of RAGE due
Cellular effects of the AGE-RAGE interaction to the action of its ligands and to several mediators from ac-
RAGE is expressed in many tissues and is most abundant in tivated inflammatory cells.5-7,16,17 In turn, the binding of ligands
the heart, lung, skeletal muscle, and vessel wall. In addition, it to RAGE induces further upregulation of the receptor (posi-
is present in monocytes/macrophages and lymphocytes. In tive feedback), leading to a vicious circle. Unsurprisingly, one
vessels, it is located in the endothelium and in smooth muscle of the locations where RAGE expression is enhanced is in the
cells. Physiologically, the receptor might play a role in devel- diabetic atherosclerotic plaque (particularly at the vulnerable
opmental processes, at least as shown in a few experimental regions of the plaque and in macrophages), where it colo-
models. For example, RAGE activation contributes to axonal calizes with cyclooxygenase 2, microsomal prostaglandin E2,
sprouting that accompanies neuronal development, while re- and metalloproteases.
duction of functional regeneration of the sciatic nerve occurs
after blockade of RAGE.15,16 However, RAGE-/- mice demon- The most important pathological consequence of RAGE in-
strate neither obvious neuronal deficits nor overt behavior ab- teraction with its ligands is the activation of several intracel-
normalities, indicating that RAGE may contribute to neuronal lular pathways, leading to the induction of oxidative stress
development, but that there are redundant systems that sub- and a broad spectrum of signaling mechanisms, schematical-
stitute for this receptor in its absence.16 ly represented in Figure 4. The interactions lead to prolonged

260 MEDICOGRAPHIA, Vol 31, No. 3, 2009 AGEs and RAGEs in diabetic vascular disease – Marchetti
 NEW A D VA N C E S
inflammation, mainly as a result of the RAGE-dependent ex-
pression of proinflammatory cytokines and chemokines. In the
vasculature, the first pathological consequence of RAGE in-
teraction with its ligands is the induction of increased intra-
cellular reactive oxygen species (ROS), the generation of which
is linked, at least in part, to the activation of the NAD(P)H-ox-
idase system. In addition, in endothelial cells, mitochondrial
sources of ROS are also involved, following the AGE-RAGE
interaction. Experimental evidence demonstrates that RAGE
dependent modulation of gene expression and cellular prop-
erties depends upon signal transduction. Based on the inten-
sity and duration of stimulation, diverse signaling pathways may
be triggered (Figure 4), including p21ras, erk1/2, mitogen-ac-
tivated protein kinases (MAPKs), p38 and SAPK/JNK MAPKs,
PI3K, and the JAK/STAT pathway. The downstream conse-
quence of these changes is the activation of key transcription
factors (nuclear factor-κB [NFκB], in particular), which in turn
cause induction of molecules with damaging actions on the
cells (Figure 4). In human endothelial cells, RAGE activation
enhances the expression of adhesion molecules, including
VCAM-1, ICAM-1, and E-selectin. AGE bound to RAGE on
the endothelium also determines alterations to the surface
antithrombotic properties of flowing blood, as shown by a
reduction in thrombomodulin expression and the concomi-
tant induction of tissue factor expression that confers pro-
coagulant properties. The interaction of AGEs with RAGEs in
monocytes induces their activation to macrophages, which
manifests with the induction of platelet-derived growth factor,
insulin-like growth factor 1, and proinflammatory cytokines,
such as IL-1 and TNF-α. In addition to all this, AGE-RAGE in-
teraction promotes monocyte chemotaxis and, at the level of
smooth muscle cells, is associated with increased cellular
proliferation. Viewed together, these findings indicate that the
AGE-RAGE interaction elicits and potentiates inflammatory
responses through the enhanced generation of reactive oxy-
gen species, proinflammatory adhesion molecules, and cyto-
kines, causing continued amplification of inflammatory events.
AGE, RAGE, and diabetes
It has long been recognized that increased HbA1c (a precur-
sor of AGEs) levels are associated with a higher incidence
of vascular complications and reduced life expectancy in dia-
betic patients. In addition, intervention studies to reduce HbA1c
lead to lower micro- and macrovascular lesions and a reduced
death rate over several years.18,19
Serum levels of AGEs in patients with type 2 diabetes and
coronary heart disease are higher than those in patients with-
out heart disease and correlate with the severity of the coro-
nary syndrome.3,4,20 Furthermore, AGE levels are higher in
type 2 diabetic patients with peripheral artery occlusive dis-
ease compared with those without it. Serum levels of AGE in
type 1 diabetic patients are associated with decreased iso-
volumetric relaxation time of the left ventricle, a marker of left
ventricular diastolic dysfunction.21 AGEs are also related to oth-
AGEs and RAGEs in diabetic vascular disease – Marchetti
IN THE T R E AT M E N T OF TYPE 2 DIABETES
er features of cardiovascular disease, such as carotid steno-
sis, peripheral artery occlusive disease, increased pulse pres-
sure, and a low ankle-brachial index.3,4,22 Unsurprisingly, other
studies have demonstrated that serum AGE level is a pre-
dictor for heart failure and new cardiac events.3,4 In addition,
work has shown that high AGE levels correlate with poor out-
comes, as demonstrated by adverse cardiac events in pa-
tients after cardiac surgery, prolonged ventilation times, and
longer stays in intensive care units.3,4 Finally, in diabetic pa-
tients receiving cardiac stents, an elevated level of serum AGEs
appears to be an independent risk factor for the development
of angiographic restenosis.23
In terms of relationship with life expectancy, it has been re-
ported that increased serum levels of AGE predicted in-
creased total cardiovascular and coronary mortality in wom-
en with type 2 diabetes during a follow-up period of 18 years.24
AGE level remained a strong predictor of survival even after
adjustment for confounding factors, including C-reactive pro-
tein.
Nondiabetic
Diabetic
9000 P<0.0001
8000
7000
6000
Density units
5000
4000
3000
2000
1000
0
RAGE expression
Figure 5. RAGE (receptor for advanced glycation end products)
expression is higher in plaques from type 2 diabetic patients.
Adapted from reference 27: Cipollone F, Iezzi A, Fazia M, et al. Circulation. 2003;
108:1070-1077. Copyright © 2003, American Heart Association, Inc.
At a pathological level,25,26 when atherosclerotic plaques re-
trieved from human subjects were studied, it was found that,
compared to nondiabetics, plaques from diabetic subjects
had increased RAGE expression, especially in smooth muscle
cells and in macrophages within the lesion (Figure 5).27 In a
prospective study, type 2 diabetic patients were randomized
to treatment with diet alone or with diet plus the addition of a
statin for four months before carotid endarterectomy.28 The ex-
pression of AGEs and RAGEs as well as myeloperoxidase,
NFκB, cyclooxygenase 2, and metalloproteinases 2 and 9
was significantly lower in the plaques of statin-treated patients.
Fewer macrophages, T cells, and HLA-DR–expressing cells
were noted in the lesions of these subjects. Notably, the ex-
MEDICOGRAPHIA, Vol 31, No. 3, 2009 261
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE
pression of RAGE in statin-treated, plaque-derived macro-
phages can be restored by in vitro incubation with AGEs.
Additional findings from plaques retrieved from type 2 dia-
betic patients include larger necrotic cores and a correlation
between RAGE expression on macrophages and apoptotic
smooth muscle cells.25-29 Altogether, the findings indicate that
the AGE-RAGE axis may compromise cell survival and, there-
by, promote mechanisms linked to plaque destabilization.
As mentioned above, sRAGEs bind to AGEs in the circulation
and are, therefore, capable of neutralizing the action of AGEs
on cells. Recent clinical studies have investigated the poten-
tial implications of serum sRAGE concentration in a number
of pathological conditions. The first study, upon circulating
sRAGE levels, indicated that, in age-matched male subjects
without diabetes, lower levels of plasma sRAGE were asso-
ciated with enhanced risk of angiographically detected coro-
nary artery disease.30 In another study, it was reported that in
type 1 diabetic patients circulating sRAGE levels were signif-
icantly lower than in nondiabetic subjects and were inversely
associated with the severity of some vascular complications.31
Other clinical investigations examined plasma levels of sRAGE
in relation to the components of metabolic syndrome. In one
of these reports,32 the sRAGE level was significantly lower in
diabetic patients than in nondiabetic controls and significant-
ly and inversely correlated with components of metabolic syn-
drome, including body mass index, HbA1c , indexes of insulin
resistance, and with carotid or femoral atherosclerosis. The
same authors demonstrated, in another report, that low cir-
culating sRAGE levels were predictive for cardiovascular mor-
tality in both diabetic and nondiabetic subjects with end-
stage renal disease.33 Accordingly, it has been demonstrated
that plasma sRAGE levels correlate with glycemic control, pro-
inflammatory factors, insulin resistance, and other risk factors
for cardiovascular disease.34 Thus, although the consistency
of findings is not absolute35 and more studies are needed, it
appears sRAGE is likely to have protective functions.
Therapeutic perspectives
Reducing blood glucose levels in both type 1 and type 2 di-
abetes, as documented by decreased HbA1c , remains the
most appropriate way to reduce vascular complications and
prolong patients’ life expectancy. Of course, all the other risk
factors for cardiovascular disease (in particular obesity, dys-
lipidemia, and hypertension) must be treated aggressively
as well. It is very likely that the beneficial effects of intensive
diabetic treatment occur, at least in part, through a reduction
in AGEs. In fact, when the relationships between long-term
intensive control of glycemia and indicators of skin collagen
glycation, glycoxidation, and crosslinking were examined in a
few subgroups of type 1 diabetic patients from the Diabetes
Control and Complications Trial (DCCT), intensive treatment
was associated with significant improvements in all AGE-re-
lated parameters that were studied.36 Furthermore, multiple
262 MEDICOGRAPHIA, Vol 31, No. 3, 2009
2 DIABETES
logistic regression analyses showed that diabetic microvas-
cular complications were significantly associated with mark-
ers of AGEs and that the associations generally remained sig-
nificant even after adjustment for HbA1c .
Interestingly, a few molecules already in use to treat diabetes
might have a positive impact on the AGE-RAGE pathway, be-
yond glycemic control. Metformin prevented AGE-induced
cell death and RAGE protein expression in osteoblastic cells
in culture,37 and protected Schwann cells from apoptosis in-
duced by methylglyoxal.38 In addition, the drug was able to
reduce RAGE and lectin-like oxidized receptor 1 expression in
endothelial cells exposed to high glucose levels or AGEs.39
More importantly, in women with polycystic ovary syndrome,
Control
250
AGEs
AGEs + gliclazide
200 *
Relative units
150
100
50
0
NFκB immunoreactivity
Figure 6. NFκ B activation by AGEs is reduced by the presence
of gliclazide.
*P<0.05 vs the other groups.
Abbreviations: AGE, advanced glycation end product; NFκ B, nuclear factor-κB.
Adapted from reference 43: Mamputu JC, Renier G. Diabetes Obes Metab.
2004;6:95-103. Copyright © 2004, Blackwell Publishing, Ltd.
treatment with metformin reduced AGE levels, which, in the
normotolerant group, occurred without significant changes in
body weight and metabolic parameters.40 These beneficial
actions of the drug are likely to be due, at least in part, to the
reduction of oxidative stress associated with metformin.41
Gliclazide has also been able to counteract AGE-induced
damage in several experimental settings. When bovine reti-
nal endothelial cells were incubated with AGEs,42 this caused
enhanced VEGF mRNA and protein expression, accompa-
nied by protein kinase C (PKC) activation. These changes
were prevented by PKC inhibitors, antioxidants, or gliclazide
(but not glibenclamide). In the same model, gliclazide was
shown to prevent NFκB activation (Figure 6).43 To assess
whether the molecule could interfere with glycation process-
es, bovine serum albumin was incubated with a high concen-
tration of glucose or methylglyoxal in the presence or ab-
sence of gliclazide.44 AGE production increased significantly
in untreated samples, whereas this was prevented by gli-
AGEs and RAGEs in diabetic vascular disease – Marchetti
 NEW
clazide, which has an effect similar to that of aminoguanidine,
a well-known glycation inhibitor (see below). Again, it is pos-
sible that these beneficial effects are due to the antioxidant
properties of the molecule.45 Finally, drugs acting on the renin-
angiotensin system, statins, and glitazones may also have a
protective action against the AGE-RAGE interaction, possibly
through antioxidant and/or anti-inflammatory mechanisms.46
Obviously, direct intervention on the AGE-RAGE system might
lead to new and more targeted therapeutic approaches. Mol-
ecules under investigation for possible clinical use can be
roughly subdivided into two main groups: those that prevent
the formation of AGEs and those that degrade existing AGEs.
For example, aminoguanidine is a hydrazine compound that
prevents AGE formation by interacting with derivatives of ear-
ly glycation products that are not bound to proteins. In ani-
mal models of diabetes, aminoguanidine treatment increased
arterial elasticity, decreased vascular AGE accumulation as
well as the severity of atherosclerotic plaques, and, in addi-
tion, reduced accumulation of fibronectin and laminin in the
extracellular membrane of streptozotocin-induced diabetic
rats with diabetic nephropathy.46 In a placebo-controlled, ran-
domized trial in patients with type 1 diabetes mellitus,47 amino-
guanidine caused a slower reduction in glomerular filtration
rate, diminished 24-hour urinary proteinuria and progression
of retinopathy, but it did not attenuate the time-to-doubling
of serum creatinine.
A molecule which is being actively studied is 4,5-dimethyl-3-
phenacylthiozolium chloride (ALT-711, or alagebrium), a com-
pound that breaks the crosslinks of AGEs.46 Diabetic rats treat-
ed for 4 months with ALT-711 showed reduced collagen III,
increased collagen solubility, and reduced RAGE mRNA ex-
pression compared with placebo. In addition, ALT-711 has
been shown to improve left ventricular function, to reduce
ventricular collagen, and to lengthen survival in diabetic an-
imals. Interestingly, in patients with isolated systolic hyper-
tension, ALT-711 has been reported to enhance peripheral
artery endothelial function and improve overall impedance
matching,48 and, in another study, the molecule improved total
References
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arterial compliance in old people with vascular stiffening.49
Pyridoxamine, the natural form of vitamin B6, and benfoti-
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tibodies reduced atherosclerosis in uremic mice.54 Clinical
phase 2 trials are being conceived to assess the potential of
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Accelerated chemical modification of proteins and lipids dur-
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tribute to the development and progression of diabetic vascu-
lar complications through a number of mechanisms, including
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centrations of advanced glycation end products: a marker of coronary artery
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25. Schalkwijk CG, Baidoshvili A, Stehouwer CD, van Hinsbergh VW, Niessen HW.
Increased accumulation of the glycoxidation product Nepsilon-(carboxy-
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28. Cuccurullo C, Iezzi A, Fazia ML, et al. Suppression of RAGE as a basis of sim-
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29. Burke AP, Kolodgie FD, Zieske A, et al. Morphologic findings of coronary ath-
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30. Falcone C, Emanuele E, D'Angelo A, et al. Plasma levels of soluble receptor
for advanced glycation end products and coronary artery disease in nondiabet-
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31. Katakami N, Matsuhisa M, Kaneto H, et al. Decreased endogenous secretory
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32. Koyama H, Shoji T, Yokoyama H, et al. Plasma level of endogenous secretory
RAGE is associated with components of the metabolic syndrome and athero-
sclerosis. Arterioscler Thromb Vasc Biol. 2005;25:2587-2593.
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Keywords: AGE; RAGE; diabetes; vascular disease
264 MEDICOGRAPHIA, Vol 31, No. 3, 2009
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35. Tan KC, Shiu SW, Chow WS, Leng L, Bucala R, Betteridge DJ. Association be-
tween serum levels of soluble receptor for advanced glycation end products
and circulating advanced glycation end products in type 2 diabetes. Diabetolo-
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36. Monnier VM, Bautista O, Kenny D, et al. Skin collagen glycation, glycoxidation,
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43. Mamputu JC, Renier G. Signalling pathways involved in retinal endothelial cell
proliferation induced by advanced glycation end products: inhibitory effect of
gliclazide. Diabetes Obes Metab. 2004;6:95-103.
44. Li W, Ota K, Nakamura J, et al. Antiglycation effect of gliclazide on in vitro AGE
formation from glucose and methylglyoxal. Exp Biol Med. 2008;233:176-179.
45. Del Guerra S, Grupillo M, Masini M, et al. Gliclazide protects human islet beta-
cells from apoptosis induced by intermittent high glucose. Diabetes Metab
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46. Desai K, Wu L. Methylglyoxal and advanced glycation endproducts: new ther-
apeutic horizons? Recent Pat Cardiovasc Drug Discov. 2007;2:89-99.
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formation of advanced glycation end products in diabetic nephropathy. Am J
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48. Zieman SJ, Melenovsky V, Clattenburg L, et al. Advanced glycation endprod-
uct crosslink breaker (alagebrium) improves endothelial function in patients
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50. Williams ME, Bolton WK, Khalifah RG, Degenhardt TP, Schotzinger RJ, McGill
JB. Effects of pyridoxamine in combined phase 2 studies of patients with
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605-614.
51. Stirban A, Negrean M, Stratmann B, et al. Benfotiamine prevents macro- and
microvascular endothelial dysfunction and oxidative stress following a meal
rich in advanced glycation end products in individuals with type 2 diabetes.
Diabetes Care. 2006;29:2064-2071.
52. Du X, Edelstein D, Brownlee M. Oral benfotiamine plus alpha-lipoic acid nor-
malises complication-causing pathways in type 1 diabetes. Diabetologia. 2008;
51:1930-1932.
53. Tan KC, Shiu SW, Chow WS, Leng L, Bucala R, Betteridge DJ. Association be-
tween serum levels of soluble receptor for advanced glycation end products
and circulating advanced glycation end products in type 2 diabetes. Diabetolo-
gia. 2006;49:2756-2762.
54. Bro S, Flyvbjerg A, Binder CJ, et al. A neutralizing antibody against receptor
for advanced glycation end products (RAGE) reduces atherosclerosis in ure-
mic mice. Atherosclerosis. 2008;201:274-280.
AGEs and RAGEs in diabetic vascular disease – Marchetti
 NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

PRODUITS DE GLYCATION AVANCÉE (AGE ADVANCED GLYCATION END PRODUCTS )

ET LEURS RÉCEPTEURS (RAGE RECEPTORS FOR ADVANCED GLYCATION END PRODUCTS )
DANS LA MALADIE VASCULAIRE DIABÉTIQUE
Les produits de glycation avancée (AGE) sont de plus en plus impliqués comme acteur central dans le développe-
ment et la progression des lésions vasculaires diabétiques. Les AGE résultent d’une hyperglycémie chronique. L’in-
teraction avec les RAGE provoque et perpétue des événements responsables de lésions vasculaires comme le stress
oxydatif, l’augmentation de l’inflammation et l’accumulation de protéines constitutives de la matrice extracellulaire.
La réduction des complications chroniques et la prolongation de l’espérance de vie des diabétiques passent par le
contrôle de la glycémie et le traitement des autres facteurs de risque comme l’obésité, la dyslipidémie et l’hyperten-
sion. Dans cette perspective, la recherche sur les traitements destinés à diminuer les effets délétères de l’interaction
AGE-RAGE est active et prometteuse.

AGEs and RAGEs in diabetic vascular disease – Marchetti MEDICOGRAPHIA, Vol 31, No. 3, 2009 265

‘‘ The results of ADVANCE have
shown, for the first time, that re-
ducing HbA 1c below 6.5%, (ie, a
level approximating the normal
range) using established drugs in
the routine care setting is feasible,
beneficial, and safe… there was
no deterioration in patient clinical
status and no premature cardio-
vascular or all-cause mortality, in
contrast to the ACCORD study
(Action to Control CardiOvascular
Risk in Diabetes.”
Michel MARRE, MD, PhD
Service d’Endocrinologie
Diabétologie Nutrition
Groupe Hospitalier Bichat
Claude Bernard
Paris, FRANCE
Address for correspondence:
Prof Michel Marre, Service
d’Endocrinologie Diabétologie
Nutrition, Groupe Hospitalier
Bichat - Claude Bernard,
46 rue Henri Huchard,
75722 Paris Cedex 18, FRANCE.
(e-mail: marre.michel@gmail.com)
www.medicographia.com
266 MEDICOGRAPHIA, Vol 31, No. 3, 2009
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES
How should
future guidelines implement
the results of ADVANCE?
b y M . M a r re , Fra n c e
C
urrent guidelines for patient care in type 2 diabetes rest on random-
ized controlled trials and key opinion leader opinion grounded in
clinical experience. The most recent guidelines (2006) and update
(October 2008) were a response to the emergence of new drug classes, while
the rationale for patient care continues to be informed by the United Kingdom
Prospective Diabetes Study (UKPDS), which was conducted in newly diag-
nosed type 2 diabetics recruited between 1977 and 1991 and the results of
which became available in 1998. The Action in Diabetes and Vascular disease:
PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) trial updates
the UKPDS data on the control of blood glucose (BG) and blood pressure (BP)
in the light of contemporary patient care. It also frames these data within the
high vascular risk profile that applies to the vast majority of type 2 diabetics.
The ADVANCE results support the goal of reducing BG and BP to near-nor-
mal levels using a sulfonylurea (gliclazide modified release [Diamicron MR])
and a fixed combination of perindopril/indapamide (Preterax) as first-line ther-
apy. The study shows that lowering HbA1c below 6.5% improves microvascu-
lar prognosis without increasing the risk of major hypoglycemia, weight gain,
or premature mortality. ADVANCE also supports the use of fixed combination
antihypertensive therapy, such as Preterax, to reduce BP, while recognizing
that individual patient risk profiles, rather than set BP thresholds, should in-
form clinical decisions on antihypertensive treatment.
Medicographia. 2009;31:266-271 (see French abstract on page 271)
The basis of current guidelines for type 2 diabetic patient care
T
ype 2 diabetes (T2D) is a condition defined by a degree of hyperglycemia
known to enhance microvascular risk.1 Evidence for a causal relationship be-
tween high blood glucose (BG) and microvascular risk (with particular regard
to kidney and retina) is based on three sources: follow-up studies,2 experimental med-
icine,3 and randomized controlled trials. In T2D, the case for reducing microvascular
disease by reducing BG rests on a single such trial: the United Kingdom Prospective
Diabetes Study (UKDPS).4 This was conducted in newly diagnosed diabetics three
decades ago, before HbA1c entered clinical use (baseline HbA1c was retrospectively
extrapolated from fasting BG levels). These results supported the concept of primary
intervention on BG. Thus, current guidelines for T2D care were extrapolated from data
obtained in newly diagnosed T2D patients, when we now know that abruptly reduc-
ing BG in uncontrolled type 1 diabetics with established microangiopathy can accel-
erate microvascular lesions in the initial months5 or years6 following intervention.
How should future guidelines implement the results of ADVANCE? – Marre
 NEW
A major impetus for BG control in T2D is the associated high
risk of cardiovascular (CV) disease. All traditional CV risk fac-
tors are usually elevated in T2D. However, there is no clear
causal relationship between high BG and CV disease: BG
reduction in UKPDS did not reduce the risk of stroke or CV
and all-cause mortality, although its benefit in reducing the
risk of nonfatal myocardial infarction was close to being
significant (P=0.057).4
Based on an epidemiological analysis of the UKPDS data re-
lating HbA1c levels to microvascular and CV risk and the HbA1c
level achieved in the intensive BG arm, the current American
Diabetes Association and European Association for the Study
of Diabetes (ADA/EASD) recommendation is to reduce HbA1c
to 7%.7 Other guidelines, eg, from the International Diabetes
Federation Task Force and American Association of Clinical
Endocrinologists, have proposed an upper limit of 6.5%,8,9
given the linear relationship between HbA1c achieved and CV
risk found in the epidemiological analysis of UKPDS.10 But
association is far from causation. Cohort studies in the gen-
eral population support the concept that fasting BG begins
to be associated with CV risk at values >110 mg/dL.11 The
BG interval between 110 and 126 mg/dL is associated with
higher insulin levels and concomitant increases in all CV risk
factors.12 This association between CV risk factors and dys-
glycemia is purely epidemiological. An ongoing intervention
study with the insulin analog glargine is assessing the effect
of reducing fasting BG to normal (<5 mmol/L) on CV risk re-
duction.13 UKPDS suggested that the only CV benefit in T2D
was achieved in overweight patients in the metformin arm,
by reducing weight and insulin resistance.14 Meanwhile, the
2008 ADA/EASD consensus statement remains somewhat
vague as to the best means of lowering HbA1c below 7%.15
Further studies were thus clearly needed to justify lowering
SELECTED ABBREVIATIONS AND ACRONYMS
ACCORD Action to Control CardiOvascular Risk in
Diabetes
ACE angiotensin-converting enzyme
ADA American Diabetes Association
ADVANCE Action in Diabetes and Vascular disease:
PreterAx and DiamicroN MR Controlled
Evaluation
BG blood glucose
BP blood pressure
CV cardiovascular
EASD European Association for the Study of Diabetes
HOT Hypertension Optimal Treatment
MICRO-HOPE MIcroalbuminuria, Cardiovascular and Renal
Outcomes in the Heart Outcomes Prevention
Evaluation
T2D type 2 diabetes
TZD thiazolidinedione
UKPDS United Kingdom Prospective Diabetes Study
How should future guidelines implement the results of ADVANCE? – Marre
A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES
HbA1c below 6.5%, an ambitious goal in subjects already at
risk and with several years of T2D already behind them.
Another major determinant of microvascular risk, and CV risk
in general, is high blood pressure (BP). Current recommenda-
tions to reduce BP below 130/80 mm Hg in all T2D and be-
low 125/75 mm Hg in proteinuric T2D are unsupported by
direct evidence. Data from the BP arm of UKPDS were ob-
tained in the 40% of participants with established hyperten-
sion (BP >160/90 mm Hg). Those allocated to the intensive
BP arm were reduced to 145/85 mm Hg, ie, far above levels
now recommended16 and themselves based on an epidemi-
ological analysis of UKPDS data.17 The MIcroalbuminuria,
Cardiovascular and Renal Outcomes in the Heart Outcomes
Prevention Evaluation (MICRO-HOPE) showed that an angio-
tensin-converting enzyme (ACE) inhibitor, ramipril 10 mg/day,
reduced CV risk by 20% to 25% versus placebo in high-risk
subjects, but reduced conventionally measured BP by only
3 mm Hg.18 Thus, there was room for strengthening the evi-
dence from the hypertensive participants in UKPDS that re-
ducing BP, irrespective of its value, reduces microvascular and
CV risk in T2D.
Challenges to current guidelines
Current international guidelines are based on little evidence
of a relationship between BG and BP levels or of clinical out-
come, beyond UKPDS data. All other sources are short-term
studies with surrogate primary end points. In addition, there
is no consensus for a preferred drug class, based on clinical
events. UKPDS used established antidiabetic drugs (although
acarbose was used for only 3 years).19 Insulin and sulfony-
lureas performed equally well, while metformin performed bet-
ter in terms of myocardial infarction and death, but did not
achieve significance for microvascular end points.14 There are
no studies using clinical end points with new classes of drugs,
except for pioglitazone.20 This prompted the authors of the
ADA/EASD consensus to propose a two-tiered approach to
T2D therapy: first-line therapy, based on a well-validated core
of established drugs (metformin, sulfonylureas, and insulin),
and newer therapies, for meeting glycemic goals in individual
patients only, using thiazolidinediones (TZDs), glucagon-like
peptide 1 (GLP1) agonists, α-glucosidase inhibitors, glinide,
pramlintide, and dipeptidyl peptidase 4 (DPP-4) inhibitors,
whose rationale is based on their mode of action and effect
on BG, body weight, BP, and other risk factors in short-term
studies.15
Current guidelines suffer from insufficient investigation into
the benefit of intensive BG lowering in T2D of several years
standing with or without established micro- and/or macrovas-
cular disease (secondary prevention). Until 2008, not a single
study had tested this recommendation in this specific, yet
prevalent, setting. The guidelines were simply tailored to indi-
vidual needs and preferences.15 Recently, however, the UKPDS
group released excellent news: 10 years after completion of
MEDICOGRAPHIA, Vol 31, No. 3, 2009 267
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

the study, the benefit of good glycemic control

remained imprinted in patients’ body memo-
ries (“legacy effect”), with significantly reduced 80 Myocardial infarction
relative risks of micro-vascular disease, myo- Microvascular end points
cardial infarction, and all-cause mortality.21 Thus,
an intensive BG-lowering regimen appears an

Adjusted incidence per 1000 person years (%)

excellent investment for improving long-term
outcome in T2D. 60

A similar situation exists for BP: current recom-

mendations are only partially evidence-based,
since UKPDS intervention targeted patients
40
with both T2D and hypertension (possibly dif-
ferent diseases, despite speculation as to their
common roots).22,23 Although epidemiological
analysis suggests that reducing BP benefits
normotensive patients with T2D,17 there is no
20
direct evidence for this assumption. Strategies
confined to hypertensive patients suggest that
ambitious objectives (eg, reducing diastolic BP
below 80 mm Hg, as in the Hypertension Op-
timal Treatment [HOT] study) may benefit pa- UKPDS
0 ADVANCE
tients with T2D more than those without T2D.24
5 6 7 8 9 10 11
UKPDS provided no evidence supporting one
Updated mean hemoglobin A1c concentration (%)
particular drug class over another.25

ADVANCE: new findings and progress Figure 1. Results of the ADVANCE glucose reduction arm: comparison with UKPDS.
Action in Diabetes and Vascular disease: ADVANCE, with more than 11 000 patients, is the largest ever prospective study carried out in type
2 diabetes for the prevention of vascular disease.
PreterAx and DiamicroN MR Controlled Evalu- Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR
ation (ADVANCE) used a 22 factorial design Controlled Evaluation; UKPDS, United Kingdom Prospective Diabetes Study.
to study the impact on micro- and macrovas- Modified from reference 17: Adler AI, Stratton IM, Neil HA, et al. BMJ. 1998;317:703-713. [Erra-
tum. BMJ. 1999;318:29.] Copyright © 1998, BMJ Publishing Group Ltd.
cular outcomes, both jointly and separately, of
intensive lowering of BP, on the one hand, and BG, on the cro- or macrovascular disease), ie, the BG arm was essen-
other, in T2D patients at high CV risk.26 Intensive BP interven- tially a secondary intervention study.
tion was based on the use of Preterax/Bipreterax, a fixed com-
bination of indapamide, a thiazide-like diuretic (0.625 mg, then In the BP arm, reducing systolic BP by 5.6 mm Hg reduced
1.25 mg/ day), and perindopril, an angiotensin-converting en- the composite primary end point by 9%, with relative risk
zyme (ACE) inhibitor (2 mg, then 4 mg/day), compared on a reductions of 18% in CV mortality, 14% in all-cause mortality,
double-blind parallel basis to placebo, on top of ongoing treat- 18% in new or worsening nephropathy, and 21% in new mi-
ment. Perindopril could also be added, up to 4 mg/day, if the croalbuminuria.27 These results were achieved across all sub-
investigator considered it advisable. Since the inclusion criteria groups, whether defined by sex, age, previous/no micro- or
did not require a given BP value, about one third of subjects macrovascular disease, baseline BP, HbA1c , lipids, or use/
were normotensive. nonuse of cardioprotective drugs. In particular, no difference
in benefit was seen between normotensives and hyperten-
The BG intervention aimed at reducing HbA1c to 6.5% ver- sives. Side effects were rare, mild, and mostly expected (eg,
sus usual treatment based on local recommendations. Glicla- cough was slightly more frequent in the intensive arm). The re-
zide modified release (Diamicron MR), a long-acting sulfony- sults confirm and extend some of the UKPDS findings and
lurea, was used as first-line therapy in the intensive arm at help to explain the epidemiological data,17 with a marked re-
a goal-appropriate dose, plus any other antidiabetic drugs, in- duction in the prevalence of microvascular and CV risk in T2D
cluding insulin, in order to achieve the 6.5% target. Accord- and significant improvements in renal prognosis, CV mortal-
ing to the parallel, randomized, open, blinded evaluation de- ity, and all-cause mortality (Figure 1).
sign, the same medications were allowed in the control arm—
including all sulfonylureas, with the exception of gliclazide— In the BG arm, the benefits achieved with intensive gliclazide
if required. Participants were selected primarily on the basis MR therapy are particularly instructive for T2D patient care.
of their risk profile (age, diabetes duration, and previous mi- Again, they confirm and extend the UKPDS data by showing

268 MEDICOGRAPHIA, Vol 31, No. 3, 2009 How should future guidelines implement the results of ADVANCE? – Marre
 NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE 2 DIABETES

algorithms and drugs that are tried and tested,

rather than on experimental algorithms and rel-
50 Myocardial infarction atively new drugs such as TZDs.
Microvascular end points
ADVANCE benefits came at little cost: the ab-
solute increase in the risk of severe hypogly-
Adjusted incidence per 1000 person years (%)

40 cemia (the traditional fear of both patients and

carers with sulfonylureas or insulin) was ex-
tremely small (4 extra episodes per 1000 pa-
tients per year compared to the control group);
30 there were no sequelae of hypoglycemia attrib-
utable to the intensive strategy; and weight
gain was nonsignificant, with an intergroup dif-
ference <1 kg and a temporal trend towards
20 weight loss in the control group versus weight
maintenance in the intensive group.28 By com-
parison, in ACCORD, the severe hypoglycemia
rate was several times higher and mean weight
10
gain was 3 kg, with one third of participants
gaining more than 10 kg over 3.5 years.29 Inter-
group CV and all-cause mortality did not differ
ADVANCE UKPDS significantly in ADVANCE (although P values of
0
0.28 and 0.12 mean that the probabilities of the
110 120 130 140 150 160 170
intensive strategy is better than conventional
SBP
strategy hypotheses being untrue are only 28%
and 12%). However, results for these end points
Figure 2. Results of the ADVANCE blood pressure reduction arm: comparison
with UKPDS.
were similarly nonsignificant at the end of
Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR UKPDS, but the intensive BG-lowering strate-
Controlled Evaluation; UKPDS, United Kingdom Prospective Diabetes Study. gy proved beneficial after a further 10 years
Modified from reference 30: Adler AI, Stratton IM, Neil HA, et al. BMJ. 2000;321:412-419. Copy-
right © 2000, BMJ Publishing Group Ltd.
had elapsed.21 Thus, follow-up of the ADVANCE
participants may show a similar mortality ben-
that reducing HbA1c by 0.67% compared with the conven- efit several years hence. Overall, the results of the BG arm of
tional strategy (and effectively achieving the 6.5% objective) ADVANCE confirm and extend the UKPDS evidence (Fig-
reduced the composite primary end point by 10%, with a 21% ure 2).30 Although the study design offered no method of ap-
reduction in the relative risk of new or worsening nephropa- portioning the benefit specifically attributable to gliclazide MR,
thy and a nonsignificant trend for reductions in CV events, the ADVANCE results strongly support the preferential use
CV mortality, and all-cause mortality.28 Again, there was no of this long-acting sulfonylurea in an intensive BG-lowering
subgroup heterogeneity in the results: the data were valid strategy.
across both sexes, all ages, presence or absence of previous
micro- or macrovascular disease, diabetes duration, previous How generalizable are the ADVANCE results? This was a mul-
HbA1c level, lipid profile, and use/nonuse of cardioprotective ticontinental study conducted under day-to-day conditions
drugs.28 A gradual trend in the reduction of HbA1c was ob- similar to those in the routine practice of diabetologists and
served over 2 years and was maintained up to the end of the primary care physicians worldwide, whether in the public or
study, showing that intensive BG reduction is feasible in rou- private sector. With the noticeable exception of black Afri-
tine T2D patient care. cans, the ADVANCE results can be generalized to most of
the world’s patients with T2D. Baseline characteristics in the
These data are extremely reassuring for T2D patients and ADVANCE population closely resembled those of T2D pa-
their carers in providing a firm basis for key opinion leader rec- tients in many countries, eg, the T2D patient profile in a typi-
ommendations to reduce BG to near-normal levels (HbA1c cal Western country, such as France.31
<6.5%).8,9 They contradict those of the Action to Control Car-
diOvascular Risk in Diabetes (ACCORD) study which was ter- Recommendations for the use of ADVANCE results
minated due to excess mortality in the intensive BG arm.29 in everyday diabetic care: summary and conclusions
The ADVANCE data show that BG can be safely reduced to Current T2D care rests on two broad strategies: the glycemic
near-normal levels in both the primary and secondary inter- and nonglycemic. Glycemic strategies are subject to debate
vention settings provided the therapeutic strategy is based on over the intensity of glycemic control required and how best

How should future guidelines implement the results of ADVANCE? – Marre MEDICOGRAPHIA, Vol 31, No. 3, 2009 269
NEW A D VA N C E S IN THE T R E AT M E N T OF TYPE
to achieve it. Nonglycemic strategies are based on the early
intensified control of all other CV risk factors, in particular BP.
How can the ADVANCE results help to improve the guidelines
in these respects?
 Glycemic strategies
The ADVANCE results have shown, for the first time, that re-
ducing HbA1c below 6.5% (ie, a level approximating the nor-
mal range) using established drugs in the routine care setting
is feasible, beneficial, and safe.
It is feasible in that it was achieved in all participating study
centers worldwide (no intersite heterogeneity), and it was
sustained for as long as the study lasted. In fact, BG control
improved over time, in contrast to the observations made just
3 years after inclusion in UKPDS.32 Note also that weight gain,
which the UKPDS data suggested was inevitable over time,
was not observed in ADVANCE. It is beneficial in terms of mi-
crovascular prognosis, with particular respect to the kidney.
Renal benefit was of the same magnitude (21% reduction in
relative risk of the composite of new proteinuria, doubling of
serum creatinine, and end-stage renal failure) as that report-
ed with the angiotensin II subtype 1 receptor antagonists
losartan and irbesartan in T2D.33-35 That reducing the risk of
renal involvement in T2D improves the overall prognosis has
already been established.36 The presently nonsignificant CV
benefit may become significant in the long term, based on the
UKPDS 10 year follow-up data.21 It is safe in that there was no
deterioration in participants’ clinical status and no premature
CV or all-cause mortality, in contrast to the ACCORD study 29
(despite identical HbA1c follow-up values in the intensive arms
of each study). There was no weight gain. The risk of severe
hypoglycemia admittedly increased, but caused no sequelae.
No cases of dementia could be attributed to treatment group
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mented as effective38,39 and safe.27 ADVANCE confirmed the
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T2D patients from micro- and macrovascular disease, via ear-
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Keywords: type 2 diabetes; blood glucose control; blood pressure control; gliclazide; perindopril; indapamide; ADVANCE; UKPDS

COMMENT DE FUTURES RECOMMANDATIONS POURRAIENT- ELLES CONCRÉTISER

LES RÉSULTATS D ’ADVANCE ?
Les recommandations actuelles de la prise en charge du diabétique de type 2 reposent sur des études contrôlées
randomisées et l’avis des leaders d’opinion fondé sur l’expérience clinique. Les recommandations les plus récentes
(2006) et leur mise à jour (octobre 2008) ont été une réponse à l’émergence de nouvelles classes de médicaments,
l’argumentaire des soins au patient continuant à être alimenté par l’étude UKPDS (United Kingdom Prospective Dia-
betes Study) conduite chez des diabétiques de type 2 nouvellement diagnostiqués entre 1977 et 1991, et dont les
résultats ont été disponibles en 1998. L’étude ADVANCE (Action in Diabetes and Vascular disease : PreterAx and Dia-
microN MR Controlled Evaluation) actualise les données de l’UKPDS sur le contrôle de la glycémie et de la pression
artérielle (PA) à la lumière des acquits thérapeutiques actuels, en resituant ces données dans le cadre du risque vas-
culaire élevé inhérent à la plupart des diabétiques de type 2. Les résultats de l’étude ADVANCE confirment l’intérêt
d’une réduction de la glycémie et de la PA jusqu’à des niveaux aussi proches de la normale que possible grâce à un
traitement de première intention alliant une sulfonylurée (gliclazide à libération modifiée [Diamicron LM]) à une asso-
ciation fixe de perindopril et d’indapamide (Preterax). L’étude montre que l’abaissment de l’HbA1c en dessous de 6,5 %
améliore le pronostic microvasculaire sans augmenter le risque d’hypoglycémie majeure, de prise de poids ou de
mortalité prématurée. L’étude ADVANCE préconise également l’utilisation d’une association fixe antihypertensive telle
que Preterax) pour réduire la PA, en prenant en compte le fait que c’est le risque propre à chaque patient qui doit gui-
der la décision clinique pour le traitement antihypertenseur plus que des seuils prédéfinis de PA.

How should future guidelines implement the results of ADVANCE? – Marre MEDICOGRAPHIA, Vol 31, No. 3, 2009 271
 THE QUESTION CONTROVERSIAL QUESTION

I
n diabetic patients, microan-
giopathy is associated with dia-
betic nephropathy, proliferative

Is microalbuminuria
retinopathy, and neuropathy, while
macroangiopathy is associated
with myocardial infarction, stroke,
cardiovascular mortality, all-cause
mortality, and congestive heart
failure. There is an established
a marker for microangiopathy
or macroangiopathy?
relationship between microalbu-
minuria and micro- and macroan-
giopathy: does this make microal-
buminuria a reliable marker of
microangiopathy and macroan-
giopathy in diabetic patients?

1. M. Burnier, Switzerland

2. P. Fioretto, Italy

3. J. Gumprecht, Poland

4. G. Halaby, Lebanon

5. R. Unnikrishnan and V. Mohan, India

6. F. Puchulu, Argentina

7. R. Roussel, France

8. G. Schernthaner, Austria

9. M. Shestakova, Russia

10 . J.-G. Wang, Y. Li, and C.-S. Sheng, China

Is microalbuminuria a marker for microangiopathy or macroangiopathy? MEDICOGRAPHIA, Vol 31, No. 3, 2009 273
CONTROVERSIAL QUESTION
1. M. Burnier, Switzerland
Michel BURNIER, MD
Professor, Department of Nephrology
CHUV, University Hospital
17 Rue du Bugnon, CH 1011 Lausanne
SWITZERLAND
(e-mail: michel.burnier@chuv.ch)
T
he presence of a low concentration of albumin in the
urine (microalbuminuria) was originally considered a
marker of renal microangiopathy, thus confining its clin-
ical usefulness mainly to the early detection of patients at
higher risk of diabetic nephropathy. In the last 10 years, this
concept has been challenged in several respects. Microal-
buminuria was found in nondiabetic patients and in the gen-
eral population, where the risk of nephropathy is extremely low.
Several large epidemiological studies, eg, the Prevention of
REnal and Vascular ENdstage Disease (PREVEND) and Eu-
ropean Prospective Investigation of Cancer-Norfolk (EPIC-
Norfolk) studies, showed that microalbuminuria was associat-
ed with a higher risk of cardiovascular complications, such as
coronary artery disease or death from a cardiovascular event,
in unselected populations. As such, microalbuminuria prob-
ably reflects an alternative mechanism of cardiovascular path-
ogenicity. It is now generally considered a surrogate marker
of endothelial dysfunction present in most patients with car-
diovascular complications.
Large clinical studies, such as the Heart Outcomes Preven-
tion Evaluation (HOPE) and the Losartan Intervention For End-
point reduction in hypertension (LIFE), provided further con-
firmation of the association between microalbuminuria and
macroangiopathy. The prevalence of cardiovascular problems,
such as coronary artery disease, peripheral vascular disease,
and cerebrovascular disease, was significantly and dose-de-
pendently associated with the intensity of proteinuria, as was
274 MEDICOGRAPHIA, Vol 31, No. 3, 2009
the risk of cardiovascular death. Most interestingly, post-hoc
analysis showed that the ability to lower microalbuminuria
using a renin-angiotensin system blocker in LIFE and HOPE
lowered the risk of an adverse cardiovascular end point. This
was further evidence that intervention against microalbumin-
uria could delay disease progression.
However, in the ONgoing Telmisartan Alone and in combina-
tion with Ramipril Global Endpoint Trial (ONTARGET), coad-
ministration of an angiotensin-converting enzyme (ACE) in-
hibitor with an angiotensin receptor blocker failed to impact
the cardiovascular event rate, despite having a greater pro-
teinuria-lowering effect than ACE inhibition alone. This is a sur-
prising discrepancy that still needs explanation.
In the recently published Action in Diabetes and Vascular
disease: PreterAx and DiamicroN MR Controlled Evaluation
(ADVANCE) trial, the risk of end-stage renal disease or renal
disease progression was again significantly associated with
the level of proteinuria. Hazard ratios for a renal event were
around 12 in patients with macroalbuminuria and 5-6 in
type 2 diabetics with microalbuminuria. In this study, microal-
buminuria was clearly associated with the development of
microangiopathy and was reduced by the administration of
perindopril and indapamide. Interestingly, however, both be-
fore and during treatment in this population, microalbumin-
uria was, in addition, directly and significantly associated with
the risk of cardiovascular death, suggesting that proteinuria
is also marker of macroangiopathy.
This new evidence suggests that microalbuminuria is prob-
ably an indicator of both micro- and macroangiopathy, rather
than a preferential or exclusive indicator of either. However, a
major outstanding issue is whether pharmacological targeting
of microalbuminuria will lower the incidence of cardiovascu-
lar complications independently of any effect on blood pres-
sure. This remains a major challenge for future studies. 
Is microalbuminuria a marker for microangiopathy or macroangiopathy?

2. P. Fioretto, Italy
Paola FIORETTO, MD, PhD
Professor, Department of Medical and
Surgical Sciences, University of Padova
Via Giustiniani, 2 – 35128 Padova, ITALY
(e-mail: paola.fioretto@unipd.it)
T
he term microalbuminuria was introduced in 1982 to
describe concentrations of urinary albumin, undetected
by standard dipsticks, that predicted the development
of overt proteinuria in diabetics. Given that diabetic nephropa-
thy is a common manifestation of microangiopathy, microal-
buminuria is naturally associated with other microangiopath-
ic complications, especially diabetic retinopathy. Shortly after
the first reports, it became evident that microalbuminuria also
predicted mortality, largely from cardiovascular disease, in
diabetics and nondiabetics. In the last decade, microalbumin-
uria has become recognized as an independent predictor of
cardiovascular and renal events in diabetes and hyperten-
sion, with the result that most guidelines now recommend
screening.
Meta-analysis showed that microalbuminuria doubles car-
diovascular morbidity and mortality and all-cause mortality
in type 2 diabetics, after correction for traditional risk factors.
Similar findings were reported in hypertensives and the gen-
eral population. Yet the values associated with increased car-
diovascular risk are consistently lower than the cut-offs cur-
rently used to define microalbuminuria. Although lower cut-offs
have been proposed, no consensus has been reached. Thus,
albumin excretion rate (AER) should be considered a con-
tinuous, rather than categorical, variable. The pathophysiology
of the association with cardiovascular disease remains un-
elucidated, but microalbuminuria is a marker of generalized
vascular dysfunction, as borne out by its associations with
hypertension, lipid abnormalities, insulin resistance, endothe-
lial dysfunction, low-grade chronic inflammation, peripheral
vascular disease, and prothrombotic status.
Retrospective studies in the early 1980s reported that 80%
of type 1 diabetics with microalbuminuria progressed to pro-
teinuria over 6-14 years. Although microalbuminuria remains
the best available marker for nephropathy risk, prospective
Is microalbuminuria a marker for microangiopathy or macroangiopathy?
CONTROVERSIAL QUESTION
studies suggest that the percentage of patients with microal-
buminuria progressing to proteinuria over a decade is much
lower (30%); this may be due to initial overestimation, im-
proved treatments, or both. Many microalbuminuric patients
spontaneously revert to normoalbuminuria. In type 2 diabetes,
the progression rate from microalbuminuria to proteinuria is
similar (30% in 10 years): in the Steno 2 study, 31% progressed
to proteinuria over 7.8 years, 31% reverted to normoalbumin-
uria, and 38% remained microalbuminuric. Decline in glomeru-
lar filtration rate (GFR) was much slower in patients reverting
to normoalbuminuria than in those progressing to protein-
uria, suggesting that reversion is associated with preserved
renal function. Overall, AER remains the strongest indicator
of nephropathy risk in diabetics, but is a weaker predictor of
proteinuria than first thought. Its accuracy can be improved by
combining it with other parameters, eg, GFR, blood pressure,
glycemia, lipid levels, retinopathy, family history, and smoking.
Diabetics with microalbuminuria are 2-3 times more likely to
progress to proteinuria than those with a normal AER.
In hypertensives, in contrast, a relationship between microal-
buminuria and subsequent nephropathy has yet to be estab-
lished. The available data are conflicting and, in the absence
of large well-performed prospective studies, the predictive
value of microalbuminuria for hypertensive renal damage re-
mains a tempting, but speculative, hypothesis. Most general
population studies have detected no correlation between mi-
croalbuminuria and GFR. Thus, it remains to be documented
whether microalbuminuria predicts renal dysfunction in hyper-
tensive and general populations as in diabetics. An increased
AER may be due to increased intracapillary glomerular pres-
sure (in hypertension), structural damage to the capillary bar-
rier (in diabetes), or tubular dysfunction (in a subset of diabetic
patients). These differing pathogenetic mechanisms proba-
bly carry different renal risk, accounting for the imprecise pre-
dictive value of microalbuminuria for renal disease.
In conclusion, microalbuminuria predicts micro- and macroan-
giopathy in diabetics and cardiovascular risk in hypertensive
patients and the general population. Its accuracy in predicting
nephropathy risk is less than originally believed. In nondiabet-
ics, there is no clear evidence that microalbuminuria predicts
renal disease, but it is widely accepted as a strong and pow-
erful predictor of cardiovascular disease in diabetics and non-
diabetics alike. 
MEDICOGRAPHIA, Vol 31, No. 3, 2009 275
CONTROVERSIAL QUESTION
3. J. Gumprecht, Poland
Janusz GUMPRECHT, MD, PhD
Professor, Department and Clinic of Internal
Medicine, Diabetology, and Nephrology
Medical University of Silesia
Zabrze, POLAND
(e-mail: jgumprecht@sum.edu.pl)
V
iberti et al introduced the term “microalbuminuria” in
1982 to denote a subclinical rise in urinary albumin
excretion (UAE) >30 mg/24 hours in type 1 diabetics.
It is typically defined as a UAE of 20-200 μg/min in an overnight
collection or 30-300 mg in a 24-hour collection.1 We now
know that 5% to 10% of nondiabetic, normotensive individu-
als have UAE values within the microalbuminuric range and
that hypertension is the major risk factor for microalbuminuria
in the general population. Microalbuminuria occurs in 53% to
71% patients with essential hypertension, and is highest in un-
controlled disease, increasing with age, disease severity, and
disease duration.
The prevalence of microalbuminuria in type 1 diabetes increas-
es gradually from disease onset to over 50% after 20 years
and is a strong risk factor for overt nephropathy. In type 2
diabetes, it is an accurate predictor of cardiovascular events
and has a prevalence of 20% to 25%, regardless of disease
stage.2 The most probable reasons for the difference between
types 1 and 2 diabetes in this regard are greater disease het-
erogeneity, association with risk factors (eg, insulin resistance,
metabolic control, dyslipidemia, central obesity, and the ab-
sence of a nocturnal drop in both systolic and diastolic blood
pressure), and premature cardiovascular death.
Population studies suggest that UAE starting in the submi-
croalbuminuric range is an independent predictor of renal and
cardiovascular events. It is also recognized as a significant
risk factor for cardiovascular and noncardiovascular mortality
in diabetics and the general population.3
Cardiovascular mortality is higher in type 2 diabetics with mi-
croalbuminuria than in those without, especially in the pres-
ence of retinopathy or raised von Willebrand factor (vWf). Per-
sistence of microalbuminuria in type 1 diabetes is a marker
not only of renal and cardiac risk, but also of severe and pre-
dominantly proliferative retinopathy. In type 2 diabetes, on the
other hand, there is no prognostic relationship between mi-
croalbuminuria and retinopathy progression.Vascular risk is
not distributed equally in diabetics. Although most type 1 di-
276 MEDICOGRAPHIA, Vol 31, No. 3, 2009
abetics develop vascular complications, some never experi-
ence severe angiopathy, presumably because of genetic or
environmental factors. The pathophysiological mechanism
underlying the association between UAE and angiopathy re-
mains unelucidated. In 1989, in an attempt to explain why the
development of microalbuminuria foreshadows serious mul-
tiple organ failure, Deckert et al presented the “Steno hypoth-
esis,” viewing elevated UAE as an indicator of more general-
ized vascular dysfunction simultaneously involving not only
the glomeruli and retina, but also the macrovascular intima
via increased endothelial permeability. Microalbuminuria was
described as a renal marker of generalized endothelial dys-
function, predisposing to vascular complications (retinopathy,
nephropathy, and atherosclerosis) in diabetes types 1 and 2.4
UAE indeed correlates with endothelial dysfunction in type 1
and type 2 diabetics as well as in nondiabetics and is related
not only to symptomatic vascular disease, but also to incip-
ient atherosclerosis.5 Data suggest a link between microal-
buminuria and cardiovascular disease via coagulation and
fibrinolytic dysfunction. Microalbuminuria itself is associated
with increased levels of fibrinogen, vWf, plasminogen activa-
tor inhibitor 1, and thrombomodulin as well as with impaired
fibrinolysis. It may thus serve as a marker of a prothrombot-
ic state.
Microalbuminuria is a frequent finding in renal and cardiovas-
cular organ damage in diabetics, hypertensives, and the gen-
eral population. Regardless of the pathogenesis of the vas-
cular injury, it identifies incipient micro- and macrovascular
disease. UAE is thus a useful parameter in assessing risk, in
identifying patients needing more intensive management
(stricter blood pressure, glucose, and lipid control), and in tai-
loring vasculoprotective treatment before glomerular filtration
rate declines.6 Reduction or reversal of microalbuminuria in-
dicates correction of generalized endothelial dysfunction and
a potential reduction in overall cardiovascular risk. 
References
1. Viberti GC, Hill RD, Jarret RJ, et al. Microalbuminuria as a predictor of clinical
nephropathy in insulin-dependent diabetes mellitus. Lancet. 1982;1:1430-1432.
2. Mattock MB, Morrish NJ, Viberti GC, et al. Prospective study of microalbumin-
uria as predictor of mortality in type 2 diabetes. Diabetes. 1992;41:736-741.
3. Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality
in maturity-onset diabetes. N Engl J Med. 1984;310:356-360.
4. Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, et al. Albuminuria reflects wide-
spread vascular damage. The Steno hypothesis. Diabetologia. 1989;32:219-226.
5. Furtner M, Kiechl S, Mair A, et al. Urinary albumin excretion is independently as-
sociated with carotid and femoral artery atherosclerosis in the general popula-
tion. Eur Heart J. 2005;26:279-287.
6. Weir MR. CME microalbuminuria in type 2 diabetics: an important, overlooked
cardiovascular risk factor. J Clin Hypertens. 2004;6:134-143.
Is microalbuminuria a marker for microangiopathy or macroangiopathy?

4. G. Halaby, Lebanon
Georges HALABY, MD
Professor of Endocrinology
Saint Joseph University
Rue de Damas, BP 17-5208 Mar Mikhaël
Beirut 1104-2020, LEBANON
(e-mail: mjhalaby@sodetel.net.lb)
A
lbumin measurement is useful in various clinical set-
tings, in particular to identify and monitor glomerular
disease and assess cardiovascular risk. The preferred
parameter of urinary albumin excretion (UAE) is the total al-
bumin-to-creatinine ratio, preferably in an early morning urine
sample.1 Microalbuminuria is considered positive between
20 and 200 μg/mg creatinine. Above this level it becomes
macroalbuminuria. Even when it remains within the normal
range an elevated UAE probably reflects abnormal glomeru-
lar hemodynamics and permselectivity, which may predispose
to diabetic glomerulopathy.2 The most significant modifiable
predictor for microalbuminuria is hemoglobin A1c .
Microalbuminuria has a prevalence of 28% and a mean dura-
tion of 15 years in type 1 and 2 diabetics, 33% of whom pro-
ceed to macroalbuminuria. Microalbuminuria is often pres-
ent at diagnosis. In the United Kingdom Prospective Diabetes
Study (UKPDS), the yearly rates of progression from diagnosis
of diabetes to microalbuminuria, microalbuminuria to macroal-
buminuria, and macroalbuminuria to an elevated plasma crea-
tinine or renal replacement therapy were 2.0%, 2.8%, and 2.3%.3
Microalbuminuria is not only an indicator of incipient renal
damage, but also associated with essential hypertension and
glucose intolerance, suggesting its involvement in early vascu-
lar damage and its utility in predicting the onset and progres-
sion of cardiovascular disease. In the European Prospective
Investigation of Cancer-Norfolk (EPIC-Norfolk) and Losartan
Intervention For Endpoint reduction in hypertension (LIFE)
studies, microalbuminuria predicted the incidence of stroke.
For every 10-fold increase in UAE, the hazard ratio for stroke
increased by 51% in nondiabetics and by 37% in diabetics.
Microalbuminuria is an important cardiovascular and mortal-
ity risk factor, irrespective of diabetes or hypertension. It in-
creases the relative risk of major cardiovascular events, even
after adjustment for other cardiovascular risk factors. Risk
increases with the albumin-to-creatinine ratio, starting well
below the microalbuminuria cutoff. Multivariate analysis has
shown that left ventricular (LV) hypertrophy is associated with
a 1.6-fold higher prevalence of microalbuminuria, independ-
ent of age, systolic or diastolic blood pressure (BP), diabetes,
gender, race, serum creatinine, or smoking status.
Is microalbuminuria a marker for microangiopathy or macroangiopathy?
CONTROVERSIAL QUESTION
The Framingham Heart Study revealed the relationship be-
tween low-grade microalbuminuria, hypertension, and BP
progression in normotensive nondiabetics. Microalbuminuria
appears to correlate with the severity and duration of hyper-
tension. Although it has been shown to correlate with anoth-
er inflammatory biomarker of cardiovascular risk, C-reactive
protein (CRP), little is known about the relative effectiveness
of either indicator or of any other indicator, alone or in com-
bination, in predicting cardiovascular risk.
In addition to being linked to hypertension and diabetes, mi-
croalbuminuria is independently associated with several mod-
ifiable cardiovascular risk factors and markers of cardiovas-
cular disease, including obesity, smoking, insulin resistance
syndrome, LV hypertrophy, LV dysfunction, and elevated CRP.
It is also a reliable indicator of endothelial dysfunction, itself
associated with the transendothelial albumin escape rate and
plasma von Willebrand factor levels. Microalbuminuria corre-
lates with endothelial dysfunction in the brachial artery. Such
dysfunction is an early step in atherosclerosis and represents
an increased risk for cardiovascular events.4
Lowering systolic BP lowers microalbuminuria. So does renin-
angiotensin system blockade, irrespective of lowering BP. Most
effective of all are intensive antihypertensive regimens that ef-
fectively block the renin-angiotensin system. Microalbuminuria
screening and antihypertensive therapy that lowers microal-
buminuria in high-risk patients should improve cardiovascular
and renal outcomes. Treatment with a fixed combination of
perindopril and indapamide significantly reduced all renal
events.5 Many trials have confirmed the long-term benefits of
glycemic control in reducing new-onset microalbuminuria,
nephropathy, and, perhaps, in reducing cardiovascular events.6
Intensive intervention with multiple drug combinations and
behavior modification is associated with a sustained reduc-
tion in vascular complications and in cardiovascular and all-
cause mortality in type 2 diabetics with microalbuminuria. 
References
1. National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kid-
ney disease: evaluation, classification and stratification. Am J Kidney Dis. 2002;39
(2 suppl 1):S1-S266.
2. Hostetter TH, Rennke HG, Brenner BM. The case for intrarenal hypertension in
the initiation and progression of diabetic and other glomerulopathies. Am J Med.
1982;72:375-380.
3. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR. Development
and progression of nephropathy in type 2 diabetes: the United Kingdom Prospec-
tive Diabetes Study (UKPDS 64). Kidney Int. 2003;63:225-232.
4. Quyyumi AA. Prognostic value of endothelial function. Am J Cardiol. 2003;91:
19-24.
5. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Effects
of a fixed combination of perindopril and indapamide on macrovascular and mi-
crovascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE
trial): a randomized controlled trial. Lancet. 2007;370:829-840.
6. ADVANCE Collaborative Group. Intensive blood glucose control and vascular out-
comes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.
MEDICOGRAPHIA, Vol 31, No. 3, 2009 277
CONTROVERSIAL QUESTION
5. R. Unnikrishnan and V. Mohan, India

Ranjit UNNIKRISHNAN, I, MD
Viswanthan MOHAN, MD, FRCP, PhD, DSc
Corresponding author:
Viswanthan Mohan, Doctor
Chairman and Chief of Diabetology
Madras Diabetes Research Foundation
Dr Mohan’s Diabetes Specialities Centre
& WHO Collaborating Centre for Noncommu-
nicable Diseases, Prevention and Control
4, Conran Smith Road, Gopalapuram
Chennai, 600 086, INDIA
(e-mail: drmohans@vsnl.net)
T
he term microalbuminuria refers to a level of urinary al-
bumin excretion, commonly defined as being between
30 and 299 mg albumin per day and below the sensi-
tivity threshold of conventional dipsticks. It is usually detected
by measuring the albumin-creatinine ratio, either in a spot urine
sample or in a timed urine collection.
Microalbuminuria is considered the earliest detectable stage
of diabetic nephropathy. This stage is potentially reversible:
prompt intervention with angiotensin-converting enzyme (ACE)
inhibitors or angiotensin receptor blockers (ARBs) is extreme-
ly effective in slowing the progression to overt nephropathy.
Microalbuminuria is considered to result from a defect in the
glomerular filtration barrier, which consists of the glomerular
capillary endothelium, basement membrane, and visceral ep-
ithelium. The endothelial defect responsible for microalbu-
minuria may be a marker for a more widespread pathological
process, involving blood vessels in several organs and shar-
ing the common etiological factor of prolonged uncontrolled
hypoglycemia. The mechanisms of endothelial dysfunction in
diabetes may involve the polyol pathway, aldose reductase
pathway, and/or the formation of advanced glycation end
products. The finding of microalbuminuria should alert the cli-
nician to signs of vascular disease at other sites in the body
in addition to the kidney.
Diabetic nephropathy and retinopathy, the two major micro-
vascular complications of diabetes, share many risk factors.
Hence, it is not surprising that many studies have shown a
strong correlation between microalbuminuria and diabetic
retinopathy.1 The association persists after adjustment for age,
duration of diabetes, and quality of glycemic control. More-
over, retinopathy increases in severity with increase in albu-
minuria.2
278 MEDICOGRAPHIA, Vol 31, No. 3, 2009
The association of microalbuminuria with macrovascular dis-
ease, such as coronary artery disease, stroke, and peripheral
arterial disease, has been well established.3,4 In type 2 diabet-
ic subjects, the albumin excretion rate is a significant predic-
tor of coronary morbidity, even after adjustment for potential
confounders, such as hypertension and other cardiovascular
risk factors.4 It is of interest to note that the association be-
tween elevated albumin excretion and coronary artery dis-
ease is also largely valid in nondiabetics.5 Microalbuminuria is
associated with increased mortality not only in diabetic sub-
jects, but also in the general elderly population.3,5
Thus, microalbuminuria is not only a marker of diabetic nephro-
pathy, of which it is the earliest detectable stage, but also of
other complications, both microvascular, such as diabetic
retinopathy, and macrovascular. Its presence in a diabetic sub-
ject therefore warrants a careful search for such complications.
In addition to ACE inhibitors and ARBs, patients found to have
microalbuminuria should receive treatment to minimize their
known cardiovascular risk factors. This should include cessa-
tion of smoking and, possibly, the addition of aspirin or hydrox-
ymethylglutaryl coenzyme A inhibitors (ie, statins). In the Action
in Diabetes and Vascular disease: PreterAx and DiamicroN MR
Controlled Evaluation (ADVANCE) trial, the ACE inhibitor perin-
dopril in combination with indapamide reduced the risk of ma-
jor vascular events and death in type 2 diabetics, irrespective
of the use of other antihypertensive agents and initial blood
pressure levels.6 Such an approach will help to reduce mor-
bidity and mortality from both micro- and macroangiopathy. 
References
1. Klein R, Klein BE, Linton KL, Moss SE. Microalbuminuria in a population-based
study of diabetes. Arch Intern Med. 1992;152:153-158.
2. Gall MA, Rossing P, Skøtt P, et al. Prevalence of micro- and macroalbuminuria,
arterial hypertension, retinopathy and large vessel disease in European type 2
(non-insulin-dependent) diabetic patients. Diabetologia. 1991;34:655-661.
3. Yudkin JS, Forrest RD, Jackson CA. Microalbuminuria as predictor of vascular
disease in non-diabetic subjects. Islington Diabetes Survey. Lancet. 1988;2:530-
533.
4. Mattock MB, Keen H, Viberti GC, et al. Coronary heart disease and urinary albu-
min excretion rate in type 2 (non-insulin-dependent) diabetic patients. Diabetolo-
gia. 1988;31:82-87.
5. Damsgaard EM, Frøland A, Jørgensen OD, Mogensen CE. Microalbuminuria as
predictor of increased mortality in elderly people. BMJ. 1990;300:297-300.
6. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Effects
of a fixed combination of perindopril and indapamide on macrovascular and mi-
crovascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE
trial): a randomised controlled trial. Lancet. 2007;370:829-840.
Is microalbuminuria a marker for microangiopathy or macroangiopathy?

6. F. Puchulu, Argentina
Felix PUCHULU, MD
Doctor, Juncal 1177 5º B (1021)
Capital Federal, Buenos Aires
ARGENTINA
(e-mail: fpuchulu@gmail.com)
M
icroalbuminuria is an early marker of nephropathy, a
chronic microangiopathic complication of diabetes.
It also represents an increased risk of retinopathy
and an independent cardiovascular risk factor in diabetes
types 1 and 2. Additionally, it is a cardiovascular risk factor in
nondiabetics and a component of the metabolic syndrome.
Its prevalence in nondiabetic essential hypertension is around
25%.
Two main factors in the shared underlying pathogenesis are
generalized endothelial dysfunction and chronic low-grade in-
flammation. The pathophysiology of the transcapillary escape
rate of albumin is poorly understood, but probably involves
hemodynamic changes and damage to the structure and/or
function of the vascular wall. The permeability of the glomeru-
lar filtration barrier depends on a three-layer structure: endo-
thelium (with fenestrae filled by glycocalyx), glomerular base-
ment membrane, and podocytes (glomerular epithelial cells).
The glycocalyx is a dynamic layer of glycoproteins and pro-
teoglycans with adsorbed plasma proteins. In diabetics and
nondiabetics, microalbuminuria is related to changes in the
size and charge selectivity of the glomerular filtration barrier.
Defects in charge selectivity occur earlier than loss of size se-
lectivity,1 probably due to damage to the negatively charged
glycocalyx. Removing the glycocalyx increases vascular pro-
tein permeability, ie, the presence of significant endothelial gly-
cocalyx implies that glomerular endothelium has a key role in
retaining macromolecules.2
Reactive oxygen species (ROS) disrupt the glycocalyx, caus-
ing proteinuria with no structural changes in the glomerular
filtration barrier identifiable on electron microscopy. Hyper-
glycemia increases the production of ROS, increasing nuclear
factor-κ B, interfering with nitric oxide bioavailability, directly
disrupting the endothelial glycocalyx,3 and decreasing heparan
sulfate proteoglycan production. Podocytes also produce
ROS during hyperglycemia. Since glomerular endothelium is
exposed to the same diabetic disorders as endothelium else-
where, it is presumably also dysfunctional.
Several markers of endothelial cell dysfunction are increased
in microalbuminuria. Brachial artery bloodflow is decreased
during reactive hyperemia in type 1 diabetics with microalbu-
Is microalbuminuria a marker for microangiopathy or macroangiopathy?
CONTROVERSIAL QUESTION
minuria. Impaired endothelial nitric oxide synthesis may link
microalbuminuria with cardiovascular risk, regardless of dia-
betes: endothelial dysfunction precedes and predicts microal-
buminuria onset in both diabetics and nondiabetics.4 Micro-
albuminuria represents increased albumin leakage through
the glomerular capillary wall due to an increase in wall perme-
ability, intraglomerular pressure, or both. Hyperglycemia and
hypertension are both risk factors for microalbuminuria and
can increase intraglomerular pressure. Hyperglycemia also
alters the charge selectivity of the glomerular capillary wall,
thereby increasing its permeability.
Endothelial dysfunction increases glomerular pressure and
glomerular barrier permeability. The endothelium appears to
be directly involved in determining permeability to albumin.
Abnormalities in endothelial glycocalyx are also implicated in
the pathogenesis of atherosclerosis, thus providing a poten-
tial common pathogenesis for albuminuria and cardiovascu-
lar disease.5 Chronic low-grade inflammation, also common in
diabetes, is the other major factor in shared pathogenesis. It
is reflected in the plasma levels of C-reactive protein and cy-
tokines, such as interleukin 6 and tumor necrosis factor α .
These markers have shown that, irrespective of diabetes,
low-grade inflammation is associated with the occurrence and
progression of microalbuminuria and atherothrombotic risk.6
A major aspect of microalbuminuria is disruption of the en-
dothelial glycocalyx by the direct or indirect actions of media-
tors related to hyperglycemia. Glycocalyx dysfunction reflects
the generalized endothelial dysfunction that may link microal-
buminuria to vascular disease. Microalbuminuria is probably
more a marker of generalized endothelial dysfunction than
of micro- or macroangiopathy, and should always extend the
clinician’s concern from the kidney to other territories, such
as the retina and heart. 
References
1. Deckert T, Kofoe-Enevoldsen A, Vidal P, Norgaard K, Andreasen HB, Feldt-Ras-
mussen B. Size and charge selectivity of glomerular filtration in type 1 (insulin de-
pendent) diabetic patients with and without albuminuria. Diabetologia. 1993;36:
244-251.
2. Satchell SC, Tooke JE. What is the mechanism of microalbuminuria in diabetes:
a role for the glomerular endothelium? Diabetologia. 2008;51:714-725.
3. Vink H, Duling BR. Identification of distinct luminal domains for macromolecules,
erythrocytes, and leukocytes within mammalian capillaries. Circ Res. 1996;79:
581-589.
4. Stehouwer CDA. Endothelial dysfunction in diabetic nephropathy: state of the art
and potential significance for nondiabetic renal disease. Nephrol Dial Transplant.
2004;19:778-781. Editorial.
5. Nieuwdorp M, Meuwese MC, Vink H, Hoekstra JB, Kastelein JJP, Stroes ES. The
endothelial glycocalix: a potential barrier between health and vascular disease.
Curr Opin Lipidol. 2005;16:507-511.
6. Schram MT, Chaturvedi N, Schalkwijk CG, Fuller JH, Stehouwer CDA; EURODIAB
Prospective Complications Study Group. Markers of inflammation are cross-sec-
tionally associated with microvascular complications and cardiovascular disease
in type 1 diabetes: the EURODIAB Prospective Complications Study. Diabetolo-
gia. 2005;48:370-378.
MEDICOGRAPHIA, Vol 31, No. 3, 2009 279
CONTROVERSIAL QUESTION
7. R. Roussel, France
Ronan ROUSSEL, MD, PhD
Doctor, Assistance Publique-Hôpitaux
de Paris, Hôpital Bichat, Département
d’Endocrinologie, Diabétologie et Nutrition
46 rue Huchard, 75018 Paris, FRANCE
(e-mail: ronan.roussel@bch.aphp.fr)
M
icroalbuminuria is the persistently increased uri-
nary excretion of albumin above 30 mg/24 hours (or
20 mg/L, or 20 mg/g creatinine), but below 300 mg/
24 hours (200 μg/L, or 200 mg/g). The National Health And
Nutrition Examination Survey showed a prevalence of 8.8% in
US adults.1 Prevalence increases markedly in diabetes and hy-
pertension, reflecting disease duration: it reached 25% in con-
trols in the United Kingdom Prospective Diabetes Study.2
Microalbuminuria as a marker of micro- and
macroangiopathic outcome
The relationship with adverse clinical outcome is continuous
and positive. In the Heart Outcomes Prevention Evaluation
(HOPE), microalbuminuria was associated with myocardial
infarction, stroke, cardiovascular death, all-cause mortality, and
hospitalization for congestive heart failure, not only in all pa-
tients, but also in the diabetic and nondiabetic subgroups.3 It
has been associated with mortality in other populations, in-
cluding those at lower cardiovascular risk than in HOPE,4 and
even in the general population (Prevention of REnal and Vas-
cular ENdstage Disease [PREVEND] study). Risk is also in-
creased in high-normal albuminuria. The Action in Diabetes
and Vascular disease: PreterAx and DiamicroN MR Controlled
Evaluation (ADVANCE) study found an impressively positive
linear relationship between log albumin excretion rate and end-
stage renal disease or cardiovascular death.4 Microalbumin-
uria also correlated with stroke risk in the European Prospec-
tive Investigation of Cancer-Norfolk (EPIC-Norfolk). PREVEND
reported a matching trend in peripheral arterial disease.
Microalbuminuria is strongly associated with microangiopathy
in type 1 diabetes, especially with progression to severe dia-
betic nephropathy,5 proliferative retinopathy, and neuropathy.
Is microalbuminuria a useful marker of micro- and
macroangiopathy?
Undoubtedly yes, ever since pioneering evidence from the
Danish groups and others prompted the American Diabetes
Association to recommend screening for incipient nephropa-
thy: “Perform an annual test to assess urine albumin excretion
in type 1 diabetic patients with diabetes duration of 5 years
and in all type 2 diabetic patients, starting at diagnosis.” As
for macroangiopathy, especially coronary heart disease and
280 MEDICOGRAPHIA, Vol 31, No. 3, 2009
stroke, microalbuminuria is both practical to measure, using
an early morning or random spot urine sample, and independ-
ent of other validated risk factors. The epidemiological data
show that it remains associated with future cardiovascular
events after adjustment for such validated common risk fac-
tors as age, smoking, gender, weight, waist circumference,
blood pressure, glycated hemoglobin, and lipids.6 The HOPE
study found that relative risks for major cardiovascular events
were similar in diabetics and nondiabetics, again after adjust-
ing for cardiovascular risk factors. Thus, microalbuminuria pro-
vides added value in cardiovascular prognosis.
Microalbuminuria and cardiovascular risk reduction
The Losartan Intervention For Endpoint reduction in hyperten-
sion (LIFE) found that although changes in albuminuria during
antihypertensive treatment over time translated into reduction
in cardiovascular risk, this was not explained by the in-treat-
ment blood pressure level, suggesting the benefit of repeat-
ed albuminuria assessment during treatment. However, only
13% of the participants were diabetic. In type 2 diabetes, re-
duced proteinuria is undoubtedly associated with improved
renal outcome (Reduction of Endpoints in NIDDM with the An-
giotensin II Antagonist Losartan [RENAAL] study and Irbe-
sartan in Diabetic Nephropathy Trial [IDNT]). Of course, with
nephropathy being defined by urinary albumin level, decreas-
ing microalbuminuria, by definition, decreases the risk of overt
nephropathy. However, data in type 2 diabetes are lacking to
test for a relationship between reduced microalbuminuria and
reduced cardiovascular events. Extrapolated evidence from
nondiabetics (hypertensive LIFE patients) suggests that dia-
betologists should measure albuminuria in every diabetic and
be as aggressive in reducing this modifiable risk factor as they
are in reducing blood pressure, lipids, or glycemia in the early
stages of diabetes. 
References
1. Coresh J, Byrd-Holt D, Astor BC, et al. Chronic kidney disease awareness,
prevalence, and trends among U.S. adults, 1999 to 2000. J Am Soc Nephrol.
2005;16:180-188.
2. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of
macrovascular and microvascular complications in type 2 diabetes: UKPDS 38.
BMJ. 1998;317:703-713.
3. Gerstein HC, Mann JF, Yi Q, et al; HOPE Study Investigators. Albuminuria and risk
of cardiovascular events, death, and heart failure in diabetic and nondiabetic in-
dividuals. JAMA. 2001;286:421-426.
4. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Effects
of a fixed combination of perindopril and indapamide on macrovascular and mi-
crovascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE
trial): a randomised controlled trial. Lancet. 2007;370:829-840.
5. Mogensen C, Christensen CK, Vittinghus E. The stages in diabetic renal disease.
With emphasis on the stage of incipient diabetic nephropathy. Diabetes. 1983;32
(suppl 2):64-78.
6. Brantsma AH, Bakker SJ, Hillege HL, de Zeeuw D, de Jong PE, Gansevoort RT;
PREVEND Study Group. Urinary albumin excretion and its relation with C-reac-
tive protein and the metabolic syndrome in the prediction of type 2 diabetes. Di-
abetes Care. 2005;28:2525-2530.
Is microalbuminuria a marker for microangiopathy or macroangiopathy?

8. G. Schernthaner, Austria
Guntram SCHERNTHANER, MD
Professor, Head of the Department of
Medicine I, Rudolfstiftung Hospital
Juchgasse 25, A-1030 Vienna
AUSTRIA
(e-mail: guntram.schernthaner@
meduniwien.ac.at)
I
n the past three decades, urinary albumin excretion has
played a central role in the diagnosis and management of
nephropathy in type 1 and type 2 diabetics. Microalbumin-
uria was found to predict overt albuminuria (>300 mg/24
hours), which in turn predicted loss of kidney function. More
recent data indicate that glomerular filtration rate and albu-
minuria are twin manifestations of nephropathy in diabetes.
In 1984, Mogensen demonstrated that microalbuminuria pre-
dicts increased mortality in type 2 diabetes.1 The United King-
dom Prospective Diabetes Study showed that cardiovascular
mortality increased significantly with increasing nephropathy
( P<0.0001), with annual mortality rates of 0.7% for subjects
without nephropathy, 2.0% for those with microalbuminuria,
3.5% for those with macroalbuminuria, and 12.1% for those
with elevated plasma creatinine or renal replacement therapy.
During the last 20 years, many prospective and epidemio-
logic studies have found that microalbuminuria is predictive,
independently of traditional risk factors, of all-cause and car-
diovascular mortality and cardiovascular disease events with-
in groups of patients with diabetes or hypertension and in the
general population. In 1989, Deckert et al had already postu-
lated that albuminuria reflects widespread vascular damage.2
The pathophysiological mechanism underlying the associa-
tion between albumin excretion and cardiovascular disease
has, to this day, not been fully elucidated. One hypothesis is
that microalbuminuria may be a marker of cardiovascular risk
because it reflects subclinical vascular damage in the kidneys
and other vascular beds. It may also signify systemic endo-
thelial dysfunction that predisposes to future cardiovascular
events.
Is microalbuminuria a marker for microangiopathy or macroangiopathy?
CONTROVERSIAL QUESTION
A positive test for urinary albumin excretion should be taken
as a clarion call to initiate an intensive multifactorial interven-
tion strategy, including behavior modification and targeted
pharmacotherapy aimed at preventing further renal deteriora-
tion and improving the overall cardiovascular risk factor profile.3
Data from intervention studies suggest that treatment with an-
giotensin-converting enzyme inhibitors or angiotensin II re-
ceptor blockers, statins, and/or strict glycemic control (in di-
abetics) offer significant reductions in cardiovascular and/or
renal morbidity in patients with albuminuria. Use of the microal-
buminuria marker may allow improved use of medications and
strategies for secondary prevention.
There has been good news from the Action in Diabetes and
Vascular disease: PreterAx and DiamicroN MR Controlled
Evaluation (ADVANCE) study. Its results indicate that both rou-
tine blood pressure lowering 4 and intensive glucose control 5
significantly decrease new or worsening nephropathy by 18%
and 19%, respectively, attaining a relative risk reduction of 33%
for the joint effect of both interventions.6 Since microalbumin-
uria and, in particular, macroalbuminuria are strong predic-
tors of end-stage renal disease, cardiovascular morbidity, and
cardiovascular mortality, the routine use of the intervention
strategies deployed in ADVANCE will help to improve the per-
sistently poor overall prognosis of large numbers of type 2
diabetic patients worldwide. 
References
1. Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality
in maturity-onset diabetes. N Engl J Med. 1984;310:356-360.
2. Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen
A. Albuminuria reflects widespread vascular damage. The Steno hypothesis. Di-
abetologia. 1989;32:219-226.
3. Schernthaner G. Kidney disease in diabetology: lessons from 2007. Nephrol Dial
Transplant. 2008;23:1112-1115.
4. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Effects
of a fixed combination of perindopril and indapamide on macrovascular and mi-
crovascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE
trial): a randomised controlled trial. Lancet. 2007;370:829-840.
5. ADVANCE Collaborative Group. Intensive blood glucose control and vascular out-
comes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.
6. Chalmers J et al. Joint effects of routine blood pressure lowering with Coversyl
Plus and intensive glucose control with a gliclazide MR-based regimen. In: The
44th Annual Meeting of the European Association for the Study of Diabetes;
September 7-11, 2008; Rome, Italy.
MEDICOGRAPHIA, Vol 31, No. 3, 2009 281
CONTROVERSIAL QUESTION
9. M. Shestakova, Russia
Marina SHESTAKOVA, MD, PhD
Professor, Director, Diabetes Institute
Endocrinology Research Center, 117036
Dm Ulyanov str 11, Moscow, RUSSIA
(e-mail: nephro@endocrincentr.ru)
D
iabetic nephropathy has long laid the largest single
claim on dialysis services in developed countries, ac-
counting for 44% of dialysis facilities in the USA. The
rates of progression to proteinuria 15 years after diagnosis are
15% and 20% in diabetes types 1 and 2.1 The Datamonitor
multiclient study in type 2 diabetes suggests that the overall
prevalence of nephropathy (microalbuminuria, proteinuria, and
end-stage renal disease [ESRD]) is 48% across the seven
countries, representing 18.6 million patients.
However, the markers of diabetic nephropathy—micro- and
macroalbuminuria—are not only predictors of progression,
but also independent cardiovascular risk factors. This associ-
ation constitutes the cardiorenal syndrome. In the current set-
ting of timely nephrological care, diabetics no longer die from
uremia, but from cardiovascular disorders (myocardial infarc-
tion, stroke, and large artery thrombosis). ESRD is responsible
for 30% of deaths in type 1 diabetes and 5% in type 2, with
cardiovascular accidents still accountable for the majority.2
In the Wisconsin Epidemiological Study of Diabetic Retinopa-
thy in type 2 diabetics, micro- and macroalbuminuria (or pro-
teinuria) increased cardiovascular mortality 2.2-fold and 3.7-
fold in comparison with patients without renal disease, even
after adjusting for traditional coronary risk factors (age, gen-
der, blood glucose, blood pressure [BP], and family history).
In the Heart Outcomes Prevention Evaluation (HOPE) in over-
55s with coronary risk factors, microalbuminuria also doubled
cardiovascular mortality in patients without renal disease, in
both type 2 diabetics and nondiabetics. Every 0.4 mg/mmol
increase in albumin/creatinine ratio increased major cardio-
vascular events by 5.9%, all-cause mortality by 6.8%, and
heart failure–related hospitalization by 10.6%.3
Two large trials, Losartan Intervention For Endpoint reduction
in hypertension (LIFE) and Reduction of Endpoints in NIDDM
with the Angiotensin II Antagonist Losartan (RENAAL), pro-
282 MEDICOGRAPHIA, Vol 31, No. 3, 2009
vided robust evidence linking urinary albumin excretion to
cardiovascular mortality. Both showed parallel decreases in
urinary albumin excretion in response to long-term antihyper-
tensive treatment, on the one hand, and in cardiovascular
mortality, stroke, and myocardial infarction, on the other. The
atherogenicity of microalbuminuria remains unexplained. Mi-
croalbuminuria may reflect systemic endothelial dysfunction
and increased plasma membrane permeability throughout
the vascular tree; there is also an association with inflamma-
tory markers. In diabetes, it reflects endothelial dysfunction,
resulting in increased permeability to blood corpuscles, pro-
teins, lipids, and other plasma components.4
The Action in Diabetes and Vascular disease: PreterAx and
DiamicroN MR Controlled Evaluation (ADVANCE) trial, the
largest ever in diabetes (>11 000 type 2 diabetics, mean age
66 years, 10% and 32% with micro- and macrovascular com-
plications), has shed light on the clinical relationship between
nephropathy markers and cardiovascular events.5 Nephropa-
thy markers were equally sensitive to intensive blood glucose
control (using Diamicron MR) and intensive BP control (using
Preterax Forte): total renal events decreased significantly by
21% in both arms. Joint intensive control achieved the great-
est decrease in renal events (33%),6 and in total and cardio-
vascular mortality (18% and 24%).
The parallel between renoprotection and decrease in cardio-
vascular mortality confirms the hypothesis of a relationship
between the markers of renal and cardiovascular disorders.
ADVANCE provides convincing evidence that even in elderly
longstanding type 2 diabetics at high cardiovascular risk, treat-
ments such as Diamicron MR and Preterax Forte are a safe and
effective strategy for decreasing the development and progres-
sion of cardiorenal syndrome and cardiovascular mortality. 
References
1. Hovind P, Tarnow L, Rossing P, et al. Predictors for the development of microal-
buminuria and macroalbuminuria in patients with type 1 diabetes: inception co-
hort study. BMJ. 2004;328:1105-1116.
2. Allen KV, Walker JD. Microalbuminuria and mortality in long-duration type 1 dia-
betes. Diabetes Care. 2003;26:2389-2391.
3. Gerstein HC, Mann JFE, Yi Q, et al. Albuminuria and risk of cardiovascular events,
death, and heart failure in diabetic and non-diabetic individuals. JAMA. 2001;286:
421-426.
4. Shestakova MV, Jarek-Martynowa IR, Ivanishiva NS, et al. Role of endothelial dys-
function in the development of cardiorenal syndrome in patients with type 1 dia-
betes mellitus. Diab Res Clin Pract. 2005;68(suppl 1):S65-S72.
5. ADVANCE Collaborative Group. Intensive blood glucose control and vascular out-
comes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.
6. www.advance-trial.com.
Is microalbuminuria a marker for microangiopathy or macroangiopathy?

10. J.-G. Wang, Y. Li, and C.-S. Sheng, China

Ji-Guang WANG, MD, PhD
Yan LI, MD, PhD
Chang-Sheng SHENG, MD
Corresponding author:
Ji-Guang Wang, Professor
Shanghai Institute of Hypertension
Ruijin 2nd Road 197
Shanghai 200025, CHINA
(e-mail: jiguangw@gmail.com)
M
icroalbuminuria is a biological indicator or marker of
structural and/or functional lesions in small arteries.
Given the difficulties in imaging arteriolar structure
and function, microalbuminuria is probably the best available
measure of microangiopathy. Numerous studies in various
populations have demonstrated that it predicts not only end-
stage renal disease, but also major cardiovascular disease,
such as myocardial infarction and stroke.1 There is also abun-
dant evidence that contemporary cardiovascular treatments,
such as angiotensin-converting enzyme (ACE) inhibitors and
angiotensin receptor blockers (ARBs), reduce urinary albu-
min excretion in addition to lowering blood pressure.2
There is no doubt that microalbuminuria is a predictor of car-
diovascular mortality and morbidity. However, the main con-
troversial issue is whether pharmacologically reducing urinary
albumin excretion using ACE inhibitors or ARBs is clinically
relevant in preventing cardiovascular events. The Irbesartan in
Diabetic Nephropathy Trial (IDNT) compared an ARB, irbesar-
tan (titrated from 75 mg to 300 mg/day), with a calcium chan-
nel blocker, amlodipine (titrated from 2.5 mg to 10 mg/day),
in type 2 diabetics with proteinuria (at least 900 mg/day) and
blood pressure 135/85 mm Hg or receiving antihypertensive
therapy.3 During follow-up (mean 2.6 years), irbesartan signif-
icantly reduced the risks of serum creatinine doubling (–37%,
P<0.001), end-stage renal disease (–23%, P=0.07),3 and con-
gestive heart failure (–35%, P=0.004) versus amlodipine.4 How-
ever, the risks of myocardial infarction (+54%, P=0.07), stroke
(+55%, P=0.16), and cardiovascular mortality (+36%, P=0.15)
were higher in the irbesartan group.4
The recently published ONgoing Telmisartan Alone and in
combination with Ramipril Global Endpoint Trial (ONTARGET)
observed the same paradoxical results in three parallel groups
Is microalbuminuria a marker for microangiopathy or macroangiopathy?
CONTROVERSIAL QUESTION
of patients receiving an ACE inhibitor, ramipril (10 mg/day),
alone, an ARB, telmisartan (80 mg/day), alone, and the com-
bination of ramipril and telmisartan (10 mg & 80 mg/day).5
There was a significant difference in urinary albumin excretion
at 2 years and at the end of the trial, the most pronounced
effect being in the combination therapy group of ramipril and
telmisartan (2-year urinary albumin/creatinine ratio to base-
line, 1.05; P<0.0001 vs ramipril), with an intermediate effect
in the telmisartan group (1.08, P= 0.001 vs ramipril), and the
least effect in the ramipril group (1.17).6 However, the risk of
the primary outcome (cardiovascular death, myocardial infarc-
tion, stroke, and hospitalization for congestive heart failure)
was similar in the three groups (16.3% vs 16.7% vs 16.5%).5
The IDNT and ONTARGET results suggest that the reduction
of urinary albumin excretion cannot be translated into hard
cardiovascular outcome benefit in patients at high cardio-
vascular or renal risk. However, the contradictory effects of
treatment on albuminuria and cardiovascular outcome do not
entirely exclude the possibility that the long-term ameliora-
tion of microalbuminuria is protective against cardiovascular
disease because, in both these trials, patients were at high
risk and follow-up duration was short (2.6 to 4.8 years). Fu-
ture studies should focus on patients with microalbuminuria,
but without preexisting cardiovascular disease or evidence
of large arterial lesions in order to investigate the influence
of ACE inhibitors and ARBs (potentially beneficial because of
their dilating effect on the microcirculation, including arterioles
and venules). 
References
1. Diercks GF, van Boven AJ, Hillege JL, de Jong PE, Rouleau JL, van Gilst WH.
The importance of microalbuminuria as a cardiovascular risk indicator: a review.
Can J Cardiol. 2002;18:525-535.
2. de Zeeuw D, Parving HH, Henning RH. Microalbuminuria as an early marker for
cardiovascular disease. J Am Soc Nephrol. 2006;17:2100-2105.
3. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angio-
tensin-receptor antagonist irbesartan in patients with nephropathy due to type 2
diabetes. N Engl J Med. 2001;345:851-860.
4. Berl T, Hunsicker LG, Lewis JB, et al. Cardiovascular outcomes in the Irbesartan
Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephro-
pathy. Ann Intern Med. 2003;138:542-549.
5. ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for
vascular events. N Engl J Med. 2008;358:1547-1559.
6. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan,
ramipril, or both, in people at high vascular risk (the ONTARGET study): a multi-
centre, randomised, double-blind, controlled trial. Lancet. 2008;372:547-553.
MEDICOGRAPHIA, Vol 31, No. 3, 2009 283

‘‘ The findings and conclusions
of ADVANCE confirm and reinforce
those of UKPDS by providing fur-
ther evidence of the benefits of a
multifactorial approach combining
intensive blood pressure lowering
[with Preterax] and intensive blood
glucose control [with Diamicron
MR], in patients with type 2 dia-
betes…. This therapeutic strategy
provides the most effective and
safe multifactorial approach for
ensuring maximum benefit for all
type 2 diabetic patients.”
Sylvie LAROCHE, MD
Stefano CORDA, MD, PhD
Servier International
Suresnes
FRANCE
Address for correspondence:
Sylvie Laroche/Stefano Corda,
Servier International,
35 rue de Verdun, 92284 Suresnes
Cedex, France
(e-mail: sylvie.laroche@fr.netgrs.com/
stefano.corda@fr.netgrs.com)
www.medicographia.com
284 MEDICOGRAPHIA, Vol 31, No. 3, 2009
DIAMICRON MR - PRETERAX
Management
of type 2 diabetes:
a multifactorial approach
to a complex disease
b y S . L a ro c h e a n d S . C o rd a , Fra n c e
T
he epidemic of type 2 diabetes is increasing dramatically throughout
the world. Action in Diabetes and Vascular disease: PreterAx and Dia-
microN MR Controlled Evaluation (ADVANCE) is a landmark trial that ex-
plored the appropriateness of a two-pronged therapeutic strategy consisting
of intensive blood pressure lowering, based on adding a single tablet com-
bination of perindopril/indapamide (Preterax) on top of current contempo-
rary treatment, together with intensive glucose control, based on gliclazide
modified release (Diamicron MR)—one dose of up to 4 tablets per day fol-
lowed by a stepwise combination of other oral antidiabetic drugs, where nec-
essary. The blood pressure–lowering strategy yielded strong and significant
reductions in death from any cause and death from cardiovascular disease,
as well as reductions in coronary and renal complications. The glucose-low-
ering strategy yielded a significant reduction in a composite of macrovascu-
lar and microvascular events, driven by a significant reduction in renal compli-
cations together with a reduction in cardiovascular complications, all while
displaying excellent safety, with regard to hypoglycemia, and with no weight
gain. These properties make Diamicron MR a key therapy for type 2 diabetes,
with potential benefits over and above those achievable with good glycemic
control alone. ADVANCE thus provided clear answers by confirming the val-
ue of this new, simple, and pragmatic treatment algorithm combining inten-
sive blood pressure lowering, based on Preterax, and intensive glucose low-
ering, based on Diamicron MR, and by showing that their clinical benefits
were additive. This therapeutic strategy constitutes a genuine multifactori-
al approach ensuring maximum benefit and safety for all type 2 diabetic pa-
tients.
Medicographia. 2009;31:284-294 (see French abstract on page 294)
ADVANCE: a clear answer in diabetes care
 ADVANCE in the context of landmark studies
T
he prevalence of diabetes mellitus is assuming epidemic proportions world-
wide.1 Cardiovascular disease is a common cause of morbidity and mortal-
ity in individuals with type 2 diabetes, as demonstrated by the Framingham
study.2 Macrovascular and microvascular complications contribute to death, disabil-
ities, and reduction in life expectancy in diabetes. Overall, the risk of vascular disease
in people with diabetes is significantly elevated compared with that of nondiabetic
individuals, due to diabetes per se as well as to risk factors, such as high blood pres-
sure and high blood lipids.
Management of type 2 diabetes: a multifactorial approach – Laroche and Corda

In this context, it clearly appears that multiple risk factor man-
agement offers great potential to reduce the risks of macro-
vascular and microvascular disease.3 Two specific treatment
modalities have been shown to reduce the risk of major macro-
vascular and microvascular events in individuals with diabetes:
blood pressure lowering4 and blood glucose lowering.5 Many
trials have looked at whether more intensive treatment reg-
imens or newer drugs can extend the vascular disease pro-
tection provided to individuals with diabetes. Two questions
were still unanswered at the time ADVANCE (Action in Dia-
betes and Vascular disease: PreterAx and DiamicroN MR Con-
trolled Evaluation) started: (i) what should the magnitude of
blood pressure lowering be; and (ii) which HbA 1c target should
blood glucose reduction aim to achieve, in view of the fact that
the classic recommended targets were a systolic blood pres-
sure (SBP) below 140 mm Hg and HbA 1c below 7%.
 Rationale for blood pressure lowering in type 2 diabetes
In patients with diabetes, average blood pressure levels are
higher than those in nondiabetic people.4,5 A continuous rela-
tionship exists between blood pressure and development of
macrovascular disease, including coronary heart disease and
stroke, without any identifiable lower level of blood pressure
below which risk does not decline.6 Lowering blood pressure
prevents cardiovascular and renal outcomes in people with
hypertension and diabetes. Blood pressure is also a major de-
terminant of risk among those whose blood pressure is in the
normal range.
At the time ADVANCE was designed, randomized clinical tri-
als had clearly established that intensive blood pressure low-
ering reduced the risk of stroke and major cardiovascular
events in hypertensive individuals with type 2 diabetes.7-9
SELECTED ABBREVIATIONS AND ACRONYMS
ACCORD Action to Control CardiOvascular Risk in
Diabetes
ADVANCE Action in Diabetes and Vascular disease:
PreterAx and DiamicroN MR Controlled
Evaluation
HOPE Heart Outcomes Prevention Evaluation
HOT Hypertension Optimal Treatment
IDNT Irbesartan in Diabetic Nephropathy Trial
IRMA IRbesartan for MicroAlbuminuria in type 2
diabetes
MICRO-HOPE MIcroalbuminuria, Cardiovascular and Renal
Outcomes in the Heart Outcomes Preven-
tion Evaluation
RENAAL Reduction of Endpoints in Noninsulin-depend-
ent diabetes mellitus with Angiotensin II
Antagonist Losartan
STRATHE STRAtegies of Treatment in Hypertension:
Evaluation
UKPDS United Kingdom Prospective Diabetes Study
Management of type 2 diabetes: a multifactorial approach – Laroche and Corda
DIAMICRON MR - PRETERAX
UKPDS 38 (United Kingdom Prospective Diabetes Study 38)
showed that tight control of blood pressure achieved a reduc-
tion in the risk of stroke and total major cardiovascular events
of 30% to 40% compared with less intensive blood pressure
lowering, although no clear effect on the risk of coronary heart
disease was observed.4 The Hypertension Optimal Treatment
(HOT) study reported a 30% reduction in the risk of total ma-
jor cardiovascular events in people with diabetes.10 The Heart
Outcomes Prevention Evaluation (HOPE) showed that treat-
ment with an angiotensin-converting enzyme (ACE) inhibitor
reduced stroke risk by around a third and coronary events by
around a fifth among individuals with high-risk diabetes, the
majority of whom had preexisting coronary heart disease, and
that these results were independent of baseline blood pres-
sure.11,12 Furthermore, in HOPE,11 there was a reduction of
around a sixth in nephropathy and retinopathy in people with
diabetes treated with an ACE inhibitor, while the UKPDS tri-
al4 reported a reduction of more than a third in microvascular
events (mainly in the need for retinal photocoagulation) in hy-
pertensive patients with diabetes assigned to the more inten-
sive blood pressure–lowering regimen.
 Rationale for blood glucose lowering
Although the relationship between glycemic control and dia-
betic microvascular and macrovascular complications is con-
tinuous, as is the case with blood pressure lowering, it is less
clear that improving blood glucose below recommended tar-
gets would translate into a further reduction in cardiovascu-
lar complications. By the time ADVANCE was planned (at the
beginning of 2000), the landmark UKPDS study had already
confirmed the benefit of intensive blood glucose control.5 In
particular, lowering HbA 1c by an average of 0.9% over 10
years resulted in a trend toward reduction of myocardial in-
farction (by 16%) as well as a statistically significant 25% re-
duction in microvascular disease that was mainly driven by
a decrease in retinopathy.
More recently, the Steno 2 study highlighted the need for mul-
tifactorial risk reduction based on treatment combining an in-
tensive glucose-lowering strategy (using Diamicron), lipid low-
ering, and antihypertensive treatment to reduce the risk of
microvascular and macrovascular complications in high-risk
patients.13 Such an approach yielded a more than 50% reduc-
tion in all major outcomes, including macrovascular disease,
among individuals with diabetes randomized to a multifacto-
rial intervention compared with conventional treatment.13,14
 ADVANCE study design
ADVANCE was a combined 22 factorial study, conducted in
215 centers and 20 countries. The main aim of the trial was
to assess the effects of lowering blood pressure and HbA 1c to
6.5%, or lower, on major vascular outcomes in diabetes. Pa-
tients were at least 55 years of age and had a history of mi-
crovascular and macrovascular disease or at least one car-
diovascular risk factor.7 Patients were randomly assigned to
MEDICOGRAPHIA, Vol 31, No. 3, 2009 285
DIAMICRON MR - PRETERAX

either standard blood pressure control or reinforced blood

pressure control with Preterax (perindopril/indapamide) and
to either intensive glucose-lowering therapy, with an HbA 1c 5 --18%
target of 6.5%, or lower, or standard glucose control. The prin- P=0.02

Cumulative incidence (%)

cipal treatment in the intensive glucose-lowering regimen was
Diamicron MR (30 to 120 mg daily, ie, 1 to 4 tablets daily).7,15,16
Patients in each study group were followed up for a median
of 5 years. The primary end points of ADVANCE were a com-
posite of macrovascular events and a composite of microvas-
cular events, considered together or separately, and the two
treatment strategies were assessed separately as well as to-
gether (in those patients receiving both intensive regimens),
so as to determine their joint effect.
The ADVANCE population was very representative of daily clin-
ical practice, with a mean age of 66 years and a mean age
of type 2 diabetes diagnosis of 58 years. The two treatment
groups had similar blood glucose parameters at baseline in-
cluding mean HbA 1c (7.5%), and fasting plasma glucose (8.5
mmol/L). In both groups, 1 in 3 patients had a history of macro-
vascular disease and 1 in 10 had microvascular disease. Car-
diovascular risk factors, including mean blood pressure, serum
cholesterol and triglycerides, body mass index, and cigarette
smoking were comparable in the two groups.15,16
 Main results of the ADVANCE blood pressure–
lowering arm
The main results of the blood pressure–lowering arm published
in the Lancet (2007)15 are briefly summarized here. A total of
11 140 individuals with type 2 diabetes were randomized. The
Placebo
+ current therapy
Preterax
+ current therapy
0
0 1 2 3 4 5
Follow-up (years)
Figure 1. Cardiovascular mortality reduction in ADVANCE (Action
in Diabetes and Vascular disease: PreterAx and DiamicroN MR
Controlled Evaluation).
Based on data from reference 15.
mean duration of follow-up was 4.3 years and only 15 par-
ticipants were lost to follow-up. The mean entry blood pres-
sure was 145/81 mm Hg, with 41% having a blood pressure
below 140/90 mm Hg. The reduction in blood pressure in par-
ticipants assigned active treatment with Preterax was 5.6/
2.2 mm Hg, significantly greater than the placebo group. The
average SBP achieved during follow up was 140.3 mm Hg in
the placebo group and 134.7 mm Hg in the active treatment
group; the average diastolic blood pressure (DBP) during fol-
low-up was 77.0 mm Hg in the placebo group and 74.8 mm
Hg in the Preterax group.

Perindopril-indapamide
End point (No. of events/patients [%]) Placebo HR (95% CI) P NNT

Progression of nephropathy
All renal events 1243/5569 (22.3) 1500/5571 (26.9) 0.79 (0.73 to 0.85) <0.0001 20
Progression of 1 albuminuria stage 1179/5436 (21.7) 1442/5412 (26.6) 0.78 (0.72 to 0.84) <0.0001 18
New-onset microalbuminuria 1094/3995 (27.4) 1317/3991 (33.0) 0.79 (0.73 to 0.86) <0.0001 16
New-onset macroalbuminuria 114/5436 (2.1) 163/5412 (3.0) 0.69 (0.54 to 0.88) 0.0027 97
- Patients with normoalbuminuria 25/3995 (0.6) 35/3991 (0.9) 0.71 (0.42 to 1.18) 0.1841 NA
- Patients with microalbuminuria 89/1441 (6.2) 128/1421 (9.0) 0.69 (0.52 to 0.91) 0.0074 32
Doubling of serum creatinine >200 μmol/L 55/5569 (1.0) 45/5571 (0.8) 1.21 (0.81 to 1.79) 0.3483 NA
End-stage kidney disease† 25/5569 (0.4) 21/5571 (0.4) 1.18 (0.66 to 2.11) 0.5736 NA

Regression of nephropathy
Regression of 1 albuminuria stage 908/1638 (55.4) 816/1625 (50.2) 1.16 (1.06 to 1.28) 0.0017 19
Regression to normoalbuminuria 848/1638 (51.8) 745/1625 (45.8) 1.15 (1.04 to 1.27) 0.0059 16
- Patients with microalbuminuria 797/1441 (55.3) 698/1421 (49.1) 1.15 (1.04 to 1.27) 0.0067 16
- Patients with macroalbuminuria 51/197 (25.9) 47/204 (23.0) 1.08 (0.72 to 1.60) 0.7146 NA

* NA, not applicable; NNT, number needed to treat to prevent one event of nephropathy progression or to promote one event of nephropathy regression over 5 years.
† Defined as requirement of renal replacement therapy or renal death.

Table I. Incidence of renal end points* in ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled
Evaluation).
Reproduced from reference 17: de Galan BE et al. J Am Soc Nephrol. 18 February 2009 [Epub ahead of print]. Copyright © 2009, American Society of Nephrology.

286 MEDICOGRAPHIA, Vol 31, No. 3, 2009 Management of type 2 diabetes: a multifactorial approach – Laroche and Corda
 DIAMICRON MR - PRETERAX

Number (%) of patients

with event
Perindopril- Placebo Favors Favors Relative risk
indapamide (n=5571) perindopril- placebo reduction
(n=5569) indapamide (95% CI)

Combined macro+micro 861 (15.5%) 938 (16.8%) 9% (0 to 17)

Macrovascular 480 (8.6%) 520 (9.3%) 8% (–4 to 19)

Microvascular 439 (7.9%) 477 (8.6%) 9% (–4 to 20)

All deaths 408 (7.3%) 471 (8.5%) 14% (2 to 25)

Cardiovascular death 211 (3.8%) 257 (4.6%) 18% (2 to 32)

Noncardiovascular disease death 197 (3.5%) 212 (3.8%) 8% (–12 to 24)

Total coronary events 468 (8.4%) 535 (9.6%) 14% (2 to 24)

Major coronary events 265 (4.8%) 294 (5.3%) 11% (–6 to 24)

Other coronary events* 283 (5.1%) 324 (5.8%) 14% (–1 to 27)

Total cerebrovascular events 286 (5.1%) 303 (5.4%) 6% (–10 to 20)

Major cerebrovascular events 215 (3.9%) 218 (3.9%) 2% (–18 to 19)

Other cerebrovascular events† 79 (1.4%) 99 (1.8%) 21% (–6 to 41)

Total renal events 1243 (22.3%) 1500 (26.9%) 21% (15 to 27)

New or worsening nephropathy 181 (3.3%) 216 (3.9%) 18% (–1 to 32)

New microalbuminuria 1094 (19.6%) 1317 (23.6%) 21% (14 to 27)

Total eye events 2531 (45.4%) 2611 (46.9%) 5% (–1 to 10)

New or worsening retinopathy 289 (5.2%) 286 (5.1%) –1% (–18 to 15)

Visual deterioration 2446 (43.9%) 2514 (45.1%) 5% (–1 to 10)

0.5 1.0 2.0

Hazard ratio

* Other coronary events = unstable angina requiring hospitalization, coronary revascularization, or silent myocardial infarction.
† Other cerebrovascular events = transient ischemic attack (including amaurosis fugax) or subarachnoid hemorrhage.
Blue squares = point estimates (with area proportional to number of events); horizontal lines = 95% CI.
Diamonds = point estimate and 95% CI for overall effects.
Vertical broken lines = point estimates for overall effect, within categories.

Figure 2. Effects of study treatment on deaths, coronary events, cerebrovascular events, renal events, and eye events.
Reproduced from reference 15: ADVANCE Collaborative Group. Lancet. 2007;370:829-840. Copyright © 2007, Elsevier Ltd.

Treatment with Preterax reduced the risk of the combined
composite primary microvascular and macrovascular out-
comes by 9% (0% to 17%) (P=0.41). The reductions in the pri-
mary macrovascular and microvascular outcomes, analyzed
separately, were of similar magnitude, though no longer sig-
nificant.15 Preterax also significantly reduced all-cause mortal-
ity by 14% (P=0.025) and cardiovascular mortality by 18%
(P=0.027) (Figures 1 and 2), while achieving a substantial re-
duction in total coronary events (14%; P=0.02), total renal
events (21%; P=0.0001), and new-onset microalbuminuria
(21%; P=0.001) (Table I).17 No statistically significant reduc-
tion in cerebrovascular events or microvascular eye disease
was evidenced; however, a trend in favor of treatment was ob-
served concerning total cerebrovascular events.15
When analyzed separately, reductions in macrovascular and
microvascular events were similar, but did not achieve statis-
tical significance. The 9% overall reduction in the risk of major
macrovascular or microvascular events was driven by an 18%
reduction in the risk of death from cardiovascular disease,
largely contributing to the 14% reduction in total mortality.
Based on ADVANCE data, it appears that 1 death would be

Management of type 2 diabetes: a multifactorial approach – Laroche and Corda MEDICOGRAPHIA, Vol 31, No. 3, 2009 287
DIAMICRON MR - PRETERAX
prevented over 5 years in every 79 patients treated with the
study drugs. In a recent subanalysis, Preterax was shown to
significantly reduce the risk of renal events by 21% (P<0.0001).
Progression of albuminuria was reduced by 22% (P<0.0001)
and regression of albuminuria was increased by 16% (P=0.002).
Furthermore, the rate of renal events decreased log-linearly
with decreasing achieved follow-up blood pressure, down to
levels of SBP below 110 mm Hg.17
 Main results of the intensive blood glucose–lowering
strategy with Diamicron MR
In ADVANCE, intensive blood glucose lowering based on Dia-
micron MR progressively lowered mean HbA 1c to the target
of 6.5% after 36 months, a level that was maintained until the
end of the study. More than 60% of the patients achieved
an HbA 1c target below 6.5%. In contrast, standard glucose
lowering reduced mean HbA 1c to 7.3% after 6 months and
this figure remained stable thereafter (Figure 3).16
10.0
9.5
Mean glycated hemoglobin (%)
9.0
8.5
8.0
P<0.001
7.5
7.0
6.5
6.0
5.5
5.0
0.0
0 6 12 18 24 30
Months of follow-up
Value
Standard 7.32 7.30 7.29
Intensive 7.01 6.93 6.70
Figure 3. Glucose control at baseline and after follow-up in
ADVANCE (Action in Diabetes and Vascular disease: PreterAx and
DiamicroN MR Controlled Evaluation).
Reproduced from reference 16: ADVANCE Collaborative Group. N Engl J Med.
2008;358:2560-2572. Copyright © 2008, Massachusetts Medical Society.
Intensive glucose control with Diamicron MR induced a signif-
icant 10% relative risk reduction (RRR) in the combined primary
end point of macrovascular and microvascular events, com-
pared with standard control (18% versus 20%, respectively;
P=0.01). Considering each component of the primary end
point separately, intensive glucose control yielded a 14% RRR
of major microvascular events (9.4% versus 10.9%; P=0.01)
and a 6% RRR in major macrovascular events (10.0% versus
10.6%; P=0.32). In addition, the Diamicron MR–based inten-
sive glucose-lowering strategy showed a beneficial impact on
renal events, with a 21% significant reduction in new or wors-
ening nephropathy (P=0.006), and, in particular, a 30% de-
crease in macroalbuminuria (P<0.001) and a 9% decrease in
288 MEDICOGRAPHIA, Vol 31, No. 3, 2009
microalbuminuria (P=0.018). Importantly, there was a trend
toward reduction in total mortality (7%, P=0.28), with an even
more pronounced reduction in cardiovascular mortality (12%
decrease, P=0.12) (Figure 4).
The effects of study treatment were consistent across sub-
groups by age, sex, baseline blood pressure, baseline HbA 1c,
previous vascular disease, or concomitant cardiovascular med-
ications.15,16
 Combined treatments, joint effects
The factorial design of ADVANCE also allowed the assessment
of the interaction of the two treatment strategies (Preterax and
Diamicron MR) at the end of the follow-up period for the blood
pressure–lowering arm of the study (4.3 years). The effects of
the two treatments were independent of one another and fully
additive for all prespecified clinical outcomes, including the pri-
mary outcome. In particular, the additive effects of treatment
with Preterax and Diamicron MR amplified the benefits of each
treatment taken individually, with a significant 24% reduction
in cardiovascular mortality, a 33% reduction in renal disease,
and an 18% reduction in all-cause mortality.18
Blood pressure and glucose reduction in ADVANCE
in the light of existing evidence
Standard control  Blood pressure results with Preterax
In the ADVANCE blood pressure–lowering arm, the fixed com-
bination of Preterax (perindopril and indapamide) reduced the
Intensive control risk of death and major macrovascular or microvascular events
in a broad range of patients with type 2 diabetes. The bene-
fits were achieved against a background of excellent contem-
porary treatment, which, by the end of follow-up, included non-
36 42 48 54 60 66 study blood pressure–lowering drugs (in 75% of participants),
statins, aspirin (in around half of all participants), and one or
7.29 7.31 7.33 7.29 more glucose-lowering agents (in more than 90% of partici-
6.53 6.50 6.52 6.53 pants), including insulin in a third of patients.
In ADVANCE, the overall event rate in the combined compos-
ite primary macrovascular and microvascular end point was
only 4% per year, ie, much lower than that reported by previous
large-scale blood pressure–lowering trials in type 2 diabetes.
Indeed, the benefits observed in ADVANCE are all the more re-
markable as the baseline blood pressure values and incidence
of macrovascular and microvascular events, as well as mor-
tality, were themselves lower than in those other studies.
ADVANCE findings showed that Preterax achieved a further
reduction in blood pressure and macrovascular and microvas-
cular events on top of that elicited by the standard background
treatment, and which, over a period of 5 years, would avert
1 major vascular event among every 66 patients. Blood pres-
sure lowering in ADVANCE started where UKPDS left off: in
the intensive blood pressure–lowering arm of UKPDS, the
systolic blood pressure at study end was 145 mm Hg. SBP in
ADVANCE was lowered from 145 to 136 mm Hg. A further re-
Management of type 2 diabetes: a multifactorial approach – Laroche and Corda

Figure 4. Effects of intensive glucose-lowering therapy on primary end points in ADVANCE (Action in Diabetes and Vascular disease:
PreterAx and DiamicroN MR Controlled Evaluation).
Modified after reference 16: ADVANCE Collaborative Group. N Engl J Med. 2008; 358:2560-2572. Copyright © 2008, Massachusetts Medical Society.
duction in mortality, cardiovascular events, and renal events as
well as an impressive reduction in microalbuminuria (the largest
ever in a hypertensive/normotensive population) were report-
ed. These effects of Preterax are important in view of the high
risk of progression to end-stage renal failure and premature
death in patients who develop diabetic nephropathy, as well as
emerging evidence of substantial cardiovascular risks asso-
ciated with the progression of renal impairment.19 ADVANCE
also goes beyond MICRO-HOPE (MIcroalbuminuria, Cardio-
vascular and Renal Outcomes in the Heart Outcomes Preven-
tion Evaluation) in showing that Preterax provided further ef-
ficacy on top of all other preventive therapies, including ACE
inhibition.11,15 Lastly, ADVANCE goes well beyond studies car-
ried out with angiotensin receptor blockers (ARBs) in diabetic
hypertensive populations with albuminuria (IRMA, IDNT, and
RENAAL: respectively, IRbesartan for MicroAlbuminuria in
type 2 diabetes; Irbesartan in Diabetic Nephropathy Trial; and
Reduction of Endpoints in Noninsulin-dependent diabetes mel-
litus with Angiotensin II Antagonist Losartan).20-22 Although these
studies did show benefits, these were limited to the progres-
sion of nephropathy, without any evidence of reduction in to-
tal and cardiovascular mortality. A recent meta-analysis com-
paring the effects of ACE inhibitors and ARBs has confirmed
that these two classes of drugs have similar effects on renal
outcomes, but, whereas ACE inhibitors reduce all-cause mor-
tality compared with placebo, ARBs do not, and actually in-
crease the absolute risk of myocardial infarction.23,24
 ADVANCE results of intensive glucose lowering with Dia-
micron MR in the context of other morbidity-mortality trials
In the blood glucose–lowering arm of ADVANCE,16 intensive
blood glucose lowering with Diamicron MR achieved progres-
Management of type 2 diabetes: a multifactorial approach – Laroche and Corda
DIAMICRON MR - PRETERAX
sive and sustained blood glucose control, as evidenced by a
reduction in HbA 1c levels to 6.5%, and lower, with no weight
gain and very acceptable levels of hypoglycemia over 5 years’
follow-up. These findings contrast with those reported by the
ACCORD trial (Action to Control CardiOvascular Risk in Di-
abetes), which was prematurely terminated due to excess
deaths in the intensive therapy group, presumably related to
adverse cardiovascular events associated with hypoglycemia
when aiming at normal HbA 1c levels (<6%) too rapidly, suggest-
ing that aggressive glucose-lowering treatment is harmful.25
In contrast to the increase in mortality reported in ACCORD, a
trend toward reduction in mortality (a 7% decrease), associat-
ed with a 12% reduction in cardiovascular mortality, was ob-
served in ADVANCE.16 The intensive glucose control strategies
used in ADVANCE and ACCORD differed substantially, both re-
garding the HbA1c target and how this target was achieved.16,25,26
In ADVANCE, optimized titration of Diamicron MR up to the
maximum dose was implemented before adding any other oral
antidiabetic drug (OAD), which resulted in progressive rather
than aggressive glucose control, as in ACCORD.
Even though no significant difference in reduction in macro-
vascular events and mortality could be observed between the
intensive and standard blood glucose–lowering treatment
groups, a reduction in the intensive blood glucose–lowering
group taking Diamicron MR became obvious from the 5th
year of treatment onward. This observation suggests that the
effect on macrovascular outcomes and mortality benefits may
be delayed, only translating into a more dramatic reduction
in macrovascular events after several years. The findings of
ADVANCE may thus be explained by a “legacy” effect, simi-
MEDICOGRAPHIA, Vol 31, No. 3, 2009 289
DIAMICRON MR - PRETERAX
lar to that which occurred in UKPDS, where a recent analysis
of 10 years’ follow-up showed that risk reduction for myo-
cardial infarction and all-cause mortality with intensive glu-
cose control became clearly significant only after long-term
follow-up.27
The findings and conclusions of ADVANCE confirm and rein-
force those of UKPDS28 by providing further evidence of the
benefits of a multifactorial therapeutic approach combining
intensive blood pressure lowering and intensive blood glucose
Figure 5. Correlation between risk of cardiovascular death and
albuminuria level achieved at follow-up as evidenced in ADVANCE
(Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR
Controlled Evaluation).
Based on John Chalmers, oral communication, EASD 2008.
Abbreviations: BMI, body mass index; HbA1c , glycated hemoglobin; UACR,
urine albumin–creatinine ratio.
control in patients with type 2 diabetes. Previously reported
benefits of multifactorial risk management in the Steno 2 study
were obtained through a combination of optimal blood pres-
sure, glucose control, lipid modification, and antiplatelet thera-
py.13 Data from ADVANCE show that intensification of glycemic
control to achieve HbA 1c levels of less than 6.5% increase the
benefits obtained with blood pressure–lowering treatment, par-
ticularly with respect to renal events. Here it should be stressed
that the benefits in terms of diabetic nephropathy are impor-
tant in light of the strong relationship between cardiovascular
events and indexes of renal impairment (Figure 5).19
The substantial renal benefits observed in both arms of
ADVANCE, which were magnified in the group receiving both
treatment strategies, are also likely to translate into future car-
diovascular benefits beyond those reported in UKPDS. High
290 MEDICOGRAPHIA, Vol 31, No. 3, 2009
levels of albuminuria are a risk factor for cardiovascular dis-
ease in patients with type 2 diabetes,11 and treatment of albu-
minuria per se may reduce cardiovascular events.19 Long-term
follow-up of UKPDS27 has also shown that the cardiovascu-
lar and mortality benefits of intensive glucose control emerge
over time. The combined treatment strategy employed by
ADVANCE would therefore be anticipated to further reduce
cardiovascular risk in the long term.
Such an approach has benefits not only for people with type 2
diabetes who have hypertension29 or microalbuminuria,30 but,
given the linear relationship between blood pressure and albu-
minuria, on the one hand, and cardiovascular risk, on the other,
also for the much broader cross section of people with type 2
diabetes that are normotensive and normoalbuminuric.18
In conclusion, ADVANCE has demonstrated that the effects
of intensive blood pressure lowering with Preterax and in-
tensive blood glucose control with a Diamicron MR–based
regimen in patients with type 2 diabetes are fully additive and
independent of one another for all prespecified outcomes,
and that they significantly reduce all-cause mortality, cardio-
vascular death, and renal outcomes. This suggests that the
multifactorial management of type 2 diabetes should include
intensive blood pressure lowering with Preterax and intensive
blood glucose control with Diamicron MR, in order to reduce
the overall burden of vascular disease in people with diabetes.
 Excellent safety profile and weight neutrality
Administration of Preterax to patients with type 2 diabetes was
well tolerated and reduced the risks of death and major vas-
cular events, regardless of initial blood pressure level or con-
comitant treatments received.15
The Diamicron MR–based intensive blood glucose–lowering
regimen used in ADVANCE was also well tolerated through-
out the study.16 Intensive blood glucose control did not result
in any weight gain, a previously reported side effect of inten-
sive blood glucose–lowering strategies using sulfonylureas
and insulin. Furthermore, only 2.7% of patients experienced
at least one severe hypoglycemic episode over the 5 years
of follow-up, and the average rate of severe hypoglycemic
events each year was 0.7%. This is two times less than in
UKPDS and six times less than in ACCORD.5,25 This low inci-
dence of side effects was noted in spite of the fact that Dia-
micron MR was administered at maximal dosage (120 mg/
day) to 70% of the patients in the intensive blood glucose
control group.
 Preterax: rationale for choice and clinical efficacy
The fixed-dose antihypertensive combination of the ACE in-
hibitor perindopril and the thiazide-like diuretic indapamide
(2 mg/0.625 mg and 4 mg/1.25 mg) was selected to lower
blood pressure in type 2 diabetes patients in ADVANCE, the
vast majority of whom were hypertensive.
Management of type 2 diabetes: a multifactorial approach – Laroche and Corda

This fixed dosage in one tablet, once daily, ensured optimal
ease of use, thereby enhancing patient compliance. Preterax
provides additional antihypertensive efficacy compared with
each component used alone and with current monotherapies,
with major efficacy on SBP, an important predictor of cardio-
vascular risk. Preterax ideally combines the vasodilatory and
microcirculatory action of ACE inhibition and the volume-deple-
tion effect of a diuretic, while minimizing potassium imbalance.
Several studies have reported conclusive evidence of the ben-
efits of Preterax, regarding blood pressure lowering and end-
organ protection, in populations at high cardiovascular risk.
In clinical trials, Preterax significantly lowered blood pressure
compared with other first-line therapies (atenolol, losartan,
and irbesartan). This was the case in STRATHE (STRAtegies
of Treatment in Hypertension: Evaluation),31 a randomized
study versus current monotherapies and stepped-care ther-
apy with different classes of antihypertensive agents, includ-
ing ARBs, β-blockers, and calcium channel blockers, accord-
ing to a sequential or a stepped-care strategy. In this study,
the percentage of patients achieving target blood pressure
n= 177 176 180
80 P=0.005
Patients with BP <140/90 mm Hg (%)
P=0.01
60
40
20
0
Stepped-care Sequential Low-dose
monotherapy combination
Figure 6. Percentage of patients achieving target blood pressure
(BP) in STRATHE (STRAtegies of Treatment in Hypertension:
Evaluation).
After reference 31: Mourad J et al. J Hypertens. 2004;22:2379-2386. Copyright
© 2004, Lippincott Williams & Wilkins.
was significantly higher in the Preterax group (62%) than in the
sequential monotherapy (49%, P=0.02) and the stepped-
care groups (47%, P<0.005) (Figure 6). Similarly, the percent-
age of patients in whom blood pressure was normalized
without the occurrence of drug-related adverse events was
also significantly higher in the Preterax group (56%) than in the
sequential monotherapy (42%, P=0.002) or stepped-care
(42%, P=0.004) groups, confirming the value of Preterax as
a first-line treatment in essential hypertension.31 The effica-
cy/safety ratio (both clinical and with regard to laboratory
parameters) of Preterax was good.
Management of type 2 diabetes: a multifactorial approach – Laroche and Corda
DIAMICRON MR - PRETERAX
Hypertension is accompanied by dysfunctional changes af-
fecting the heart, kidney, large vessel wall, and the microcircu-
lation, which may lead to renal failure, heart failure, coronary
disease, and vascular disease.
While ADVANCE was being carried out, evidence accumulat-
ed in smaller randomized trials based on intermediate end
points that Preterax also reduced target-organ damage in
patients at high cardiovascular risk (cardiac hypertrophy32,33
and type 2 diabetics with albuminuria34 ) as well as surrogate
markers of cardiovascular risk, such as large artery stiffness
and wave reflections (now included as surrogate markers in
current guidelines).30,35
Microcirculatory alterations and arteriolar capillary rarefaction
are features of hypertension that may impair coronary perfu-
sion, despite angiographically normal coronary arteries.36 A
higher risk of adverse cardiac events in patients with arterial
hypertension and left ventricular hypertrophy is due to coro-
nary microvascular dysfunction (CMD) caused by remodeling
of intramural coronary arterioles and microvessel rarefaction.36
Studies with Preterax suggest that this treatment can reverse
CMD, most likely by improving myocardial perfusion and re-
modeling, as demonstrated in hypertensive patients with and
without cardiac hypertrophy.31,37 This may ultimately explain
the benefits of Preterax on cardiovascular outcome and mor-
tality in ADVANCE.
 Rationale for choice and clinical efficacy of Diamicron MR
 An innovative formulation allowing once-daily dosing
Compliance of patients is crucial in the clinical management
of diabetes. The once-daily formulation of Diamicron MR was
one of the reasons justifying its choice in ADVANCE. Diami-
cron MR is the first oral hypoglycemic agent with an innova-
tive formulation based on a hypromellose-derived polymer that
expands in the gastrointestinal tract to form a gel that pro-
gressively releases gliclazide over 24 hours, enabling once-
daily administration (a factor for improved patient compliance),
and that releases the active ingredient synchronously with the
circadian hyperglycemic profile, which ensures 24-hour blood
glucose control. Thanks to progressive and constant titration,
at the end of follow-up in ADVANCE, 70% of patients in the
intensive glucose-lowering group were receiving the maximal
and optimal dose of 120 mg/day Diamicron MR (ie, 4 tablets
daily).
 Diamicron MR restores a near-normal insulin secretion
profile
One of the earliest demonstrable abnormalities in type 2 dia-
betes is the loss of the first peak of insulin secretion. Restor-
ing this peak results in improved postprandial glucose control
and lower second-phase postprandial insulin levels. Diami-
cron MR’s pharmacokinetic profile favors this restoration and
improves β-cell function, restoring glucose-stimulated insulin
secretion to a near-normal profile, ie, enhancing the first peak
MEDICOGRAPHIA, Vol 31, No. 3, 2009 291
DIAMICRON MR - PRETERAX
of insulin secretion and normalizing the late secretion phase.
This has been confirmed by clamp experiments in type 2 dia-
betic patients as well as in isolated perfused pancreas.38,39
The physiological insulin secretion response afforded by Dia-
micron MR could provide one explanation for the lower hypo-
glycemic risk and weight neutrality reported in ADVANCE.16
 Metabolic efficacy of Diamicron MR
Sustained glycemic control is a very important goal in the
management of type 2 diabetes. In ADVANCE, the target of
HbA 1c 6.5% was achieved with Diamicron MR–based inten-
sive therapy, and this effect was obtained progressively after
36 months and remained stable thereafter, as opposed to
what was observed in UKPDS.5 This was also documented in
previous studies comparing Diamicron with glibenclamide and
glipizide in type 2 diabetic patients,40 as well as with gliben-
clamide alone.41 This latter study investigated the time inter-
val before the initiation of insulin therapy and showed a sig-
nificantly longer interval before insulin with Diamicron (mean
14.5 years) than with glibenclamide (mean 8 years) with bet-
ter blood glucose control, as shown by HbA 1c values (6.8%
vs 7.4%, respectively, P<0.0001). These benefits may be ex-
plained by the direct protective effect of Diamicron MR on pan-
creatic β-cell function.42
 Diamicron MR benefits in regard to macrovascular events
Diamicron MR was shown to have beneficial effects on large
vessels. Diamicron or metformin significantly (P<0.05) and
independently reduced the progression of average intima-
media thickness (IMT) when compared with glibenclamide in
patients with type 2 diabetes.43 The antiatherogenic effect of
Diamicron MR could be due to free radical–scavenging prop-
erties,44,45 restoration of endothelial function,46 reduction in
platelet reactivity, and an anti-inflammatory effect.44,47-49
Diamicron MR and Preterax in practice
The ever-growing epidemic of type 2 diabetes and its com-
plications will inevitably increase the burden of the disease,
impairing quality of life and increasing mortality. For decades,
the management of diabetic patients has involved refining ther-
apeutic strategies to achieve better control of both blood glu-
cose and cardiovascular risk factors, which include blood
pressure. ADVANCE is a landmark trial, which addressed both
of these issues and provided clear answers with a new, sim-
ple, and pragmatic strategy characterized by cumulative clin-
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Lowering blood pressure reduces renal events in type 2 diabetes. J Am Soc
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18. Perkovic V, Ninomiya T, de Galan B, et al. Joint Effects of routine blood pres-
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Nephrol. 2008 Nov;19(11). Abstract.
19. Gerstein HC, Mann JF, Yi Q, Zinman B, et al. Albuminuria and risk of cardiovas-
cular events, death, and heart failure in diabetic and nondiabetic individuals.
JAMA. 2001;25;286421-286426.
20. Brenner BM, Cooper ME, de Zeeuw D, et al; RENAALS Study Investigators.
Effects of losartan on renal and cardiovascular outcomes in patients with type 2
diabetes and nephropathy. N Engl J Med. 2001;345:861-869.
21. Lewis EJ, Hunsicker LG, Clarke WR, et al; Collaborative Study Group. Renopro-
tective effect of the angiotensin-receptor antagonist irbesartan in patients with
nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-860.
22. Parving HH, Lehnert H, Brochner-Mortensen J, et al; Irbesartan in Patients with
Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan
on the development of diabetic nephropathy in patients with type 2 diabetes.
N Engl J Med. 2001;345:870-878.
23. Strippoli GF, Craig M, Deeks JJ, et al. Effects of angiotensin converting enzyme
inhibitors and angiotensin II receptor antagonists on mortality and renal out-
comes in diabetic nephropathy: systematic review. BMJ. 2004;329:828-831.
24. Strauss MH, Hall AS. Angiotensin receptor blockers may increase the risk of
myocardial infarction: unraveling the ARB-MI paradox. Circulation. 2006;114:
838-854.
25. ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes.
N Engl J Med. 2008;358:2545-2559.
26. Skyler JS, Bergenstal R, Bonow RO, et al; American Diabetes Association;
American College of Cardiology Foundation; American Heart Association. In-
tensive glucose control and the prevention of cardiovascular events: implica-
tions of the ACCORD, ADVANCE, and VA Diabetes trials. A position statement
of the ADA and a scientific statement of the American College of Cardiology
Foundation and the AHA. Diabetes Care. 2009;32:187-192.
27. Holman RR, Paul SK, Bethel A, et al. 10-year follow-up of intensive glucose
control in type 2 diabetes. N Engl J Med. 2008;359;1577-1589.
28. Stratton IM, Cull CA, Adler AI, Matthews DR, Neil HA, Holman RR. Additive
effects of glycaemia and blood pressure exposure on risk of complications in
type 2 diabetes: a prospective observational study (UKPDS 75). Diabetologia.
2006;49:1761-1769.
Keywords: hypertension; cardiovascular disease; diabetes; diabetic complications; treatment; clinical trial; ADVANCE;
perindopril; indapamide; gliclazide MR
Management of type 2 diabetes: a multifactorial approach – Laroche and Corda
DIAMICRON MR - PRETERAX
29. Bakris GL, Weir MR, Shanifar S, et al; RENAAL Study Group. Effects of blood
pressure level on progression of diabetic nephropathy. Arch Intern Med. 2003;
163:1555-1565.
30. Mancia G, DeBacker G, Dominiczak A, et al; Task Force for the management of
arterial hypertension of the European Society of Hypertension (ESH) and of the
European Society of Cardiology (ESC). 2007 Guidelines for the Management of
Arterial Hypertension. J Hypertens. 2007;25:1105-1187.
31. Mourad J, Waeber B, Zannad F, et al; STRATHE Trial Investigators. Compari-
son of different therapeutic strategies in hypertension: a low dose combination
of perindopril/indapamide versus a sequential monotherapy or a stepped care
approach. J Hypertens. 2004;22:2379-2386.
32. Dahlöf B, Gosse P, Guéret P, et al; PICXEL Investigators. Perindopril/indapa-
mide combination more effective than enalapril in reducing blood pressure and
left ventricular mass: the PICXEL study. J Hypertens. 2005;23:2063-2070.
33. De Luca N, Mallion JM, O’Rourke MF, et al; REASON Project. Regression of
left ventricular mass in hypertensive patients treated with perindopril/indapa-
mide as a first-line combination. The REASON echocardiography study. Am J
Hypertens. 2004;17:660-667.
34. Mogensen CE, Viberti G, Halimi S, et al; Preterax in Albuminuria Regression
(PREMIER) Study Group. Effect of low-dose perindopril/indapamide on albu-
minuria in diabetes. Preterax in Albuminuria Regression: PREMIER. Hyperten-
sion. 2003;41:1063-1071.
35. Asmar RG, London GM, O’Rourke ME, et al; REASON Project Coordinators
and Investigators. Improvement in blood pressure, arterial stiffness and wave
reflection with a very-low-dose perindopril/indapamide combination in hyperten-
sive patients: a comparison with atenolol. Hypertension. 2001;38:922-926.
36. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med. 2007;
356:2324-2325.
37. Neglia D, Frommei E, Ghinoe S, et al. Coronary microvascular dysfunction in
hypertensive patients with left ventricular hypertrophy can be reversed by treat-
ment with a fixed combination of perindopril and indapamide. Eur Heart J.
2009. Submitted.
38. Hosker JP, Rudenski AS, Burnett MA, Matthews DR, Turner RC. Similar reduc-
tion of first- and second-phase B-cell responses at three different glucose lev-
els in type 2 diabetes and the effect of gliclazide therapy. Metabolism. 1989;38:
767-772.
39. Gregorio F, Ambrosi F, Cristallini S, Pedetti M, Filipponi P, Santeusanio F. Ther-
apeutical concentrations of tolbutamide, glibenclamide, gliclazide and gliqui-
done at different glucose levels: in vitro effects on pancreatic A- and B-cell func-
tion. Diabetes Res Clin Pract. 1992;18:197-206.
40. Harrower ADB, Wong C. Comparison of secondary failure rate between three
second-generation sulfonylureas. Diabetes Res. 1990;13:19-21.
41. Satoh J, Takahashi K, Takizawa Y, et al. Comparison of period until insulin treat-
ment between diabetic patients treated with gliclazide and glibenclamide. Dia-
betes Res Clin Pract. 2005;70:291-297.
42. Del Guerra S, Grupillo M, Masini M, et al. Gliclazide protects human islet beta-
cells from apoptosis induced by intermittent high glucose. Diabetes Metab Res
Rev. 2007;23:234-238.
43. Katakami N, Yamasaki Y, Hayaishi-Okano R, et al. Metformin or gliclazide, rather
than glibenclamide, attenuate progression of carotid intima-media thickness in
subjects with type 2 diabetes. Diabetologia. 2004;47:1906-1913.
44. O’Brien RC, Luo M, Balazs N, Mercuri J. In vitro and in vivo antioxidant proper-
ties of gliclazide. J Diabetes Complications. 2000;14;201-206.
45. Gribble FM, Reimann F. Sulphonylurea action revisited: the post-cloning era.
Diabetologia. 2003;46:875-891.
46. Fava D, Cassone-Faldetta M, Laurenti O, et al. Gliclazide improves anti-oxidant
status and nitric oxide-mediated vasodilation in type 2 diabetes. Diabetic Med.
2002;19:752-757.
47. Okouchi, Okayama N, Omi H, et al. The antidiabetic agent, gliclazide, reduces
high insulin-enhanced neutrophil-transendothelial migration through direct ef-
fects on the endothelium. Diabetes Metab Res Rev. 2004;20:232-238.
48. Drzewoski J, Zurawska-Klis M. Effect of gliclazide modified release on adipo-
nectin, interleukin 6, and tumor necrosis factor alpha plasma levels in individu-
als with type 2 diabetes. Curr Med Res Opin. 2006;22:1921-1926.
49. Rakel A, Renier G, Roussin A, Buithieu J, Mamputu JC, Serri O. Beneficial ef-
fects of gliclazide modified release compared with glibenclamide on endothelial
activation and low-grade inflammation in patients with type 2 diabetes. Diabetes
Obes Metab. 2007;9:127-129.
MEDICOGRAPHIA, Vol 31, No. 3, 2009 293
DIAMICRON MR - PRETERAX

PRISE EN CHARGE DU DIABÈTE DE TYPE 2 :

UNE APPROCHE MULTIFACTORIELLE POUR UNE MALADIE COMPLEXE
L’épidémie de diabète de type 2 connaît une augmentation spectaculaire dans le monde. L’étude ADVANCE (Action
in Diabetes and Vascular disease : PreterAx and DiamicroN MR Controlled Evaluation) est une étude de référence
qui a analysé la pertinence d’une double stratégie thérapeutique fondée sur l’abaissement intensif de la pression
artérielle (PA) par addition de 1 comprimé de Preterax (association perindopril/indapamide) en plus des traitements
en cours basés sur les recommandations actuelles, ainsi que sur un contrôle intensif de la glycémie fondé sur la prise
de 1 à 4 comprimés par jour de Diamicron LM (gliclazide à libération modifiée), suivi par l’association progressive
d’autres antidiabétiques oraux si nécessaire. La stratégie d’abaissement de la PA a entraîné une réduction impor-
tante et significative de la mortalité globale et cardio-vasculaire, de même qu’une diminution des complications co-
ronaires et rénales. La stratégie de contrôle intensif de la glycémie a entraîné une diminution significative du critère
composite constitué par les événements micro- et macrovasculaires, essentiellement représentée par une réduction
significative des complications rénales ainsi qu’une réduction des complications cardio-vasculaires, ceci avec une
excellente sécurité d’emploi en termes d’hypoglycémie et une absence de prise de poids. Ces avantages font de
Diamicron LM un traitement clé du diabète de type 2, assorti d’avantages potentiels dépassant ceux qu’il est pos-
sible d’obtenir par le seul contrôle glycémique. L’étude ADVANCE a donc donné une réponse claire, en confirmant
la valeur de ce nouveau traitement simple et pragmatique associant un abaissement intensif de la PA avec Preterax
et une diminution intensive de la glycémie avec Diamicron LM, montrant ainsi que leurs effets bénéfiques sont ad-
ditifs. Cette stratégie thérapeutique constitue une véritable approche multifactorielle assurant une tolérance et un
bénéfice maximums à tous les patients diabétiques de type 2.

294 MEDICOGRAPHIA, Vol 31, No. 3, 2009 Management of type 2 diabetes: a multifactorial approach – Laroche and Corda

‘‘ The results of ADVANCE …
emphasized that the twin strate-
gies of blood pressure lowering
and intensive glucose control ap-
pear to act independently, not
only with regard to microvascular
events, but also macrovascular
events. The joint effects of these
strategies provide very substantial
benefits, including an almost one-
third reduction in nephropathy
and renal events, a one-quarter re-
duction in cardiovascular death,
and close to a one-fifth reduction
in all-cause mortality.”
T
Jacques BRINGER, MD
Centre Hospitalier
Regional Universitaire
de Montpellier
Montpellier, FRANCE
Address for correspondence:
Prof Jacques Bringer, Hôpital
Lapeyronie, 371 avenue
du Doyen Gaston Giraud,
34295 Montpellier Cedex 5, France
(e-mail: j-bringer@chu-montpellier.fr)
www.medicographia.com
How can the results of ADVANCE be applied to daily clinical practice? – Bringer
INTERVIEW
How can the results
of ADVANCE be applied
to daily clinical practice?
I n t e r v i e w w i t h J . B r i n g e r, Fra n c e
he increasing number of therapies available to treat type 2 diabetes has
heightened the complexity of choosing the appropriate pharmaceutical
approach in diabetes. Guidelines and algorithms for the initiation and
adjustment of therapy have to be derived from well-controlled clinical trials
that compare various diabetes treatment regimens. However, clinical decision
making must be individualized according to the benefits of therapeutic choic-
es weighed against the risks and costs, for a specific diabetic patient. The trio
of goals usually targeted are to attain glucose levels close to those of the non-
diabetic range, without inducing hypoglycemia and while preventing exag-
gerated weight gain. Tight glycemic control is critical in preventing specific
microvascular complications associated with diabetes, which induce loss of
vision, kidney failure, and amputations. The Action in Diabetes and Vascular
disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) study
demonstrated the feasibility of an appropriate joint intensive management
strategy, which reduced nephropathy without significantly increasing the num-
ber of severe adverse events. It remains clear that the prevention of macrovas-
cular complications in diabetes requires an aggressive, multifactorial approach
against modifiable cardiovascular risk factors.
Medicographia. 2009;31:295-298 (see French abstract on page 298)
Background and rationale
T
he United Kingdom Prospective Diabetes Study (UKPDS)1 has confirmed the
benefit of improved glucose control in reducing macrovascular disease and
has also showed that tightly controlled blood pressure reduces the progres-
sion of both microvascular disease and macrovascular disease. There was also the
suggestion that tight glycemic control can reduce cardiovascular disease, as shown
by the 10-year posttrial monitoring of patients after the end of the controlled study.
Despite an early loss of initial glycemic difference, an emergent risk reduction for my-
ocardial infarction and, thus, for any cause of death appeared during the follow-up.
The Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled
Evaluation (ADVANCE)2 trial was designed specifically to test whether tight glucose
control can reduce macrovascular disease. ADVANCE also examined the effect of
blood pressure lowering in all type 2 diabetic subjects, regardless of their initial level
of blood pressure. The fact that the trial was conducted in many different countries,
including developing countries, and included 11140 people allowed the investigators
to judge the practicality of this approach in everyday practice around the world.
MEDICOGRAPHIA, Vol 31, No. 3, 2009 295
INTERVIEW
Patient profile
A
ll participants had type 2 diabetes, were older than 55
years, and had at least one additional risk factor, such
as a previous cardiovascular event, high cholesterol,
or smoking. Recruitment began in June 2001 and was com-
pleted in March 2003 with the inclusion of 11 140 random-
ized participants.3 Over half (57%) of the participants were
male and the mean age at baseline was 66 years.
The diagnosis of diabetes was made 8 years, on average, be-
fore study entry. At baseline, 32% and 10% of patients had
a past history of macrovascular and microvascular disease,
respectively. Mean blood pressure at baseline was 145/81
mm Hg; mean HbA1c was 7.5%; and body mass index at
baseline was 28.
ADVANCE monitoring: special consideration in
the intensive group
T
he target blood glucose level was an HbA1c 6.5% in
the intensive group (it was considered unethical to set
any target for the standard group).This reflected real
practice, one of the basic aims of this large scale trial. More in-
teresting, however, was the question of how feasible it would
be to attain good HbA1c control in large and varied popula-
tions. The pragmatic and open design of ADVANCE gave in-
vestigators the freedom to develop as many initiatives, in ad-
dition to gold standard treatment (depending on the stage
of their disease), as they wanted to improve patients’ diet,
exercise, and education. In the ADVANCE intensive group and
in the Diabetes Control and Complications Trial (DCCT) mod-
el, patients were increasingly better managed and coached
by their doctors and nurses. There was specific follow-up by
dieticians both for diet and for weight control, patients were
encouraged to restart or step up their physical activity, and
they systematically received dedicated educational programs.
All of them were trained to use home blood glucose moni-
toring. As DCCT suggested, achieving better glucose control
than that of standard treatment requires not only a stepwise
approach to drug choice, but also time and experienced staff
to coach every patient properly.
What is the current evidence regarding BP and
glucose lowering on macro- and microvascular
disease?
 Blood pressure lowering
B
lood pressure is a major determinant of the risk of car-
diovascular complications among patients with type 2
diabetes, not only in hypertensive individuals, but also in
normotensive people with diabetes. Observational studies
confirm that there is a strong and continuous relationship be-
tween blood pressure and the risk of vascular disease, both
macro- and microvascular. These studies also show that there
296 MEDICOGRAPHIA, Vol 31, No. 3, 2009 How can the results of ADVANCE be applied to daily clinical practice? – Bringer
SELECTED ABBREVIATIONS AND ACRONYMS
ACCORD Action to Control CardiOvascular Risk in
Diabetes
ACE angiotensin-converting enzyme
ADVANCE Action in Diabetes and Vascular disease PreterAx
and DiamicroN MR Controlled Evaluation
DCCT Diabetes Control and Complications Trial
HbA1c glycated hemoglobin
HOT Hypertension Optimal Treatment
UKPDS United Kingdom Prospective Diabetes Study
VADT Veterans Affairs Diabetes Trial
is no lower threshold of blood pressure below which risk does
not continue to fall. Indeed, for every 10 mm Hg drop in sys-
tolic blood pressure, UKPDS4 observed a 12% decrease in
the risk of myocardial infarction and a similar decrease in the
risk of microvascular disease (diabetic nephropathy and retino-
pathy). However, no differences were observed between an-
giotensin-converting enzyme (ACE) inhibitor and β-blocker
randomized patients. In the Hypertension Optimal Treatment
(HOT) trial,5 which randomized a calcium antagonist versus
conventional treatment, cardiovascular events were reduced by
51% in the diabetic subgroup. The conclusion of these stud-
ies is that blood pressure lowering, regardless of the agent
used, is also effective in reducing the incidence of diabetic
complications.
ADVANCE 6 demonstrated that routine administration of a fixed
combination of perindopril and indapamide to individuals with
type 2 diabetes reduced blood pressure by 5.6/2.2 mm Hg,
the risk of major vascular events by 9%, and deaths (by 14%
for all-cause mortality and by 18% for cardiovascular mor-
tality). The administration of this simple treatment on top of
all other indicated therapies, including other blood pressure–
lowering drugs, statins, aspirin, and stringent glucose-low-
ering therapy, also produced a clear reduction in the number
of total coronary events (14%), total renal events (21%), and
in new microalbuminuria cases.
 Blood glucose lowering
Most diabetologists seem to be in agreement that an HbA1c
level of 7%, the current recommendation in American guide-
lines, is still an appropriate goal. However, if patients can at-
tain lower levels than this without the use of overly aggressive
drug regimens, this would be beneficial in terms of micro-
vascular complications. New data from three trials comparing
intensive versus standard glucose lowering were reported
at the American Diabetes Association 2008 scientific ses-
sions: The Action to Control CardiOvascular Risk in Diabetes
(ACCORD) trial7—which was stopped early because of in-
creased mortality in the intensive group, the Action in Diabetes
and Vascular disease: PreterAx and DiamicroN MR Controlled
Evaluation (ADVANCE) trial,8 and the Veterans Affairs Diabetes
Trial (VADT).9

After the results, a position statement of the American Dia-
betes Association, the American College of Cardiology, and
the American Heart Association10 said that the “ADVANCE tri-
al has added evidence of the benefit of intensive glucose low-
ering on microvascular complications by demonstrating a sig-
nificant reduction in the risk of new or worsening albuminuria
when median HbA1c was lowered to 6.3% compared with
standard glycemic control achieving an HbA1c of 7% (median).”
The results also show a trend toward a reduction in cardio-
vascular deaths (8.9% in the intensive group and 9.6% in the
standard group). The 6.5% goal for HbA1c was reached with
a low incidence of severe hypoglycemic events (less than that
observed 10 years ago in the nonintensive group of UKPDS)
and no change in body weight. In contrast with ADVANCE,
the results from ACCORD indicate an increase in cardiovas-
cular deaths. However, a similar mean HbA1c value was ob-
tained in both ACCORD and ADVANCE, and there were no
obvious or major differences between the populations in both
studies. It looks as if the therapeutic strategies may explain
F
these discrepancies in the results, in particular those regard-
ing cardiovascular mortality.
The HbA1c goal for the intensive treatment group of ACCORD
was 6%, but it was 6.5% in ADVANCE. The rate and type
of decrease in blood glucose were also different for the two
studies:
 Progressive in ADVANCE, decreasing from 7.5% to 6.9%
HbA1c after one year and then on to the base level of 6.5%
after 3 years.
 Abrupt in ACCORD, decreasing from 8.3% to 6.4% HbA1c
after 1 year.
The treatment strategies were different, too: in ADVANCE, it
was based on gliclazide 30 mg modified release (MR)—up to
4 tablets at breakfast for 70% of patients—and low glitazone
(17%) and insulin use (40%) versus an aggressive strategy in
ACCORD, using multiple antidiabetic oral agents (3 to 5 class-
es in 69.5% of cases), rosiglitazone (91%), and insulin (77%),
but no gliclazide 30 mg MR.
Weight and weight increase were different in both trials. The
mean body mass index (BMI) at inclusion differed, with a BMI
of 32 kg/m2 in ACCORD and 28 kg/m2 in ADVANCE. Mean
weight increase reached 3 kg in the ACCORD intensive treat-
ment group (27% of patients gained more than 10 kg) where-
as no significant weight change was observed in ADVANCE.
In addition, the rate of severe hypoglycemic events was differ-
ent between the 2 studies.
ADVANCE, with its specific, intensive, and progressive strat-
egy based on gliclazide MR, provides evidence that reaching
a 6.5% HbA1c goal in type 2 diabetes, even in those at high
cardiovascular risk, is feasible with a low rate of side effects
and shows that this strategy permits the reduction of serious
long-term complications, in particular nephropathy.
How can the results of ADVANCE be applied to daily clinical practice? – Bringer
INTERVIEW
How do the results apply to the management of
hypertensive patients?
A
DVANCE results confirm the importance of blood glu-
cose lowering in patients with type 2 diabetes, irre-
spective of their baseline blood pressure. The single
tablet combination of perindopril and indapamide is a prac-
tical and affordable option in most clinical settings worldwide
and has the capacity to save countless lives and to reduce
the burden of coronary and renal disease.
Thus, the message to clinicians is to lower blood pressure to
recommended guideline goals and to use agents that are well-
tolerated, can be given once daily (in a single pill, if possible),
and that are cost-effective.
ADVANCE glucose-lowering results: what do they
change in daily clinical practice?
ollowing the report of a host of new data on intensive
blood glucose lowering in patients with type 2 diabetes,
the prevailing view of clinicians is that ultra-aggressive
blood sugar–lowering regimens are not the way to go, partic-
ularly in patients with cardiovascular disease. Alternatively, a
reduction in HbA1c below 7% attained by changing diet or
losing weight is ideal, being both safe and beneficial.
However, ADVANCE has demonstrated that a strategy target-
ing lower HbA1c 6.5%—which is what European and Inter-
national associations recommend—can be achievable, effec-
tive, safe, and implemented by everyone. The significant 21%
decrease in renal events is important because we know the
most costly and troublesome event for any diabetologist is
when you send patients for renal replacement.
The ADVANCE strategy, based on the use of Diamicron MR
and the stepwise use of oral antidiabetic drugs, has been
clearly demonstrated as being safe and efficient.
Multifactorial approach to type 2 diabetic patients:
what are the lessons from ADVANCE?
T
he Steno study,11 in which the glucose control regimen
used Diamicron as the study sulfonylurea, demonstrat-
ed the benefits of using a multifactorial regimen that
included an ACE inhibitor and cholesterol-lowering agents in
individuals with type 2 diabetes over 13 years of follow-up.
This regimen produced reductions of more than 50% in both
macro- and microvascular disease.
The results of ADVANCE, presented at the 44th EASD meet-
ing in Rome, emphasized that the twin strategies of blood
pressure lowering and intensive glucose control appear to act
independently, not only with regard to microvascular events,
but also macrovascular events.
MEDICOGRAPHIA, Vol 31, No. 3, 2009 297
INTERVIEW

The joint effects of these two treatment strategies provide
very substantial benefits, including an almost one-third reduc-
tion in nephropathy and renal events, a one-quarter reduc-
tion in cardiovascular death, and close to a one-fifth reduc-
tion in all-cause mortality.
So, for primary and secondary cardiovascular risk reduction
in patients with type 2 diabetes, providers should follow the
evidence-based recommendations, which include:
 A healthy lifestyle, which is a necessary prerequisite for ob-
taining optimal glycemic control, regardless of pharmaceutical
options. However, on its own, this approach fails to achieve or
maintain metabolic goals.
 Lowering HbA1c below 7%, which has been shown to reduce
microvascular complications, using a strategy like ADVANCE’s
that does not cause significant hypoglycemia or other adverse
effects, such as exaggerated weight increase as HbA1c de-
creases.
 Lowering blood pressure, regardless of initial level, using
well-tolerated and simple-to-use treatments.
 Using individualized, progressive, and less intense strate-
gies for patients with cardiovascular disease, those at higher
risk of hypoglycemia, and for elderly diabetics.
 Lipid lowering with statins.
 Aspirin prophylaxis.
 Smoking cessation. 

References
1. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-years follow-up
of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-
1589.
2. ADVANCE Management Committee. Study rationale and design of ADVANCE.
Diabetologia. 2001;44:1118-1120.
3. ADVANCE Collaborative Group. Patients recruitment and characteristics of the
study population at baseline. Diabetic Medicine. 2005;22:882-888.
4. United Kingdom Prospective Diabetes Study (UKPDS) Group. Tight blood pres-
sure control and risk of macrovascular and microvascular complications in type 2
diabetes (UKPDS 38). BMJ. 1998;317:S703-S713.
5. Hansson L, Zanchetti A, Carruthers S, et al. Effects of intensive blood pressure
lowering and low dose aspirin in patients with hypertension. Principal results of
the Hypertension Optimal Treatment (HOT) randomized trial. Lancet. 1998;351:
1755-1762.
6. ADVANCE Collaborative Group: Effects of a fixed combination of perindopril and
indapamide on macrovascular and microvascular outcomes in patients with
type 2 diabetes mellitus (the ADVANCE trial): a randomized controlled trial. Lancet.
2007;370:829-840.
7. Action to Control Cardiovascular risk in Diabetes Study Group. Effects of inten-
sive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2445-2559.
8. ADVANCE Collaborative Group. Intensive blood glucose control and vascular
outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.
9. Duckworth W, Abraira C, Moritz T, et al. Intensive glucose control and vascu-
lar complications in American Veterans with type 2 diabetes. N Engl J Med. 2009;
360:1-11.
10. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the
prevention of cardiovascular events: implications of the ACCORD, ADVANCE,
and VA diabetes trials: a position statement of the American Diabetes Associa-
tion and a scientific statement of the American College of Cardiology Founda-
tion and the American Heart Association. Diabetes Care. 2009;32:187-192.
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disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383-393.

Keywords: ADVANCE; blood glucose; blood pressure; clinical practice; macrovascular disease; microvascular disease;
multifactorial approach; type 2 diabetes

APPLICATION DES RÉSULTATS D ’ADVANCE EN PRATIQUE CLINIQUE QUOTIDIENNE

Le nombre croissant de traitements disponibles pour le diabète de type 2 rend plus complexe le choix de l’ap-
proche pharmaceutique la plus appropriée. Les recommandations et les algorithmes nécessaires à l’instauration et
à l’ajustement du traitement du diabète doivent se fonder sur des études cliniques bien contrôlées comparant les
différents schémas thérapeutiques en vigueur. Les prises de décision cliniques doivent cependant être individuali-
sées selon les effets bénéfiques des choix thérapeutiques comparés aux coûts et aux risques, pour chaque patient
diabétique pris individuellement. Trois buts sont habituellement visés : l’obtention d’une glycémie proche de celle
des non-diabétiques, sans provoquer d’hypoglycémie et sans prise de poids excessive. Un contrôle strict de la gly-
cémie est crucial pour la prévention des complications microvasculaires spécifiques du diabète, qui peuvent induire
cécité, insuffisance rénale et amputations. L’étude ADVANCE (Action in Diabetes and Vascular disease : PreterAx and
DiamicroN MR Controlled Evaluation) a démontré la possibilité d’une prise en charge intensive conjointe appro-
priée permettant de réduire la néphropathie sans augmenter de façon significative le nombre d’événements indési-
rables graves. Il reste certain que la prévention des complications macrovasculaires du diabète nécessite une ap-
proche énergique et multifactorielle contre des facteurs de risque cardio-vasculaires modifiables.

298 MEDICOGRAPHIA, Vol 31, No. 3, 2009 How can the results of ADVANCE be applied to daily clinical practice? – Bringer

‘‘ ADVANCE clearly showed the
beneficial effects on mortality of
antihypertensive treatment and
that microalbuminuria was a major
risk factor… another major finding
was the protective effect of inten-
sive glucose-lowering treatment
with gliclazide MR against diabet-
ic nephropathy. Therefore, it seems
justified that many patients with
type 2 diabetes should be treat-
ed, not only with effective anti-
hyperglycemic agents, but also
with agents that reduce blood
pressure.”
T
Carl E. MOGENSEN, MD
Medical Department M
Aarhus University Hospital
Aarhus Sygehus
Nørrebrogade, DENMARK
D
Address for correspondence:
Prof Carl Erik Mogensen, Medical
Department M, Aarhus University
Hospital, Aarhus Sygehus,
Nørrebrogade 44,
DK-8000 Aarhus C, DENMARK
(e-mail: carl.erik.mogensen@ki.au.dk)
www.medicographia.com
Blood pressure, blood glucose, and diabetic renal disease – Mogensen
FOCUS
Blood pressure,
blood glucose, and
diabetic renal disease
C . E . Mo g e n s e n , D e n m a r k
he main focuses of this paper are the crucial role of blood glucose
control as well as, and maybe even more importantly, the role of good
blood pressure (BP) control. This concept was reviewed in an edito-
rial of the British Medical Journal after publication of the main results of the
United Kingdom Prospective Diabetes Study (UKPDS) in 1998. UKPDS, which
studied patients with newly diagnosed type 2 diabetes, was a landmark study
in the field of type 2 diabetes treatment, shifting the treatment strategy to-
ward better recording of blood pressure and HbA1c as well as toward more
intensive treatment. It is clear from new studies that overly intensive gly-
cemic control in type 2 diabetes—at least in certain populations—results in
detrimental effects, namely increased mortality (as seen in the Action to
Control CardiOvascular Risk in Diabetes [ACCORD] study). Nevertheless, it
is clear that multifactorial intervention is important, as documented in the
13-year Steno 2 study follow-up. Obviously, it is important to start at the point
of type 2 diabetes diagnosis, but, on the other hand, many complications oc-
cur later on. In light of this fact, the Action in Diabetes and Vascular disease:
PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) study is es-
pecially interesting. In fact, ADVANCE continued where UKPDS left off (ie, af-
ter approximately 8 years of type 2 diabetes). This study also focused on the
relation between renal aspects of diabetes and blood pressure–lowering treat-
ment as well as the treatment of hyperglycemia. Several earlier studies from
our group focused specifically on these aspects of type 2 diabetes and on
the reduction of albuminuria. We examined the blood pressure reductions in
ADVANCE compared with those in UKPDS. In ADVANCE, BP was lowered
more, including BP in nonhypertensive diabetics, and glycemic control was
also documented to reduce complications. In both studies, it was found that
complications were reduced by better BP treatment.
Medicographia. 2009;31:299-306 (see French abstract on page 306)
iabetes research, with special reference to renal disease, hypertension, and
glycemic control, has been previously discussed by me in papers in Me-
dicographia.1-5 The main focuses of these papers were the crucial role of
good blood glucose control as well as, and maybe even more importantly, the role
of good blood pressure control. This concept was reviewed in an editorial of the
BMJ after publication of the main results of The United Kingdom Prospective Dia-
betes Study (UKPDS) 1998.6 UKPDS is a landmark study in the field of type 2 dia-
betes treatment and has shifted the treatment strategy toward better recording of
MEDICOGRAPHIA, Vol 31, No. 3, 2009 299
FOCUS

blood pressure and HbA1c as well as toward more intensive

treatment, while carefully avoiding overtreatment. It is clear
from new studies that overly intensive glycemic control in

Macro- and microvascular protection

type 2 diabetes—at least in certain populations—results in de- 
trimental effects, namely, increased mortality, as seen in the  Statins
Action to Control CardiOvascular Risk in Diabetes (ACCORD) Antiplatelet
drugs
study (recently discussed by Home)7 and in the recently pub- 
lished VADT (Veterans Affairs Diabetes Trial),8 without positive  RAAS
results in any of the clinical end points and with only border- BP ACE inhibitors
line significance in the change in albuminuria. Nevertheless,  control ARBs
Glycemic
it is clear that multifactorial intervention is important, as doc- control
umented in the 13-year follow-up of the Steno 2 study that
comprised not only glycemic control and blood pressure con-
trol, but also treatment with statins to reduce cholesterol val- 1977 2007
ues. This study showed that microalbuminuria and type 2
diabetes can have dramatic effects on cardiovascular impli- Figure 1. Recent improvements in macro- and microvascular
cations and mortality in patients.9 protection.
An illustration of how different types of measures and drugs have helped improve
vascular outcomes over the last 30 years.
UKPDS studied patients with newly diagnosed type 2 dia- Abbreviations: ACE, angiotensin-converting enzyme; ADVANCE, Action in Dia-
betes (not necessarily newly established type 2 diabetes, since betes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation;
ARB, angiotensin receptor blocker; BP, blood pressure; MR, modified release;
there may be a time lag between development of diabetes RAAS, renin-angiotensin-aldosterone system.
and diagnosis). Obviously, it is important to start from the di-
agnosis of type 2 diabetes, but, on the other hand, many com- sure–lowering treatment as well as the treatment of hyper-
plications occur later. In light of this, the Action in Diabetes glycemia (Figure 2).12 Several earlier studies from our group
and Vascular disease: PreterAx and DiamicroN MR Controlled focused specifically on these aspects of type 2 diabetes and
Evaluation (ADVANCE) study 10,11 is of special interest. In fact, on the reduction of albuminuria. Figure 2 shows the BP re-
this study continued where UKPDS stopped (after approxi- duction in ADVANCE compared with that in UKPDS. In both
mately 8 years of type 2 diabetes) (Figure 1). This study also studies, it was found that complications were reduced by
focused on renal aspects of diabetes in relation to blood pres- better BP treatment.

SELECTED ABBREVIATIONS AND ACRONYMS

Recent papers have documented a close association be-
tween high blood pressure and type 2 diabetes (as reviewed
ACCORD Action to Control CardiOvascular Risk in by Nilsson).13 Elevated blood glucose is quite often found in
Diabetes
patients suffering from hypertension in diabetic clinics. Both
ACE angiotensin-converting enzyme
elevated blood pressure and hyperglycemia are part of the
ADVANCE Action in Diabetes and Vascular disease: Prete-
rAx and DiamicroN MR Controlled Evaluation so-called metabolic syndrome, and, along with hyperlipi-
AGE advanced glycation end product demia, coexistence of these abnormalities is quite important
ARB angiotensin receptor blocker and prevalent. Discovery of one abnormality should focus the
CAD coronary artery disease attention of the physician on looking for and treating the oth-
CALM Candesartan And Lisinopril Microalbuminuria er two abnormalities. The common denominator of these ab-
DCCT Diabetes Control and Complications Trial normalities may be typical Western lifestyle, which accelerates
GFR glomerular filtration rate the development of these abnormalities. The basic mecha-
GUIDE GlUcose control In type 2 diabetes: Diamicron nisms, in relation to molecular biology, are, however, unclear.
modified release versus glimEpiride Formerly, it was believed that glycemic control was not very
HOPE Heart Outcomes Prevention Evaluation important in the treatment of patients with diabetes, but this
LIFE Losartan Intervention For Endpoint reduction in view radically changed after the publication of the Diabetes
hypertension Control and Complications Trial (DCCT) and UKPDS. The ef-
ONTARGET ONgoing Telmisartan Alone and in combination fect of better glycemic control on complications is very likely
with Ramipril Global End point Trial
related to less oxidative stress and to effects on advanced gly-
PREMIER PREterax in albuMInuria rEgRession
cation end products (AGEs).
RAS renin-angiotensin system
RENAAL Reduction of End points in NIDDM with the
Angiotensin II Antagonist Losartan
Genetic factors used to be considered important too, and,
UKPDS United Kingdom Prospective Diabetes Study before these publications, there was not much emphasis on
VADT Veterans Affairs Diabetes Trial these treatment modalities in many clinics in the US. Deck-
ert 14 focused on the fact that some diabetic patients escape

300 MEDICOGRAPHIA, Vol 31, No. 3, 2009 Blood pressure, blood glucose, and diabetic renal disease – Mogensen
 FOCUS

long-term diabetic complications, in spite of poor glycemic The paradigm, therefore, no longer seems correct because,
control, an observation that is quite common in diabetes clin- in patients with type 1 diabetes, hyperfiltration, defined as a
ics. One important, possible explanation may be that pa- GFR higher than 140 mL/min (corrected for 1.73 m2 body
tients who escape complications have low blood pressure surface area), indicates a poor prognosis.29,31 GFR is usually
as a consequence of the nature of their disease or as a re- well preserved in microalbuminuria with type 1 diabetes, with
sult of their treatment program. Clearly, treatments for elevat- no tendency to decline with higher degrees of microalbumin-
ed blood pressure are used in most diabetic patients as well uria.32 In type 2 diabetes, hyperfiltration is seen quite often in
as antihyperglycemic treatments, but one of the
problems is that, in some cases, it is difficult to
normalize or near-normalize glycemia. Over the 50 Myocardial infarction
years, several questions have emerged in the Microvascular end points
medical community, and we can now answer
most of these.
Adjusted incidence per 1000 person years (%) 40
Microalbuminuria or abnormal
albuminuria in essential hypertension
After the introduction of radioimmunoassays for
albumin in urine in the 1970s, several studies 30
showed that microalbuminuria was not un-
common in poorly treated hypertensive pa-
tients. Abnormal albuminuria may be normal-
ized by efficient antihypertensive treatment.15-17 20

New papers, such as the Heart Outcomes Pre-

vention Evaluation (HOPE),18 the Reduction of
End points in NIDDM with the Angiotensin II An-
10
tagonist Losartan (RENAAL),19 and other stud-
ies, show that albuminuria is a continuum,18,20-24
just as it is with most risk factors, such as
blood pressure, glycemia, and lipid levels. ADVANCE UKPDS
0
110 120 130 140 150 160 170
Thus, it is clear that borderline and abnormal al-
SBP
buminuria can be found in many patients with
hypertension, especially if they have other com- Figure 2. ADVANCE blood pressure reduction in relation to that of UKPDS.
plications. In fact, in the Losartan Intervention Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR
For Endpoint reduction in hypertension (LIFE) Controlled Evaluation; UKPDS, United Kingdom Prospective Diabetes Study.
Modified from reference 12: Adler AI, Stratton IM, Neil HA, et al. BMJ. 2000;321:412-419. Copy-
study and in other studies, it was shown that right © 2000, BMJ Publishing Group Ltd.
the higher the level of albuminuria, the poorer
the prognosis.25,26 In contrast with those who had high and young patients (eg, the Pima Indians), and also, to a limited
higher values, before and after treatment, reduced albumin- extent, in elderly patients.32,33 In population-based studies from
uria indicated a better prognosis.27 ADVANCE confirmed this the Netherlands, it has been suggested that increased GFR
in diabetic patients.10,11 might be related to increased risk.30 Hyperfiltration (partly re-
lated to poor glycemic control), thus, is associated with a poor
High GFR and prognosis prognosis, especially in documented type 1 diabetes.29
28
Recent guidelines from the National Kidney Foundation and
the American Society of Nephrology classify patients ac- Poor prognosis of proteinuric diabetic patients
cording to their level of estimated glomerular filtration rate It has been well established that patients with proteinuria
(GFR): the lower, the worse; the higher, the better. Reduced and diabetes have a poor prognosis, as documented in fol-
renal function indicates a poor prognosis, but, so far, there low-up studies from the Steno and Joslin centers. Progno-
are no clear-cut intervention strategies based on clinical tri- sis has, however, improved due to efficient treatments, espe-
als for this parameter, only epidemiology. This classification cially antihypertensive treatment. Nevertheless, studies in the
does not take the phenomenon of hyperfiltration into consid- early 80s documented that poor prognosis was not only de-
eration. This phenomenon, documented over the past few termined by proteinuria, but also by the then so-called micro-
decades, has mainly been seen in diabetes29 and is mainly albuminuria, which increased the risks of progression toward
based on original experimental studies by Brenner and co- proteinuria and of reduced renal function, with increased
workers.30 mortality.34

Blood pressure, blood glucose, and diabetic renal disease – Mogensen MEDICOGRAPHIA, Vol 31, No. 3, 2009 301
FOCUS
This paradigm has thus radically changed, and the concept
of microalbuminuria as a major risk marker in both type 1
and type 2 diabetes and even in population-based studies
is now firmly established.35,36 Microalbuminuria is defined as
the excretion rate between normal albumin excretion rate and
the level characterized by proteinuria. This level has been
defined as an excretion rate between 20 and 200 μg/min
or 30 to 300 mg/24 hours.37 However, the level is now indi-
cated as the albumin/creatinine ratio because collecting
urine is cumbersome. In diabetes clinics, the albumin/crea-
tinine ratio or albumin concentration is usually measured in
early morning urine.37,38
Microalbuminuria: does it only predict renal
disease?
Originally, it was hypothesized that microalbuminuria would
predict proteinuria and reduced renal function, but, surpris-
ingly, it was shown, first in type 2 diabetes, that microalbu-
minuria was also a strong predictor of early mortality 35 (later
confirmed in UKPDS by Adler et al) (Figure 3).38 The same
was found in population-based studies.36 Thus, microalbu-
No nephropathy
1.4%
2%
D this regard. Namely, that angiotensin-converting enzyme
Microalbuminuria
3% E (ACE) inhibition was useful in diabetic renal disease. The re-
2.8% A cent ADVANCE study also emphasized the importance of
Macroalbuminuria T
4.6%
2.3% H indicating good prognosis, was a key finding.10,11
Elevated plasma creatinine/
Renal replacement therapy 19.2%
Figure 3. Annual probability of death with progressive renal dete-
rioration.
Annual transition rates through the stages of nephropathy to death from any
cause. The United Kingdom Prospective Diabetes Study (UKPDS) showed that
the probability of death increases as renal deterioration progresses.
Modified after reference 38: Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull
CA, Holman RR; UKPDS Group. Kidney Int. 2003;63:225-232. Copyright ©
2003, International Society of Nephrology.
minuria is increasingly recognized as a general risk marker
for microvascular damage, such as endothelial dysfunction
or inflammation in the small blood vessels.36 The abnormal-
ities in small blood vessels are most easily detected in the
urine, where the transcapillary escape rate can be measured
in terms of urinary protein excretion. However, it must be
mentioned that there is sizeable tubular reabsorption. Nev-
ertheless, it is still clear that the albumin level in final urine is
a very strong predictive marker. Thus, microalbuminuria not
only predicts renal disease, but cardiovascular disease and
mortality also and may be the strongest parameter in this
respect.
302 MEDICOGRAPHIA, Vol 31, No. 3, 2009
BP, low kidney perfusion, and long-term effect
on GFR
Once, it was widely believed that antihypertensive treatment
would compromise renal circulation and, thus, be deleterious
to renal function.16,23 Indeed, it was observed that treatment
with antihypertensive agents acutely reduced GFR, and there
was a fear that renal function would be reduced further and
progressively over time. Therefore, it was suggested in sev-
eral centers that physicians should not reduce blood pres-
sure in patients with diabetes and hypertension or elevated
blood pressure.16
However, this paradigm appears to have been entirely wrong.
In the mid 70s, studies showed that renal disease progres-
sion, as measured by the exact rate of decline in GFR, was
closely related to blood pressure level.39,40 Subsequently, it
was shown that antihypertensive treatment could reduce al-
buminuria and, finally, that antihypertensive treatment over
time reduced the rate of decline in GFR.39-44 This was a ma-
jor breakthrough in the management of patients with type 1
diabetes. This treatment was the first to be based upon
studies utilizing β-blockers, diuretics, and other antihyperten-
sive agents. Later, agents blocking the renin-angiotensin sys-
tem (RAS) became available and important, although it was
clear that blood pressure reduction per se should also be a
focus.44 Taguma et al45 were the first to define a paradigm, in
lowering BP in type 2 diabetes, even if it was in the so-called
normal range. Prevention or reduction of microalbuminuria,
Microalbuminuric patients and antihypertensive
treatment
In recent years, it has become clear that microalbuminuria is
a major risk factor. Initially, however, the treatment of these pa-
tients with antihypertensive agents was not advocated unless
they had clearly elevated blood pressure. The definition of hy-
pertension varied: a systolic BP higher than 140 mm Hg, or,
previously, a systolic BP higher than 160 mm Hg. It was shown
that the rate of progression of microalbuminuria was related
to blood pressure—even below these levels. Therefore, the
possibility of treating these patients with persistent microal-
buminuria (even those with so-called normal or high normal
BP) and incipient diabetic nephropathy with antihypertensive
agents came as a major breakthrough. When these studies
were initiated, it was not possible to block the renin-angio-
tensin system with ACE inhibitors or angiotensin receptor
blockers (ARBs). At the same time, GFR was still well pre-
served and quite often even in the hyperfiltration range.31,35,46
Figure 4 shows renal outcomes in ADVANCE.
The paradigm shift became apparent: treatment with agents
blocking the renin-angiotensin system became much more
Blood pressure, blood glucose, and diabetic renal disease – Mogensen

Figure 4. Renal outcomes in ADVANCE.
In the ADVANCE study, the fixed combination Preterax significantly reduced all renal events and microalbuminuria in type 2 diabetic patients (presentation at the
2007 congress of the European Society of Cardiology).
Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; Per-Ind, perindopril-indapamide.
acceptable (compared with β-blockers) because of fewer side
effects, and now all guidelines propose treating patients with
microalbuminuria with agents that block the renin-angiotensin
system. New studies from Michael Mauer’s group have not
documented any structural protection afforded by RAS block-
ade in normoalbuminuric type 1 patients. However, these pa-
tients are known to have a low risk of progression, which ex-
plains the negative and disappointing findings.
The importance of reducing BP by blocking RAS
in diabetes
At present, it is recommended that patients with microalbu-
minuria or proteinuria start treatment with agents that block
the renin-angiotensin system. However, initial studies were
conducted at a point in time when only β-blockers, diuretics,
and a few other agents were available for antihypertensive
treatment.39,40 In fact, these first studies showed that decline
in renal function might be reduced, and a small and simple
meta-analysis from Denmark of all the available studies at
the time showed that decline in GFR was not improved by
blocking ACE when compared with other antihypertensive
agents.42 It is, however, now clear that treatment strategy is
more easily implemented with the new agents because they
cause fewer side effects. The most noticeable side effect in
clinical practice with ACE inhibitors is cough, and, in this case,
it is justified to switch to ARBs, although not initially. The renal
effect of these two classes of drugs are not too different, but
if blood pressure is not reduced by this strategy, the effect is
more limited. Reduction of BP is crucial.44
“Normal” values in normoalbuminuria
Normoalbuminuria was and is defined as an albumin excre-
tion rate below 20 μg/min or 30 mg/24 hours. However, the
excretion rate in young, normal individuals is usually around
5 μg/min, although some normal individuals have higher val-
ues.37 The cut-off of 20 μg/min was based upon observa-
tional studies in patients with type 1 diabetes, where an ex-
cretion rate higher than 15 to 20 μg/min was usually asso-
Blood pressure, blood glucose, and diabetic renal disease – Mogensen
FOCUS
ciated with disease progression.35,36 However, more recent
studies have shown that albuminuria in the upper normal range
is also a risk factor and the exact cut-off is difficult to define.
This is not surprising because albuminuria, just like other bi-
ological parameters, is a continuous variable. It is thus clear
that with so-called high-normal values of albuminuria, there is
a somewhat increased risk of future cardiovascular and renal
disease.
ACE inhibitors and ARBs in combination
The use of either ACE inhibitors or ARBs is both useful and
very feasible in practice (ACE inhibitors are substituted with
ARBs in the case of cough). However, using both agents at
the same time is not considered appropriate. In recent stud-
ies, it has been documented that there might be a further dual
blockade effect in diabetes, in some patients. The Candesar-
tan And Lisinopril Microalbuminuria (CALM) I study 47 showed
that so-called dual blockade with a combination of candesar-
tan and lisinopril was efficient in reducing blood pressure and
albuminuria. But in the next study, CALM II,48 it seemed pos-
sible to use a double dose of ACE inhibitors, with comparable
results.48 The recent ONgoing Telmisartan Alone and in com-
bination with Ramipril Global End point Trial (ONTARGET)
study questions the use of dual blockade in patients with ab-
normal albuminuria.24 Importantly, ARBs and ACE inhibitors
have shown the same results.49
The best parameter for recording blood pressure
Years ago, by tradition, diastolic blood pressure was consid-
ered to be the main clinical parameter. In the late 90s, the sit-
uation changed and it appeared that systolic blood pressure
was a better predictor of future cardiovascular damage. Now,
new studies suggest that pulse pressure may be an even bet-
ter parameter.50,51 The presence of raised systolic pulse pres-
sure seems highly predictive for the development and pro-
gression of renal disease and, maybe, also for cardiovascular
morbidity and mortality in type 2 diabetic subjects (although
it is difficult to determine the exact effect of systolic blood
MEDICOGRAPHIA, Vol 31, No. 3, 2009 303
FOCUS
100
96
Patients free of events (%)
P=0.036
92
88
84
80
0 50 100 150 200 250 300 350 400 450
Days from randomization
Figure 5. Serious cardiovascular events in the PREMIER study.
Abbreviation: PREMIER, PREterax in albuMInuria rEgRession.
Reproduced from reference 52: Mogensen CE, Viberti G, Halimi S, et al. Hyper-
tension. 2003;41:1063-1071. Copyright © 2003, American Heart Association, Inc.
pressure). Interestingly, according to new studies, dual block-
ade has a pronounced effect on pulse pressure compared
with high-dose monotherapy—it appears that pulse pressure
may be more strongly related to central blood pressure,
hence its effect on renal circulation.50,51
Follow-up after screening for microalbuminuria
Screening for microalbuminuria has been proposed and ac-
cepted by many guideline committees. This is highly relevant,
but new studies document that, for treatment to be effective,
a reduction in microalbuminuria is of considerable impor-
tance.18,27,32 Therefore, it is now recommended that not only
should microalbuminuria be screened for, but that treatment
should also be followed up in order to see if microalbumin-
uria has declined sufficiently during treatment. Reduction in
macroalbuminuria with antihypertensive treatment corre-
lates with a subsequent reduced rate of decline in GFR.
ACE inhibition and diuretics in type 2 diabetes
New studies such as the Steno 2 study and the ADVANCE
study clearly show that antihypertensive treatment, espe-
cially with drugs that block the renin-angiotensin system, is
useful for patients with microalbuminuria (as seen in the
Steno 2 study) and of definite benefit for many renal pa-
tients and patients with normoalbuminuria (as shown in
ADVANCE). ADVANCE clearly showed the beneficial effects
on mortality of antihypertensive treatment and that microalbu-
minuria was a major risk factor. When microalbuminuria was
reduced, there was a stronger beneficial effect. It is also inter-
esting to note that another major finding of the ADVANCE
study was the protective effect of intensive glucose-lowering
treatment, based on gliclazide MR, against diabetic nephro-
pathy.11 Therefore, it seems justified that many patients with
type 2 diabetes should be treated, not only with effective an-
304 MEDICOGRAPHIA, Vol 31, No. 3, 2009
tihyperglycemic agents, but also with agents that reduce
blood pressure, and one of the main focuses was a combina-
tion of ACE inhibitors and diuretics (as seen in ADVANCE).
Preterax
The PREterax in albuMInuria rEgRession (PREMIER) study52
showed that first line treatment with a low-dose combination
Enalapril of perindopril/indapamide induces a greater decrease in al-
buminuria than enalapril (partially independent of BP reduc-
tion). A BP-independent effect of the combination may be to
increase renal protection.
Significant effects on serious cardiovascular events may also
be observed (Figure 5).52 In this context, it is also important
to focus on the safe oral treatment of type 2 diabetes. In
the GlUcose control In type 2 diabetes: Diamicron modified
release versus glimEpiride (GUIDE) study,53 it was shown that
gliclazide MR is at least as effective as glimepiride, either as
a monotherapy or in combination. The safety of gliclazide MR
was significantly better, with approximately 50% fewer con-
firmed hypoglycemic episodes in comparison with glimepiride.
Interestingly, a recent publication retrospectively assessing
the risk of developing coronary artery disease (CAD) accord-
ing to initial sulfonylurea treatment in type 2 diabetic patients
found less risk of CAD with gliclazide when compared with
glimepiride or glipizide.54 The results showing continuous BP-
lowering and glycemic control effects in ADVANCE are very
important.55
Conventional
paradigms
Anomalies, crises,
and revolutions
Standard
Extraordinary
puzzle solving
new idea and
unexpected findings
Observations, Paradigm
ideas, and shifts
concepts
New
paradigms
Figure 6. The paradigm circle.
A schematic representation of how paradigms are formed and develop. Ac-
cording to this concept, new developments modify and improve our level of
knowledge. It shows how paradigms are constantly being developed (from the
Björn Folkow Lecture by the author at the annual meeting of the European So-
ciety of Hypertension in Milan in 2007).
Figure 6 shows the paradigm circle (modified from Thomas
Kuhn). According to the paradigm circle concept, new de-
velopments modify and improve our level of knowledge. It
shows how paradigms are in constant development and is
taken from the Björn Folkow Lecture, given by the author at
the European Society for Hypertension congress in Milan in
2007. 
Blood pressure, blood glucose, and diabetic renal disease – Mogensen

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17. Parving HH, Jensen HÆ, Mogensen CE, Evrin P-E. Increased urinary albumin
excretion rate in benign essential hypertension. Lancet. 1974;1:1190-1192.
18. Heart Outcomes Prevention Evaluation Study Investigators. Effects of an an-
giotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-
risk patients. N Engl J Med. 2000;342:145-143.
19. Keane WF, Zhang Z, Lyle PA, et al. Risk scores for predicting outcomes in pa-
tients with type 2 diabetes and nephropathy: the RENAAL study. Clin J Am Soc
Nephrol. 2006;1:761-767.
20. Böhm M, Thoenes M, Danchin N, Bramlage P, La Puerta P, Volpe M. Asso-
ciation of cardiovascular risk factors with microalbuminuria in hypertensive in-
dividual: The i-SEARCH global study. J Hypertens. 2007;25:2317-2324.
21. Klausen KP, Scharling H, Jensen JS. Very low level of microalbuminuria is as-
sociated with increased risk of death in subjects with cardiovascular or cere-
brovascular diseases. J Int Med. 2006;260:231-237.
22. Klausen KP, Scharling H, Jensen G, Jensen JS. New definition of microalbumin-
uria in hypertensive subjects. Association with incident coronary heart disease
and death. Hypertension. 2005;46:33-37.
23. Mogensen CE, Schmitz A, Christensen CK. Comparative renal pathophysiology
relevant to IDDM and NIDDM patients. Diabetes Metab Rev. 1988;5:453-483.
24. Mann JF, Schmieder RE, McQueen M, et al; ONTARGET Investigators. Renal
outcome with telmisartan, ramipril, or both, in people at high vascular risk (the
ONTARGET study): a multicentre, randomised, double-blind, controlled trial.
Lancet. 2008;372:547-553.
25. Basi S, Lewis JB. Microalbuminuria as a target to improve cardiovascular and
renal outcomes. Am J Kidney Dis. 2006;47:927-946.
26. Murussi M, Campagnolo N, Beck MO, Gross L, Silveiro SP. High-normal levels
of albuminuria predict the development of micro- and macroalbuminuria and
increased mortality in Brazilian type 2 diabetic patients: an 8-year follow-up
study. Diabet Med. 2007;24:1136-1142.
27. Tuttle KR. Albuminuria reduction: The holy grail for kidney protection. Kidney
Int. 2007;72:785-786.
28. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic
kidney disease: evaluation, classification, and stratification. Am J Kidney Dis.
2002;39:(2 suppl 1):S1-S66.
29. Mogensen CE, Christensen CK. Predicting diabetic nephropathy in insulin-de-
pendent patients. N Engl J Med. 1984;311:89-93.
30. De Jong PE, Brenner BM. From secondary to primary prevention of progres-
Blood pressure, blood glucose, and diabetic renal disease – Mogensen
FOCUS
sive renal disease: the case for screening for albuminuria. Kidney Int.
2004;66:2109-2118.
31. Caramori ML, Fioretto P, Mauer M. Enhancing the predictive value of urinary al-
bumin for diabetic nephropathy. J Am Soc Nephrol. 2006;17:339-352.
32. Mogensen CE. Renal dysfunction and hypertension. In: Goldstein BJ, Mueller-
Wieland D, eds. Type 2 Diabetes. Principles and Practice. London, United King-
dom: Informa Healthcare; 2007.
33. Premaratne E, Maciasaac RJ, Tsalamandris C, et al. Renal hyperfiltration in
type 2 diabetes: effect of age-related decline in glomerular filtration rate. Dia-
betologia. 2005;48:2486-2493.
34. Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortal-
ity in maturity-onset diabetes. N Engl J Med. 1984;310:356-360.
35. Mogensen CE. Microalbuminuria, blood pressure and diabetic renal disease:
Origin and development of ideas. Diabetologia. 1999;42:263-285.
36. Mogensen CE. Microalbuminuria, renal disease, metabolic syndrome and risks
in diabetes. Diabetes Metab Syndr Clin Res Rev. 2007;1:127-133.
37. Mogensen CE, Chachati A, Christensen CK, et al. Microalbuminuria: an early
marker of renal involvement in diabetes. Uremia Invest. 1985-1986;9:85-95.
38. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR; UKPDS
Group. Development and progression of nephropathy in type 2 diabetes: the
United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 2003;
63:225-232.
39. Mogensen CE. Long-term antihypertensive treatment inhibiting progression of
diabetic nephropathy. BMJ. 1982;285:685-688.
40. Parving HH, Smidt UM, Andersen AR, Svendsen PAA. Early aggressive anti-
hypertensive treatment reduces rate of decline in kidney function in diabetic
nephropathy. Lancet. 1983;1:1175-1179.
41. Mogensen CE. ACE-inhibitors and antihypertensive treatment in diabetes:
Focus on microalbuminuria and macrovascular disease. JRAAS. 2000;1:234-
239.
42. Hovind P, Rossing P, Tarnow L, Smidt UM, Parving HH. Progression of diabet-
ic nephropathy. Kidney Int. 2001;59:702-709.
43. Mogensen CE. Microalbuminuria and hypertension with focus on type 1 and
type 2 diabetes. J Int Med. 2003;254:45-66.
44. Casas JP, Chua W, Loukogeorgakis S, et al. Effect of inhibitors of the renin-
angiotensin system and other antihypertensive drugs on renal outcomes: sys-
tematic review and meta-analysis. Lancet. 2005;366:2026-2033.
45. Taguma Y, Kitamoto Y, Futaki G, et al. Effect of captopril on heavy proteinuria in
azotemic diabetics. N Engl J Med. 1985;313;1617-1620.
46. Mogensen CE, Poulsen PL. Microalbuminuria, glycemic control, and blood
pressure prediction outcome in diabetes type 1 and type 2. Kidney Int. 2004;66:
S40-S41.
47. Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual
blockade of the renin angiotensin system in hypertensive, microalbuminuric,
non-insulin dependent diabetes: the candesartan and lisinopril microalbumin-
uria (CALM) study. BMJ. 2000;321:1440-1444.
48. Andersen NH, Poulsen PL, Knudsen ST, et al. Long-term dual blockade with
candesartan and lisinopril in hypertensive patients with diabetes. Diabetes
Care. 2005;28:273-277.
49. Barnett A, Bain S, Bouter P, Karlberg B, Madsbad S, Jervell J, Mustonen J;
Diabetics Exposed to Telmisartan and Enalapril Study Group. Angiotensin-re-
ceptor blockade versus converting-enzyme inhibition in type 2 diabetes and
nephropathy. N Engl J Med. 2004;351:19.
50. Knudsen ST, Andersen NH, Mogensen CE. Ambulatory pulse pressure and pro-
gression of albuminuria in type 2 diabetes. Evidence provided, new questions
emerge. Hypertension. 2006;48:207-208.
51. Knudsen ST, Andersen NH, Poulsen SH, et al. Pulse pressure lowering effect of
dual blockade with candesartan and lisinopril vs. high-dose ACE inhibition in
hypertensive type 2 diabetic subjects: a CALM II study post-hoc analysis. Am J
Hypertens. 2008;21:172-176.
52. Mogensen CE, Viberti G, Halimi S, et al. Effect of low-dose perindopril/inda-
pamide on albuminuria in diabetes. Hypertension. 2003;41:1063-1071.
53. Schernthaner G, Grimaldi A, Di Mario U, et al. GUIDE study: double-blind com-
parison of once-daily gliclazide MR and glimepriride in type 2 diabetic patients.
Eur J Clin Invest. 2004;34:535-542.
54. Sadikot SM, Mogensen CE. Risk of coronary artery disease associated with ini-
tial sulphonylurea treatment of patients with type 2 diabetes: a matched case-
control study. Diabetes Res Clin Pract. 2008;82:391-395.
55. Zoungas S, Galan B, Ninomiya T, et al; ADVANCE Collaborative Group. The com-
bined effects of routine blood pressure lowering and intensive glucose con-
trol on macrovascular and microvascular outcomes in patients with type 2 dia-
betes: new results from the ADVANCE study (submitted).
MEDICOGRAPHIA, Vol 31, No. 3, 2009 305
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Keywords: blood glucose; blood pressure; diabetic renal disease; glycemic control; type 2 diabetes

PRESSION ARTÉRIELLE , GLYCÉMIE ET MALADIE RÉNALE DIABÉTIQUE

Cet article insiste sur deux sujets : le rôle essentiel du contrôle de la glycémie comme de celui, peut-être encore
plus essentiel, du contrôle de la pression artérielle (PA), idée examinée dans un éditorial du British Medical Journal
après publication des principaux résultats de l’étude UKPDS (United Kingdom Prospective Diabetes Study) en 1998.
L’étude UKPDS, qui étudia des patients atteints de diabète de type 2 récemment diagnostiqués, est une étude de
référence dans le domaine du traitement du diabète de type 2 qui instaura un meilleur suivi de la PA et de l’HbA1c
ainsi qu’un traitement plus intensif. De nouvelles études montrent clairement qu’un contrôle trop intensif de la gly-
cémie chez les diabétiques de type 2, au moins dans certaines populations, entraîne des effets délétères, à savoir une
mortalité augmentée (comme en témoigne l’étude ACCORD [Action to Control CardiOvascular Risk in Diabetes]).
D’un autre côté, comme le montre l’étude de suivi sur 13 ans Steno 2, il est important d’intervenir de façon plurifac-
torielle. Bien sûr, débuter dès le diagnostic du diabète de type 2 est essentiel mais de nombreuses complications
surviennent après. À cet égard, l’étude ADVANCE (Action in Diabetes and Vascular disease : PreterAx and Diami-
croN MR Controlled Evaluation) est très intéressante. De facto, ADVANCE a pris la suite d’UKPDS (après environ 9 ans
d’évolution de diabète de type 2) et s’est également concentrée sur la relation entre les aspects rénaux du diabète
et les traitements antihypertenseur et hypoglycémiant. Dans plusieurs études antérieures menées par notre groupe,
nous nous étions intéressés spécifiquement à ces aspects du diabète de type 2 et de diminution de l’albuminurie. Au
total, la comparaison des diminutions de la PA observées dans ADVANCE et dans UKPDS montre que la PA était
plus basse dans ADVANCE, y compris chez les diabétiques non hypertendus, et que le contrôle glycémique rédui-
sait les complications. Par ailleurs, dans les deux études, un meilleur contrôle de la PA diminuait les complications.

306 MEDICOGRAPHIA, Vol 31, No. 3, 2009 Blood pressure, blood glucose, and diabetic renal disease – Mogensen

‘‘ We can envisage a future in
which there is a change in the cur-
rent paradigms in standards of
care and we wait for increases in
“biomarkers” such as microalbu-
minuria or creatinine to be present
before treatment [of diabetes] is
initiated as a mode of “second-
ary” prevention … in the future, an
integrated strategy will allow the
combination of clinical biomarkers
with genomic and other ones that
will move us toward a scenario of
“primary” prevention of complica-
tions.”
R
 for dissecting the genetic determinants of renal and cardiovascular compli-
Pavel HAMET, MD, PhD
Johanne TREMBLAY, PhD
Gene Medicine Service
Centre de recherche du
Centre hospitalier de
l’Université de Montréal
(CRCHUM) and
Prognomix Inc, Montreal
Quebec, CANADA
Address for correspondence:
Dr Pavel Hamet, CRCHUM –
Technopôle Angus, 2901 rue Rachel
Est, Montréal (Québec) H1W 4A4,
CANADA
(e-mail: pavel.hamet@umontreal.ca)
www.medicographia.com
ADVANCE genetic substudy – Hamet and Tremblay
U P DAT E
Will ADVANCE population
genomic determinants
improve upon biomarkers
in predicting vascular
complications of diabetes?
P. H a m e t a n d J . Tre m b l a y, C a n a d a
ecent progress in genomics that allows the identification of millions of
variations in an individual’s genome has given rise to new hope over the
implementation of this knowledge in personalized medicine. The ge-
netic architecture of complex diseases, including type 2 diabetes (T2D), is be-
ing uncovered by whole genome association studies. Despite tremendous
progress in the last 3 years, their major limitation lies in their relatively low ca-
pacity to predict individual susceptibility in a general population. Fine pheno-
typing and careful consideration of various factors, including age, sex, as well
as genetic and environmental backgrounds of the individual, are required to
resolve this diagnostic challenge. Here, we summarize our initial strategies
cations in T2D, using rich data from the ADVANCE (Action in Diabetes and
Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) trial.
We discuss the relative importance of traditional clinical biomarkers, such as
cholesterol levels, hypertension, and body mass index, in the context of novel
“genomic biomarkers,” as well as the need for their eventual integration into
a more inclusive paradigm. Additional information contained in our DNA that
is susceptible to modulation by environmental factors (such as disease state,
medication, and lifestyle) includes epigenetic DNA methylation and telomeric
shortening, a scar of biological aging. These can be added to DNA sequence
variations at the single nucleotide polymorphism level, and this will acceler-
ate the path toward personalized and predictive medicine where presymp-
tomatic intervention becomes part of prevention.
Medicographia. 2009;31:307-313 (see French abstract on page 313)
T
ype 2 diabetes (T2D), a complex disease that is increasing in prevalence
worldwide, represents a major global health burden1-4 in countries with high
as well as low incomes. Diabetes is a major risk factor for the development
of serious health problems, such as kidney failure, heart attack, and stroke.5,6 Cur-
rently, there are no tests available to promptly, accurately, and specifically determine
which patients are more likely to encounter these complications (although several
risk scores have been proposed for predicting events based on population studies,
such as Framingham, or on data derived from clinical trials, such as the United King-
dom Prospective Diabetes Study [UKPDS]).7 A recent New Zealand investigation
that compared 3 different methods of assessing cardiovascular disease risk and im-
proved upon the UKPDS risk engine still only presents relatively low specificity.8 In
fact, some recommendations are predictive in nature. For example, in the United
MEDICOGRAPHIA, Vol 31, No. 3, 2009 307
U P DAT E
States, the National Cholesterol Education Program Expert
Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults proposes lowering the therapeutic
threshold of the high-density lipoprotein (HDL)/low-density
lipoprotein (LDL) ratio to 2.6 mmol/L in T2D, yet this is still
only seen as secondary prevention.9
There is growing evidence that combining multiple genetic
and clinical markers is the best way to develop a molecular
test with clinically useful predictive power. However, no such
test has emerged so far for the vascular complications of di-
abetes. Due to the multifactorial nature of diabetes and its
complications, large sample collections and high-quality data
sets combined with sophisticated study designs and robust
statistical models are required to decipher the genetic deter-
minants of susceptibility to diabetes complications. Toward
this end, we are fortunate to have access to clinical and epi-
demiological data and to biological samples from ADVANCE,
the largest clinical trial of T2D (involving over 11 000 patients)
to date.10,11 To exploit these data and samples, we developed
bioinformatic tools and, as a first step, we performed dense
genotyping of genomic DNA in registered patients who
participated in ADVANCE. To reduce genetic heterogeneity,
we started with patients of Caucasian origin. The fundamen-
tal aims of our approach were to: (i) determine the relation-
ships between genetic and clinical markers and diabetes
complications; (ii) develop a predictive model for diabetic
complications, based on genetic and clinical markers; and
(iii) implement the test as a usable, clinically relevant tool.
Progress in genomics
Until recently, genetics was a science of monogenetic disor-
ders following Mendelian law. Online Mendelian Inheritance
in Man engine statistics listed, as of January 3, 2009, a total
of 19 184 entries, with only 1677 remaining Mendelian phe-
notypes of unknown molecular basis. However, much more
has to be accomplished in the area of complex diseases with
their polygenic and environment-modifiable characters. One
encouraging step, a major technological microarray break-
through, has allowed us to determine hundreds of thousands
SELECTED ABBREVIATIONS AND ACRONYMS
ADVANCE Action in Diabetes and Vascular disease: Prete-
rAx and DiamicroN MR Controlled Evaluation
AUC area under the curve
CRP C-reactive protein
DN diabetic nephropathy
FIND Family Investigation of Nephropathy and Diabetes
ROC receiver operating characteristic
SNP single nucleotide polymorphism
T2D type 2 diabetes
UKPDS United Kingdom Prospective Diabetes Study
WHO World Health Organization
308 MEDICOGRAPHIA, Vol 31, No. 3, 2009
A D
G
IP
B
G1 IP1
D
G2 IP2
Figure 1. Network of intermediate phenotypes impacted by a
separate set of genes.
(A) Model of causal association between intermediate phenotypes as governed by
genes and disease. (B) Realistic modeling of the intermediate phenotype affected
by several genes, with their direct and indirect impact on a complex disease.
of single nucleotide polymorphisms (SNPs) in several thou-
sand subjects and in genomic association studies for a wide
variety of pathologies, including heart disease, rheumatoid
arthritis, colorectal cancer, and autoimmune disorders. In
fact, Science declared human genetic variation to be the
breakthrough of the year in 2007.12
Nevertheless, paradoxically, many investigations into com-
plex disorders, including diabetes, hypertension, and dyslipi-
demia, are still hunting for a major gene, a monogenic com-
ponent within the complexity. A good example here is the
search for the genomic characteristics of C-reactive protein
(CRP) as a cardiovascular risk factor. When a genomic deter-
minant of CRP levels in cardiovascular disease–affected sub-
jects is observed on a chromosomal location different from
the CRP gene itself, some will suspect that this is a de facto
finding, which excludes any role of the CRP gene and follows
the monogenetic reasoning of Mendelian randomization.13
Thus, for instance, our collaborators uncovered a major ge-
nomic determinant of CRP levels in German subjects with my-
ocardial infarction, an observation we validated in our French
Canadian cohort at the same locus on chromosome 10,
which has no CRP gene in this region.14 The appropriate
explanation is a model of a network of intermediate pheno-
types impacted by a separate set of genes, as illustrated in
Figures 1A and 1B.12 In spheres such as hypertension and
diabetes, this brings us back to Irving Page’s kaleidoscope
mosaic where the “nodes” are genes and phenotypes.15
An additional and sizable limitation to genomics gaining clini-
cal usefulness is the disproportionate sophistication between
ADVANCE genetic substudy – Hamet and Tremblay
 U P DAT E

today’s genomic armamentarium compared with the paucity
of its standardized and fine phenotyping counterparts. In our
search for the genomic determinants of hypertension, we have
attempted to alleviate this situation by collecting over 200
cardiovascular and metabolic phenotypes16 in a panel of ex-
tended families of French Canadian origin, which has helped
us to discover 46 significant quantitative trait loci for blood
pressure and cardiometabolic traits that, according to Allen
W. Cowley Jr, represent “the highest number of loci contrib-
uting to cardiovascular-related and metabolic traits that has
been reported to date within a single population”.17 This work,
completed in 2005, was performed with only 450 polymorphic
markers. The number of genotyping tools has since grown
exponentially: thus, over the last 2 years, we have enriched
the genotyping of our French Canadian families with more than
50 000 SNPs, and our current efforts to genotype ADVANCE
subjects are being performed with the Affymetrix Genome-
Wide Human Array 6.0 that includes a total of 1.8 million ge-
netic markers, more than 906 600 SNPs and 940 000 probes
for the detection of copy number variations. In our study of
the French Canadian founder population with 50 000 SNPs,
we were able to identify sex- and/or age-specific loci at the
level of single nucleotides.18 The lesson we learned from this
systematic, genome-wide, sex-specific linkage study was that
the traditional methods of sex adjustment would miss many
of the significant genomic contributions in one or other of the
sexes, making sex-separate analysis a must in the genomic
investigations of a wide range of traits, such as triglyceride lev-
els, which we demonstrated in experimental animal mod-
els19 initially, and of cardiovascular death risk prediction in di-
abetic men vs women.20
Genetics of type 2 diabetes and its complications
One of the areas that has witnessed the fastest growth in
knowledge regarding genomic determinants stemming from
whole genomic association studies is that of T2D. This was
initiated by Sladek et al21 and subsequently followed by sev-
eral others (as summarized in Table I).22 The main conclusion
to draw is that common variants with high penetrance do
not contribute substantially to disease variance, but rather

Number Number Sample Genotyping

Study of cases of controls source array T2D phenotype

Wellcome Trust 1924 2938 UK Affymetrix 500K Enrichment for family history of T2D
Case Control
Consortium AAO <65 years
Diabetes Genetics 1464 1467 Finland Affymetrix 500K Partial enrichment for family history and
Initiative Sweden lean T2D
deCODE Genetics 1399 5275 Iceland Illumina 300K No specific enrichment for family history
Young AAO or BMI
Finland-US Investigation 1161 1174 Finland Illumina 300K Partial enrichment for family history
of NIDDM (FUSION)
Diabetes Gene 694 645 France Illumina 300K Family history of T2D
Discovery Group + Illumina 100K AAO <45 years
BMI <30 kg/m2
DiaGen 500 497 East Finland, Illumina Enrichment for family history
Germany, UK, 300K AAO <60 years
Ashkenazi
Pima 300 334 Pima Indians Affymetrix 100K AAO <25 years, enrichment for family history
Starr County, Texas 281 280 Mexican- Affymetrix 100K Controlled for admixture
Americans
BioBank Japan 194 1556 Japanese Custom set of Enrichment for T2D cases with retinopathy
268K SNPs
JSNP
Japanese Multidisease 187 1504 Japanese Genome T2D cases
Collaborative Scan 100K
Genome Scan SNPs
Old Order Amish 124 295 Amish Affymetrix 100K Enrichment for family history
Framingham Health Study 91 1087 Massachusetts Affymetrix 100K Incident T2D cases

Table I. Overview of genome-wide scan studies for type 2 diabetes.

Abbreviations: AAO, age at onset; BMI, body mass index; JSNP, Japanese single nucleotide polymorphism; NIDDM, noninsulin-dependent diabetes mellitus; SNP,
single nucleotide polymorphism; T2D, type 2 diabetes.
Reproduced from reference 22: Prokopenko I, McCarthy MI, Lindgren CM. Trends Genet. 2008;24:613-621. Copyright © 2008, Elsevier Ltd.

ADVANCE genetic substudy – Hamet and Tremblay MEDICOGRAPHIA, Vol 31, No. 3, 2009 309
U P DAT E

many modest contributions with relatively low odds ratios Mexican Americans, Puppala et al25 reported a linkage sig-
have to be considered, as illustrated in Figure 2, with defects nal for glomerular filtration rate at a region on chromosome
in pancreatic β-cell function predominating in the overall pic- 2q near the marker D2S427 (corrected LOD score 3.3), which
ture. Here, we will focus on the renal complications of dia- was shown to be influenced by genotype with diabetes inter-
betes, bearing in mind their importance, as well as the rela- action effects. A summary of linkage studies for DN appears
tively rich evidence from genetic contributions reported in the in Figure 3.
literature and summarized in Figure 3. To date, several ge-
nomic regions or individual genetic variants have been found  Association (candidate gene) studies
to be linked or associated with the phenotypes closely relat- A number of genes and genetic polymorphisms were tested
ed to diabetic complications. for their association with DN, either because of their report-
ed relevance in metabolic and signaling
pathways connected to the pathophys-
TCF7L2 iology of diabetic complications (func-
KCNQ1
tional candidates) or a combination of
the former with their genomic position
CDKN2B
under a peak of ascertained linkage (po-
FTO
sitional candidates).
HHEX/IDE
SLC30A8 Can genomics contribute to the
THADA predictive power of biomarkers?
PPARG In the current literature, most genome-
KCNJ11 wide association studies only report the
Gene

CDKAL1 significance of association with SNPs,

IGF2BP2 while disregarding its clinical utility, ie,
NOTCH2
sensitivity and specificity, which can be
combined to increase predictive power
WFS1
and which will one day be considered
CDC123/CAMK1D
when genetics is implemented in per-
HNF1B
sonalized medicine.7,26 Predictive power
JAZF1 is determined by “area under the curve”
TSPAN8/LGR5 (AUC). This measure is widely used to
ADAMTS9 quantify the predictive power of differ-
1.0 1.05 1.1 1.15 1.2 1.25 1.3 1.35 1.4 ent classifiers in predictive studies; a val-
Per-allele odds ratio ue of 0.5 refers to a random prediction,
and a value of 1.0 indicates an optimal
Figure 2. Odds ratios of confirmed genes reported to be associated with type 2 diabetes. prediction. The measure is visualized by
receiver operating characteristic (ROC)
 Linkage studies curves, which are graphs that represent the true positive rate
Family Investigation of Nephropathy and Diabetes (FIND), a versus the false positive rate of different cutoff values. If the
recent genome-wide scan of glomerular filtration rate estima- curve tends to the top left of the graph (high true positive rate,
tion, was performed in multiethnic diabetic populations.23 For low false positive rate), the classifier is considered efficient.
all ethnicities combined, strong evidence of linkage was ob- Prediction models rely on training (fitting) and test sets. The
served on chromosomes 1q43, 7q36.1, 8q13.3, and 18q23.3. training set is used to fit models, and the test set serves to as-
Mexican American families, who comprised the major ethnic sess the classification efficiency of the model. To investigate
subpopulation in FIND, contributed to linkage on chromo- the predictive ability of the best-associated SNPs on our phe-
somes 1q43, 2p13.3, 7q36.1, 8q13.3, and 18q23.3, where- notypes, we carried out 10 iteration experiments by dividing
as African American and American Indian families displayed our data set randomly into training and testing sets. We ob-
linkage peaks on chromosomes 11p15.1 and 15q22.3, re- served that the predictive power of SNPs increases with the
spectively. In FIND,24 the strongest evidence for linkage to number of best, significantly-associated SNPs. The example
diabetic nephropathy (DN) was detected on chromosomes in Figure 4 illustrates the ROC curves obtained with the sup-
7q21.3, 10p15.3, 14q23.1, and 18q22.3. For albumin crea- port vector machine as a classifier and with 55 best-asso-
tinine ratio (883 diabetic sibling pairs), the strongest linkage ciated SNPs with diabetes complications (renal, cardiac, and
signals were located on chromosomes 2q14.1, 7q21.1, and cerebrovascular). At term, genomic and epigenomic data, such
15q26.3. These results confirmed the linkage regions for DN as DNA methylation and telomeric length, will be integrated
on chromosomes 7q, 10p, and 18q from prior reports. In with clinical data to give a personalized predictive risk score

310 MEDICOGRAPHIA, Vol 31, No. 3, 2009 ADVANCE genetic substudy – Hamet and Tremblay
 U P DAT E

1 2 3 4 5 6 7 8 9 10 11 12

13 14 15 16 17 18 19 20 21 22 X Y

Figure 3. Linkage studies for diabetic nephropathy.

Diabetic nephropathy linkage (vertical bars) and candidate genes (abbreviated) mapped from a recent review of the literature summarized until 2008 (Seda et al. Unpub-
lished data, 2009).

Fitting Testing
SVM 10 iterations; AUC=0.95 SVM 10 iterations; AUC=0.73
1.0 1.31 1.0 1.54

1.03 1.14
True positive rate (sensitivity)

True positive rate (sensitivity)

0.8 0.8

0.6 0.74 0.6 0.73

0.4 0.46 0.4 0.32

0.2 0.17 0.2 – 0.07

0.0 – 0.11 0.0 – 0.47

0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0
False positive rate (1-specificity) False positive rate (1-specificity)

Complications, 55 SNPs, 0.5/0.5 ratio, support vector machine (SVM).

Figure 4. ROC curves representing fitting (learning) versus testing as a function of true positive and false positive rates.
Abbreviations: AUC, area under the curve; SNP, single nucleotide polymorphism; ROC, receiver operating characteristic; SVM, support vector machine.

ADVANCE genetic substudy – Hamet and Tremblay MEDICOGRAPHIA, Vol 31, No. 3, 2009 311
U P DAT E

A B

First visit First visit

Current care Personalized

care Centralized lab
Patient Physician Patient Physician
Complication

Clinical
Years after
diagnosis

Complication
biomarker profile Clinical biomarker profile

Years after
diagnosis
ACE inhibitor

5 y Micro-
albuminuria PREVENTION Genomic biomarker profile
ACE inhibitor
10 y Macro- 10 y Micro-
albuminuria albuminuria

15 y Renal failure 15 y Macro- Prognomix/ADVANCE Bioinformatics

albuminuria risk score

Figure 5. Diabetes complications: care and prevention.

(A) Current standard of care, where patients are first evaluated with biomarkers, yet therapeutic intervention is reserved until the appearance of initial complications
as secondary prevention. (B) Integrated strategy for diabetes complications prevention that we are proposing, which will combine clinical and genomic biomarker
profiles via a bioinformatic risk engine. This will be able to classify subjects as being susceptible to type 2 diabetes complications and allow the administration of
medication as primary prevention against these complications.
Abbreviations: ACE inhibitor, angiotensin-converting enzyme inhibitor.

of diabetic outcomes. While our finding in an independent pop-
ulation remains to be validated, we can envisage a future where
there is a change in current standard-of-care paradigms and
in which we will have to wait for increases in “biomarkers,”
such as microalbuminuria or creatinine, to be present before
treatment is initiated as a mode of “secondary” prevention, as
 The condition sought should be an important health problem
for the individual and community.
 There should be an accepted treatment or useful intervention
for patients with the disease.
 The natural history of the disease should be adequately
understood.
 There should be a latent or early symptomatic stage.
 There should be a suitable and acceptable screening test or
examination.
 Facilities for diagnosis and treatment should be available.
 There should be an agreed policy on whom to treat as
patients.
 Treatment started at an early stage should be of more bene-
fit than treatment started later.
 The cost should be economically balanced in relation to pos-
sible expenditure on medical care as a whole.
 Case finding should be a continuing process and not a once
and for all project.
Table II. World Health Organization criteria for screening.
Adapted from reference 27: Wilson JMG, Jungner G. Geneva: WHO. 1968;86:
281. Copyright © 1968, World Health Organization.
illustrated in Figure 5A. We have reason to be optimistic and
propose that, in the future, an integrated strategy will allow
the combination of clinical biomarkers with genomic ones and
other types that will move us toward a scenario of “primary”
prevention of complications, as described in Figure 5B.
On this “journey,” we will have to ascertain the need for such
screening in populations, as specified by the World Health
Organization (WHO) (Table II).27 We believe that while such
screening strategies may today be a long way off in general
populations28—mainly due to difficulties in predicting low in-
cidences of diseases—a distinct situation exists for diabetes,
where subjects and health professionals are acutely con-
scious of the relatively high incidence of potentially avoidable
complications. Naturally, several components of this propo-
sition will have to be tested prospectively. 
Acknowledgements. The authors would like to acknowledge the support
from members of the Genetic Substudy Committee of ADVANCE: Drs
J Chalmers, S Harrap, S MacMahon, and M Woodward. The essential
contribution of the Prognomix staff, Drs Ondrej Seda, Ghislain Roche-
leau, Mounsif Haloui, and Maxime Caron, Johanna Sandoval, Carole Long,
Evelyne Morin, Pierre Chrétien, and Roberto Bellini, is greatly appreciat-
ed as is the collaboration of the Biogenix bioinformatics team. Our thanks
go to Carole Daneau and Andrée Lévesque for administrative help and
to Ovid Da Silva for editing this manuscript. The work is financially sup-
ported by Prognomix Inc, the Canadian Institutes of Health Research,
the Canadian Foundation for Innovation, and the IRAP program of the Na-
tional Research Council of Canada. Pavel Hamet is a Canada Research
Chair in predictive genomics.

312 MEDICOGRAPHIA, Vol 31, No. 3, 2009 ADVANCE genetic substudy – Hamet and Tremblay
 U P DAT E

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Keywords: biomarkers; genetics; predictive value; type 2 diabetes; vascular complications

LES DÉTERMINANTS GÉNOMIQUES DE LA POPULATION D ’ADVANCE VONT- ILS REPRÉSENTER UN PROGRÈS

PAR RAPPORT AUX BIOMARQUEURS DANS LA PRÉVISION DES COMPLICATIONS VASCULAIRES DU DIABÈTE ?
Les récents progrès de la génomique permettant l’identification de millions de déclinaisons du génome individuel
ont donné naissance à un nouvel espoir pour la mise en place d’une médecine personnalisée. Les études d’asso-
ciation sur génome entier sont en train de mettre en évidence l’architecture génétique de maladies complexes,
comme celle du diabète de type 2 (DT2). Cependant, malgré des progrès considérables ces 3 dernières années, leur
principale limite réside dans leur aptitude relativement faible à prévoir une susceptibilité individuelle dans la popu-
lation générale. Pour résoudre ce défi diagnostique, il faut un phénotypage fin et la prise en compte soigneuse de
différents facteurs tels que l’âge, le sexe et les antécédents génétiques et environnementaux de l’individu. Cet article
examine la stratégie initiale d’analyse des déterminants génétiques des complications rénales et cardio-vasculaires
du DT2, grâce aux précieuses données de l’étude ADVANCE (Action in Diabetes and Vascular disease : PreterAx and
DiamicroN MR Controlled Evaluation). Nous examinons également l’importance relative des biomarqueurs cliniques
traditionnels, comme la cholestérolémie, l’hypertension et l’indice de masse corporel, dans le contexte des nouveaux
« biomarqueurs génomiques », ainsi que l’intégration éventuelle de ces derniers dans un modèle plus global. La mé-
thylation épigénétique de l’ADN et le raccourcissement des télomères, stigmates du vieillissement biologique, font
partie des informations additionnelles portées par notre ADN susceptibles d’être modulées par des facteurs environ-
nementaux (comme l’état de santé, la prise de médicaments et le style de vie). Ces modifications viennent s’ajouter
aux variations de séquence d’ADN au niveau du polymorphisme du nucléotide simple pour offrir un ensemble de
critères susceptibles d’accélérer l’avènement d’une médecine personnalisée et prévisionnelle où les interventions
présymptomatiques deviendront partie intégrante de la prévention.

ADVANCE genetic substudy – Hamet and Tremblay MEDICOGRAPHIA, Vol 31, No. 3, 2009 313
 A TOUCH
OF FRANCE

U
nder this heading, each
issue of Medicographia
features two cultural arti-
cles. The first one touches on the Famous French diabetics
history of medicine, based around
great figures from French history,
C . R é g n i e r, Fra n c e
while the second one addresses
broader aspects of France’s her-
itage, such as history, art, litera-
ture, and the description of mu-
seum collections.

Portrait of Louis XI (1423-1483).

© Bridgeman-Giraudon.

Late Renoir, 1892-1919

I . S p a a k , Fra n c e

Culmination
of a life’s work:
The Bathers.
(1918/1919).
© RMN (Musée
d’Orsay)/Hervé
Lewandowski.

MEDICOGRAPHIA, Vol 31, No. 3, 2009 315


D
iabetes, which currently
affects nearly a quarter of
a billion people and is the
world’s fourth largest cause of
mortality, has afflicted the lives of
several French figures of renown:
the authors Jules Verne and Ho-
noré de Balzac, the painter Paul
Cézanne, Marshal Joseph Joffre,
and several kings, including
Louis XIV (the Sun King). This ar-
ticle examines how diabetes af-
fected the lives of these famous
Frenchmen and the medical meas-
ures that were historically taken
to combat the disease.
Christian Régnier, MD
Practicien Attaché des
Hôpitaux de Paris, Société
Internationale d’Histoire de la
Médecine, 9 rue Bachaumont
75002 Paris, FRANCE
(e-mail:
dr.christian.regnier@wanadoo.fr)
www.medicographia.com
316 MEDICOGRAPHIA, Vol 31, No. 3, 2009
A TOUCH OF FRANCE
Famous French diabetics
b y C . R é g n i e r, Fra n c e
I
n medicine, the systematic use of laboratory tests in patients is a modern
phenomenon that is less than half a century old. Diagnosing diabetes now
largely depends on the qualitative or quantitative measurements of blood
glucose, glycosuria, and acetonuria. If one excludes insulin-dependent dia-
betes that rapidly progresses toward death, type 2 diabetes often manifests
itself by its complications: chronic or recurrent infections, loss of sight, tuber-
culosis, and cardiac, kidney, or vascular disease. Given the absence of lab-
oratory tests in the past, we are unable to say, with absolute certainty, whether
a historical figure was diabetic. Unfortunately, old medical files—where they
exist—are comprised of information that is too imprecise to confirm a retro-
spective diagnosis. However, what we can do is compile a body of diag-
nostic evidence based on the examination a historical character’s life, dietary
habits, and the illnesses that ultimately brought about his or her death. This
historical analysis indicates that Louis XIV and his musician, Lully, who both
died from gangrene, were probably diabetic. It is even more likely that the
famous novelist Honoré de Balzac, who had the clinical characteristics of
Cushing syndrome, was too. Jules Verne, the most read of all French writ-
ers, was known to have died of a diabetes-related illness. The famous French
painter Paul Cézanne, the doctor Odilon Lannelongue, and Marshal Joseph
Joffre were all thought to be similarly afflicted, although the clinical and bi-
ological evidence is too uncertain to be sure.
Medicographia. 2009;31:316-323 (see French abstract on page 323)
I
n 2003, according to the World Health Organization (WHO), diabetes, in all its
different forms, affected 194 million people worldwide, two thirds of whom live in
developing countries. In 2008, the number of diabetics was estimated at 246
million and diabetes was ranked the fourth largest cause of mortality. In devel-
oped countries, diabetes mostly affects those over 65 years of age; elsewhere, it
affects those in the 35-60 age range. In 2030, it is estimated that there will be
370 million diabetics, 80% of whom will live in developing countries. According to
WHO experts, the progress of diabetes is linked to sedentary lifestyle and social
and economic development. Certain ethnic groups seem more susceptible, such
as the American Indian population, the Japanese, and the populations of the Mid-
dle East and North Africa. In certain hunter-fisher-gatherer peoples who have had
their diets abruptly modified, diabetes has taken a heavy toll: 50% of the Pima In-
dians of Arizona, 40% of Micronesians from the Island of Nauru, and 20% of urban-
ized Australian Aboriginals are diabetic. In Europe, the prevalence of diabetes is
Famous French diabetics – Régnier
 A TOUCH OF FRANCE

highest in the south (Greece, Italy, Portugal, and Spain)
and in Scandinavia (Sweden and Finland).1 In France, a re-
port published by the Institut de Veille Sanitaire (Institute for
Public Health Surveillance) in November 2008 reported nearly
2.5 million diabetics, of whom 90% had type 2 diabetes. The
prevalence is approximately 4% in the general population
and 13.3% in those over 65. Regional disparities exist be-
tween the north, the east, and the overseas territories (a high-
er prevalence between 4.25% and 7.81%) and the west and
the southwest of France (a lower prevalence between 2.52%
and 3.81%). Nearly 11% of French people over 65 are affect-
ed by the disease.2,3
Diabetes—from the Greek diabetes meaning “to pass
through”—has been around since the dawn of time, but was
ignored for a long time by doctors and patients alike. Physi-
cians did not understand its pathophysiology and were
helpless to treat it, while patients were often subjected to se-
vere regimes that no one was really able to explain.
The Capetians: a great family of diabetics
In the Middle Ages, the diet of the nobility and their court was
particularly rich. In Paris in the 12th century, a population of
one million inhabitants consumed 40 000 cows, 400 000
sheep, 70 000 calves, and 25 000 pigs each year.7
Philippe I (1052-1108): The fourth king of the Capetians con-
quered Vexin and Gâtinais by defeating the Duke of Nor-
mandy, William the Conqueror. He was apparently not very
suited to handling weapons; Philippe I was described by
Suger (1080-1151), the Bishop of Saint-Denis, as obese, ap-
athetic, and a big eater. He suffered from pruritic dermatoses
and recurring gingivitis, and died disabled.8

Diabetes developed during the warming of the Earth’s cli-

mate 10 000 years ago (at the end of the Würm glaciation
period). The temperate climate at that time supported the
growth of plants providing slow-release carbohydrates (eg,
sweet chestnuts and walnuts) and simple carbohydrates
(eg, berries). During the glacial periods, these types of plants
were absent, so man consumed large quantities of animal
protein (wild game and fish). Cro-Magnon man was physical-
ly active, as shown by the powerful muscle insertions on the
remains of excavated skeletons. Their daily calorie intake must
have been close to that of modern man (approximately 3000
kcal). Interestingly, excess weight was a problem even then.
Paleolithic art depicts excess weight of the gynoid, rather
than the android, type. Less than 10 000 years ago, the prac-
tice of farming and animal breeding modified the diet of man,
whose lifestyle was becoming sedentary. The production of
grain, the consumption of cattle, and the use of salt for pre-
serving meat brought about an enormous upheaval in the Doctors administering medicine with a spoon at The Sick
Bed of Louis VI “Le Gros” (1080-1137). Vellum, French School
human diet. From 10 000 to 5000 years BC, the world’s pop-
(14th century). British Library, London, UK.
ulation benefited greatly from this first big food revolution, © British Library Board. All rights reserved/Bridgeman-Giraudon.
increasing from 5 to 50 million inhabitants.4,5
Louis VI (1081-1137), known as “the Fat one” or the “the
In Gaul, the techniques brought by the Celts developed rap- Fighter”, was the son of Philipe I. He was a large, corpulent
idly: soil fertilization, crop rotation, crossbreeding of animal man with a pallid complexion. His reign was marked by the
species, the mechanization of farm equipment, and soil mar- assertion of royal power over the mighty lords of the Ile de
ling and liming. The cooked meats of Gaul—according to the France. He was reputed to be a “big eater and drinker”. By
chronicles of Caesar—were famous throughout the Roman the age of 40, his obesity was already so severe that it pre-
Empire. The Gauls were big consumers of bread and boiled vented him from riding a horse. It is likely he died of a linger-
grain (spelt, wheat, and oat). Meat—pork, beef, lamb, and ing thigh wound sustained seven years before his death.8
poultry—was consumed frequently, but in modest quantities.
Lard, butter, and cheese were regularly used in cooking. They Other sovereigns with large appetites who died of strokes or
drank milk, fruit syrups and juices, beer, and mead. Apart from acute, rapidly developing infections also showed signs of hav-
regional variations, the food of Gaul points toward what the ing diabetes-related metabolic disorders. Such was the case
French diet would become in the future: a carbohydrate- with Philippe (IV) the Beautiful (1268-1314), Charles V (1338-
rich diet.6,7 1380), and Louis XI (1423-1483).

Famous French diabetics – Régnier MEDICOGRAPHIA, Vol 31, No. 3, 2009 317
A TOUCH OF FRANCE

Burial of Philippe Le Bel (1268-1314) at St Denis. Vellum, French

School (14th century). Bibliothèque Nationale, Paris, France.
© Bridgeman-Giraudon.

Louis XIV (1638-1715): The Sun King had many ailments

during his lifetime consistent with diabetes: suppurating
periostitis (1678), dental abscesses (1696), recurring boils,
fainting spells, gout, dizziness, hot flushes, and headaches
(cephalalgias). From 1647 to 1711, the three successive
archiatres (chief doctors to the king) recorded, in detail, all the
health problems of the sovereign in the Journal de Santé
du Roi (Journal of the King’s Health), which makes it possible
to follow the sovereign’s state of health on a day to day basis.
Antoine Vallot (1594-1671), Antoine Daquin (~1620-1699),
and Guy Crescent Fagon (1638-1718) kept this journal. On
November 18, 1686, Louis XIV underwent a successful anal
fistula operation, performed by the surgeon Charles Felix de
Tassy (1635-1703), who prepared a curved scalpel especial-
ly for the occasion. In spite of the success of the operation,
the wound took more than two months to heal, and the sur-
geon needed to drain it three times. The King’s Superinten-
dent of Music, Jean-Baptiste Lully (1632-1687), composed
a Te Deum at the time to celebrate the sovereign’s recovery.
It was during a rehearsal of this work at the Theatre des Feuil-

The death of Louis XI (1461-1483) from the Memoires de Portrait of Louis XI (1423-1483).
Philippe de Commines. Vellum, French School (15th century). Oil on panel, French School (17th century). State Collection,
Musée Thomas Dobrée, Nantes, France. France.
© Bridgeman-Giraudon. © Bridgeman-Giraudon.

318 MEDICOGRAPHIA, Vol 31, No. 3, 2009 Famous French diabetics – Régnier

lants on rue Saint Honoré in Paris in January 1687, that the
composer—perhaps diabetic—wounded himself in the toe
with his “conducting stick”. This particular stick, a precursor
of the modern orchestra conductor’s baton, was a heavy
cane decorated with ribbons and topped with an ornate
knob, which was used to keep time by striking it against the
floor. Lully refused to have his toe amputated, gangrene set
in, and the musician died at his home on March 2, 1687, at
the age of 54.
A portrait of King Louis XIV of France by Hyacinthe Rigaud
(1659-1743). Oil on canvas (49.336.0 cm), 1701. Musée Condé,
Chantilly, France.
© RMN/René-Gabriel Ojéda.
The feasts of Louis XIV, another sovereign with a large ap-
petite, took their toll on his health. As he became obese to-
ward the end of his life, the Sun King was confined to bed on
the August 13, 1715; gangrene had appeared in his left leg.
On September 1, the sovereign’s life came to an end; an au-
topsy carried out the following day in the presence of the
Dean of the Faculty of Medicine in Paris was revealing:
On the outside, the entire left side appeared to be gangrenous,
from the tip of the foot to the top of the head. The epidermis
was coming off the whole body on both sides. The right side
was gangrenous in several places.
The hypothesis of type 2 diabetes was put forward by biog-
raphers of Louis XIV. Even though the English doctor Thomas
Famous French diabetics – Régnier
A TOUCH OF FRANCE
Willis (1621-1675) had already observed that the urine of di-
abetics had a sweet flavor, as if it contained “honey or sug-
ar,” the King’s doctors did not carry out this test. The Dic-
tionnaire Universel de Médecine (The Universal Dictionary of
Medicine), published in 1743 by James, defined diabetes as
follows:
The disease is characterized by a copious amount of mic-
turition in which drink passes through the body immediately
after ingestion without change and like water.” The work
specified: “The sagacious Willis has taught us that this dis-
ease is much more common in us than it was in our prede-
cessors.8-11
In Le Médecin Volant (The Flying Doctor) published in 1650,
Molière (1622-1673) alluded to this urinary tasting when
the fake doctor, Sganarelle, brought the urine of Gorgibus’s
daughter to his lips:
– Sganarelle: … Here is the urine that indicates a great heat
and a great inflammation in the intestines; but, it is not too bad.
– Gorgibus: What! Are you going to swallow it, Sir?
– Sganarelle: Don’t be so surprised. Ordinary doctors would
be satisfied to look at it, but I, no ordinary doctor, will drink
it because the taste will help me discern the cause and the
course of the disease. But, to tell you the truth, there is too
little of it to make a proper decision. We’ll have to make her
pass water again!12,13
Honoré de Balzac: hypertension and diabetes
Honoré de Balzac (1799-1850), an obese man nicknamed
the “Merry Wild Boar” and author of La Comédie Humaine
(The Human Comedy), died at 51 from heart failure. “I am
as beautiful as a marble statue and as strong as a tree,” he
said proudly. Balzac used to work for 18 hours at a stretch
without a break, eating bread piled with sardines mashed
in butter and consuming large quantities of sweetened cof-
fee (close to one pound per week). Outside these periods of
nonstop work, the large-framed Balzac ate giant, Pantagru-
elian meals and traveled a lot. According to his contempo-
raries, however, he did not smoke and only drank alcohol in
moderate quantities.
In Saché on the June 26, 1836, he became dizzy, lost con-
sciousness, and collapsed next to a tree. Upon awakening,
the writer reported experiencing some “buzzing” in his ears
accompanied by some slight trouble with his balance. Four
months later, Balzac wrote to Ewelina Hanska (1801-1882),
whom he married a few months before his death:
I sometimes lose the sense of what is up and what is down
(located in the cerebellum) even in my bed. It seems like my
head is leaning to my left or to my right, and, when I rise, I feel
moved by an enormous weight in my head…
The family physician, Jean-Baptiste Nacquart (1780-1854), a
former military doctor in the Rhine army, recommended that
he pay more attention to his lifestyle and invited him to take
MEDICOGRAPHIA, Vol 31, No. 3, 2009 319
A TOUCH OF FRANCE
a break in Touraine. In May 1840, the writer de-
scribed “cerebral neuralgias”; Nacquart pro-
nounced Balzac was suffering from “an en-
gorgement of the large vessels”. Leeches
were used as well as vesicants, enemas,
and seltzer water.
From 1842 to 1848, Balzac reported fre-
quent dizzy spells, heartburn, headaches,
problems with his vision, and diplopia.
Nacquart diagnosed “arachnitis,” chronic
meningitis linked to excessive mental strain.
On his return from Poland at the end of
1848, he had effort dyspnea and a spasmod-
ic cough. According to Guérin, the writer was
suffering from high blood pressure complicated by
cardiac insufficiency, episodes of angina pectoris, and
pulmonary edema. On April 30, 1849, while still residing in
Poland, he wrote to his sister Laure:
It has appeared (...) hypertrophy of the heart (keep that a se-
cret from mother). I cannot walk quickly or climb the small-
est slope (...) I cannot comb my hair without fits of breath-
lessness and palpitations (...) These dreadful fits come on
when I am feeling annoyed or emotional, so everything in my
life has to be rosy.
The Polish doctors administered lemon
for a “disorder of blood viscosity”. On
May 20, 1850, Nacquart rushed over
to the home of Balzac (who had re-
turned from the Ukraine with his wife).
He found him thinner, pale, nearly blind,
with large swollen legs, abdominal
swelling, and struggling for breath.
An iron band around his chest was
getting tighter and tighter. He spent
his nights fighting for breath (...) His
legs swelled and oozed. The edema
spread to his stomach and thorax,
but he neither complained nor de-
spaired,” reported Mirabeau.
Doctor Nacquart’s clinical examination
found evidence confirming “hypertro-
phy of the heart” (a term used in the
19th century to indicate cardiac fail-
ure), hepatomegaly, cardiomegaly, pul-
monary edema, and albuminuria. In ad-
dition, a varicose ulcer had appeared
on his left leg. One of Balzac’s servants
told Victor Hugo’s wife, who had come
to visit Balzac, that “he has a sore on
his left leg. Gangrene has set in. (…)
last month, Sir collided with an ornate
piece of furniture, his skin tore, and all
320 MEDICOGRAPHIA, Vol 31, No. 3, 2009
Honoré de Balzac (1799-1850),
author of La Comédie Humaine,
Eugénie Grandet, and Le Lys dans la Vallée.
© Hulton-Deutsch Collection/CORBIS.
the water in his body ran out”. In spite of
the care of three competing surgeons, who
administered leeches and drained the
wound, and in spite of the administration
of potassium iodide, henbane, and digitalis
by Nacquart, Balzac’s state of health grad-
ually deteriorated. He died during the night
of Sunday, August 18, 1850, while calling
the doctor from la Comédie Humaine (The
Human Comedy), Doctor Bianchon, to his
bedside: “Ah! yes! … I know … I need Bianchon.
Bianchon will save me, him!”
Among the retrospective diagnoses of what disease brought
Balzac’s life to an end is Cushing syndrome, which would
explain his physical appearance: obesity of the trunk, face,
and neck, described by Théophile Gautier (1811-1872) as
“the face and the neck of an athlete or bull, round like a sec-
tion of a column”. Likewise, the various illnesses from which
the writer, like his characters, suffered, included bipolar dis-
order, high blood pressure (supposed), skin infections, dia-
betes (possible), and sexual impotence
(probable). From the time of Balzac on-
ward, diabetes became characterized
by an abundance of poorly defined and
confused symptoms. The most dread-
ed complication was pulmonary tuber-
culosis (phthisis). The only objective di-
agnostic criterion for doctors keen on
chemistry remained the use of litmus
paper, which reddened in the presence
of urine containing “grape sugar,” a
name often used for glucose (isolated
in 1838). After many etymological de-
bates, the term “glucose” was adopt-
ed around the year 1890, after which
“glycose” and “gleucose” were aban-
doned. The Greek word gleukos,
“sweet wine” or “must,” and the adjec-
tive glykys, “of a sweet flavor,” were
the origins of the final term. In Adelon’s
Dictionnaire de médecine (Dictionary of
Medicine) published in 1835, the rec-
ommended treatment for diabetes
remained empirical: camphor, licorice
lozenges, coral dye, iron mineral wa-
ters, mercury preparations, and cow
bile.14-17
Balzac by Auguste Rodin
(created 1891-1898).
© Gian Berto Vanni/CORBIS.
Famous French diabetics – Régnier
 A TOUCH OF FRANCE

Jules Verne: strokes and diabetes
The master of anticipation suffered from multiple diseases
about which he complained bitterly in his correspondence:
facial paralysis, attacks of spasmodic colitis, writer's cramp,
diabetes (probably), and strokes (two).
In February 1850, Jules Verne (1828-1905) was struck with
an attack of facial paralysis that was treated with electricity,
according to the therapeutic principles set out by Duchenne
de Boulogne (1806-1875). He testified to his satisfaction
with the treatment to his mother, saying: “It is the electricity
that cured me; there is no doubt about it. But what was ex-
traordinary was that every time I used it, I became feverish.”
Five years later (in March 1855), a second attack of facial
paralysis caused him considerable suffering. On the recom-
mendation of his friend, Dr Victor Marie, he consulted Jean-
Martin Charcot (1825-1893) at the Hôpital de la Salpêtrièrie,
but, unfortunately, no good came of this consultation.
(1809-1886), author of the famous treatise De la glycosurie
ou diabète sucré (On Glycosuria or Diabetes Mellitus), pub-
lished in 1875, in which diabetic retinopathy is described.
This test was known to have been available from the begin-
ning of the 19th century. The Dictionnaire de thérapeutique
médicale et chirurgical (Dictionary of Medical and Surgical
Therapy) by Bouchut (1867) confirmed:
It is impossible to recognize specific symptoms at the onset
of diabetes. Its development is never known about until re-
vealed belatedly by feelings of malaise, great muscular weak-
ness, thickening of the tongue, thirst, bulimia, dyspepsia (…)
visual weakening, and frequent micturition of sweet urine that
makes clothing and fingers sticky.

On March 9, 1886, his nephew Gaston, in a moment of in-

sanity, shot a bullet into the ankle joint of Verne’s left foot.
This injury caused pain, a secondary infection, and gave him
a limp until the end of his days. Everyone thought that his di-
abetic condition prevented the wound from healing. On No-
vember 21, he wrote: “As for my foot, the big toe has sus-
tained an evil white (whitlow) and here I am again unable to
walk for a few days. It will never end!”

Around 1894, he lamented his poor state of health even

more, describing incessant dizziness, tinnitus, scotomata (a
sign of arterial hypertension [?]), gastralgia with attacks of
aerophagia, diabetes (?), and a cataract in the right eye. He
submitted to a milk-based diet. “Living only on a diet of milk
and eggs, I feel neither good nor bad, ovarian, lactarian, or
even vegetarian,” he wrote in a letter dated March 4, 1898.
Two years later, he developed bilateral cataracts.

Jules Verne passed away one week after suffering a hemi-

plegic stroke that initially paralyzed his right side and then
spread to his left. His sister Marie witnessed his last moments
in Amiens on March 24, 1905:
He could not say anything coherently, and it became appar-
ent that this was indeed the end. The paralysis was spread-
ing, and when I left at five o’clock, he was no longer our broth-
er and his beautiful intelligence was no longer there; there
was nothing but a body and a slowly departing soul. (…) In
short, our poor Jules has succumbed to diabetes that we
were not monitoring. Last year, he suffered a bad episode, but
after recovering, we thought no more about it. Although his
wife looked after him admirably, she did let him do whatever
he wanted.
The medical file of Jules Verne contains few precise details.
It is not known whether he ever had a urine glucose test, a
technique developed in France by Apollinaire Bouchardat
Caricature of Jules Verne (1828-1905), from the magazine
L’Algérie Comique et Pittoresque, studying life at the bottom of
the sea. Color lithograph, 1883. Bibliothèque de l’Arsenal, Paris,
France.
© Archives Charmet /Bridgeman-Giraudon.
At that time, “modified undernourishment” combined with
physical exercise was recommended as a treatment for di-
abetes. Bouchardat prohibited sugar, fruits, jams and jel-
lies, starchy foods, and milk (a source of lactose) and ad-
vised alcohol (calorie intake), green vegetables, meats, fish,
and bread with gluten. He also prescribed the “Bouchardat
potion,” containing ammonia carbonate, rum, and sugar
syrup (!) or “bowls of Bouchardat,” containing theriac (Venice
treacle) and opium extract.11,18-20

Famous French diabetics – Régnier MEDICOGRAPHIA, Vol 31, No. 3, 2009 321
A TOUCH OF FRANCE

accurate definition of objects or fine and delicate touches.”

Cézanne seldom left the region of Aix and refused to take
part in exhibitions after his failure at the Impressionist Salon
of 1877.

The diagnosis of diabetes was made in 1891 after the loss of

his ability to discern the difference between blue and green.
Moreover, Cézanne was suffering from severe myopia that he
refused to correct with the use of glasses, which he deemed
“vulgar things”. Cézanne underwent some treatments and
A self portrait of took the waters in Vichy. His contemporaries were aware of his
Paul Cézanne diabetes. In 1928, the poet Léo Larguier (1878-1950) wrote:
(1839-1906).
I only knew him when he was old and sick with diabetes, af-
Oil on canvas
(6049 cm), ter a lifetime of stubborn but disparaged work. I am sure that
1890-1894. the least encouragement would have made him a different
Bridgestone man; he said it would have given him moral support.
Museum of Art,
Tokyo, Japan. In 1904, during a walk in the Aix countryside with the painter
© Bridgeman-
Giraudon.
and writer Emile Bernard (1868-1941), an exhausted Cézanne
confided: “I am ill with diabetes, but I can scarcely talk about
Other famous French diabetics it. I sense that I am in the grasp of an evil which will carry me
Paul Cézanne (1839-1906): One of the founding fathers of away.” After a chill sustained while doing an open-air paint-
the impressionist movement, nicknamed “the good God of ing of the Sainte Victoire mountain, Cézanne slipped into a
painting” by Henri Matisse. He was a friend of Emile Zola, diabetic coma on October 15, 1906, and died six days lat-
Camille Pissaro, and Tristan Bernard, who recorded his fre- er of pneumonia. A triggering factor of Cézanne’s diabetes
quent spells of weakness. was emerald green (copper [II] acetoarsenite) poisoning
caused by his painting “à la couillarde”, that is, crude paint-
A few years before his death, he complained of having trou- ing (with his fingers).21,22
ble walking (arthritis), dizziness, and recurring headaches. In
the latter part of his life, biographers thought that he was Odilon Lannelongue (1840-1911): Professor of surgery at the
experiencing retinal degeneration, which explained—ac- Medical College of Paris and republican representative, then
cording to them—a change in the style of his painting. In jus- senator, of Gers. He was president of the Society of Surgery
tifying his gradual move away from the realistic representa- (Société de Chirurgie) in 1888, president of the General As-
tion of shapes, he wrote: “The sensations of color producing sociation of French Doctors (Association générale des mé-
light are the reason for the abstraction that prevents the decins de France) in 1892, and a president of the Academy

Montagne Sainte-Victoire by Paul Cézanne Montagne Sainte-Victoire by Paul Cézanne

(painted from 1887 to 1890, before the deterioration in his blue-green (painted from 1894 to 1900, after the deterioration in his
vision). Musée d’Orsay, Paris, France. blue-green vision)
© The Gallery Collection/CORBIS. © Francis G. Mayer/CORBIS.

322 MEDICOGRAPHIA, Vol 31, No. 3, 2009 Famous French diabetics – Régnier
 A TOUCH OF FRANCE

of Medicine (Académie de Médecine). Lannelongue was the
attending physician of Leon Gambetta and Sarah Bernhardt
as well as the Presidents of the Republic, Sadi Carnot, Ar-
mand Fallières, and Félix Faure.
Because of his diabetes, Lannelongue frequently fell ill at
the House of Representatives and the Senate, which pre-
vented him from attending meetings and taking part in par-
liamentary jousts. He looked largely overweight …
…with a complexion that was more than a little flushed with
shining cheeks , giving him a rather coarse look. He looked
like a rough-hewn barrel; like a corpulent youngster from
Gascogny.
On December 22, 1911, Lannelongue died—like many dia-
betics of the time—from a straightforward lung infection,
acute lobar pneumonia.23
Joseph Joffre (1852-1931), Marshal of France and Chief of
Staff of the Armed Forces during the First World War (until
December 1916), favored “offensive à outrance” or “all-out
attack” and was one of the most controversial French mili-
tary figures. Joffre, who became overweight after 1910, was
a big eater and not very inclined to physical exercise. He de-
veloped diabetes, which was monitored by the famous pro-
fessor Raoul Boulin (1893-1958), author of several works on
the treatment of diabetes. Joffre was given a “mixed diet”,
which contained neither bread nor starchy foods; a diet that
he did not follow. Boulin also prescribed carbonate of lime and
extracts of dried liver. He started to waste away as a result
of the disease, to suffer from arthritis of the lower limbs, and
eventually lost his mobility altogether. After several months of
inactivity on December 23, 1930, Joffre’s right leg was ampu-
tated. He died less than a fortnight later on January 3, 1931,
uttering: “I did not hurt anyone.”24,25 

References
1. Marlin A et Unwin N. Mettre le diabète à l’agenda international. Diabetes’
Voice. 2005;3:41-43.
2. Kusnik-Joinville O, Weill A, Ricordeau P, Allemand H. Diabète traité en France
en 2007: un taux de prévalence proche de 4% et des disparité géographiques
croissants. Bulletin Épidémiologique Hebdomadaire. 2008;43.
3. Vallier N, Salanave B, Weill A. Disparités géographiques de la santé en France :
les affections de longue durée. Points de repère CNAMTS. 2006.
4. Barbaza M. Les civilisations postglaciaires – La vie dans la grande forêt tem-
pérée. Paris, France: La Maison des Roches éditeur; 1999.
5. Sémah A-M et Renault-Miskovsky J. L’évolution de la végétation depuis deux
millions d’années. Paris, France: Éditions Art’Com – Errance; 2004.
6. Ferdière A, Malrain V, Matterne V, Méniel P, Nissen-Jaubert A, Pradat B. Histoire
de l’agriculture en Gaule. 500 avant J.-C.-1000 après J.-C. Paris, France: Er-
rance; 2006.
7. Toussaint-Samat M. Histoire naturelle et morale de la nourriture. Paris,
France: Larousse; 1997.
8. Cabanès A. Morts mystérieuses de l’histoire de France. Paris, France: Ed Le
François.
9. Durand A. Le Journal de santé du Roi. Paris, France: Ed Le Roi; 1862.
10. Caroly M. Le Corps du Roi-Soleil. Paris, France: Imago-PUF; 1991.
11. Peumery J-J. Histoire illustrée du diabète. Paris, France: Éditions Roger Da-
costa; 1987.
12. Molière. Théâtre complet. Paris, France: Gallimard, La pléiade; 1965.
13. Raynaud M. Les médecins au temps de Molière. Paris, France: Didier; 1863.
14. Bonnet-Roy F. Balzac. Les médecins, la médecine et la science. Paris, France:
Horizons de France; 1944.
15. Hugo V. La mort de Balzac. Chez Soi; 1907;43.
16. Guérin J. Pathologie de Honoré de Balzac. Paris, France: Thèse pour le docto-
rat en médecine; 1937.
17. Mirbeau O. La mort de Balzac. Paris, France: Felin – Arte; 1999.
18. Bouchet A. Jules Verne et la médecine. In: Conférences de l’Institut d’histoire
de la médecine de l’Université Claude Bernard (Lyon I) cycle 1982-1983; Lyon,
France: Fondation Marcel Mérieux; 1983.
19. Compère D. Jules Verne - Parcours d’une œuvre. Amiens, France: Encrage;
1996.
20. Verne J-J. Jules Verne. Paris, France: Hachette; 1973.
21. Gasquet J. Cézanne. Paris, France: Édition Bernheim jeune; 1921.
22. Rewald J. Cézanne. Paris, France: Flammarion; 2006.
23. Vanderpooten C. Odilon et Marie Lannelongue. La Revue du Praticien. 1997;
43:1637-1640.
24. Huet J-P. Joseph Joffre (1852-1931), le vainqueur de la Marne. Paris, France:
Anovi; 2004.
25. Fabry J. Joffre et son destin. Paris, France: Charles Lavauzelle; 1931.

LES DIABÉTIQUES CÉLÈBRES FRANÇAIS

En médecine, la pratique systématique d’examens de laboratoire chez les patients est une pratique très récente
(moins d’un demi siècle). Or le diagnostic de diabète repose en grande partie sur la mesure qualitative ou quantita-
tive de la glycémie, la glycosurie voire l’acétonurie. Si l’on excepte le cas du diabète insulinodépendant qui évoluait
rapidement vers la mort, le diabète de type 2 se révélait souvent par ses complications: infections graves ou à répé-
tition, perte de la vue, tuberculose, pathologies cardiaques, rénales ou vasculaires. Les diabétiques célèbres sont
donc supposés avoir été atteints de cette affection sans que l’on puisse poser le diagnostic avec certitude. Il s’agit
le plus souvent d’un faisceau d’arguments reprenant les éléments de leur biographie, de leurs habitudes alimentaires
et la pathologie qui les emporta. Les dossiers médicaux – lorsqu’ils existent – comportent des indications trop frustres
pour confirmer ces diagnostics rétrospectifs. Louis XIV mort d’une gangrène, son musicien Lully décédé de la même
façon que son protecteur furent probablement diabétiques. La certitude semble plus élevée chez le romancier Ho-
noré de Balzac qui semblait présenter les caractéristiques cliniques d’un syndrome de Cushing. Plus discutée, la
pathologie diabétique qui emporta Jules Verne, le plus lu des écrivains français. D’autres célébrités françaises au-
raient été affectées par le diabète, notamment le peintre Paul Cézanne, le médecin Odilon Lannelongue, le maré-
chal Joseph Joffre… Les éléments cliniques et biologiques sont très insuffisants pour être affirmatif…

Famous French diabetics – Régnier MEDICOGRAPHIA, Vol 31, No. 3, 2009 323
 A TOUCH OF FRANCE

P
ierre-Auguste Renoir, one of
the leading painters of the
Impressionist movement, was

Late Renoir, 1892-1919

born in Limoges, Haute-Vienne.
While studying art in Paris in the
1860s, the so-called “painter of
happiness” met several great con-
temporaries, including Alfred Sis-
ley, Frédéric Bazille, and Claude
Monet. Renoir, in turn, became a
reference for the young Picasso,
Bonnard, and Matisse. Despite
suffering from crippling rheuma-
toid arthritis from 1892 onward,
he continued to paint for the rest
of his life.

b y I . S p a a k , Fra n c e

‘‘I
Isabelle SPAAK am at a dead end,” confessed the painter Pierre-Auguste Renoir (1841-
Journalist
37 rue des Plantes
1919), one of the emblematic figures of the Impressionist movement of
745014 Paris, France the 1870s, in 1880. “I have finally come to the conclusion that I can no
(e-mail: longer paint or draw,” said the artist on giving up the “direct observation of
isabelle.spaak@wanadoo.fr)
reality” to return to “museum art,” drawing, and the great masters. Inspired by
eighteenth century painting and by the works of Raphael, Titian, and Rubens
that he discovered during his numerous travels, the painter began painting
nudes, which became increasingly voluptuous in character. Although already
universally esteemed as an artist, Renoir ushered in a new era at the begin-
ning of the 1890s. “Renoir is growing continuously,” wrote the poet Guillaume
Apollinaire. “His latest paintings are the most beautiful. They are also his fresh-
est.” The painter reconciled open air with workshop, plein air with atelier, to
invent a type of art centered on the representation of enormous odalisques
(virgin female slaves who lived in Ottoman seraglios). Although less well known
than his Impressionist period, this era of artistic maturity is marked by great
freedom in the use of color, subject, and technique and produced works that
are ripe for rediscovery.
Medicographia. 2009;31:324-332 (see French abstract on page 332)

‘‘Y
ou are a Renoir!” exclaimed Henri Matisse to a young seventeen-year-old
girl who had come to pose for him. Matisse was not mistaken in his as-
sumption. On his recommendation, Andrée Heuschling presented her-
self to the old master and was accepted. Her carefree attitude brightened up the
painter’s last days, and her magnificent skin illuminates his canvasses. She tran-
scends in The Bathers (1919), his final masterpiece. The redhead’s milky com-
plexion “caught the light better than that of any other model,” said the artist. The
latter part of Pierre-Auguste Renoir’s life, however, was not untroubled. Renoir, a
key figure of the Impressionist movement of the 1870s, underwent a major artistic
crisis around 1880. The creator of the Dance at the Moulin de la Galette (1876),
The Swing (1876), and Luncheon of the Boat Party (1881) found himself at a dead
end. Toward the end of his exploration into open-air painting, he admitted: “I have
finally come to the conclusion that I can no longer paint or draw.”

Over the next ten years, the painter tried to find a direction for his art again. The so-
lution was to be found in museums, he believed: “That is where one gets the taste
for painting which nature, on its own, cannot give you.” He gradually turned away
www.medicographia.com from open-air, or plein air, painting and the “direct observation of reality” and returned

324 MEDICOGRAPHIA, Vol 31, No. 3, 2009 Late Renoir, 1892-1919 – Spaak

to drawing and more traditional and decorative subjects. He
traveled to Algeria, in the footsteps of Delacroix, and to Italy,
where he discovered the frescoes of Raphael.
By carefully observing and learning from the work of these
masters, he finally managed to overcome his own doubts
and, from 1890 onward, once again enjoyed undisputed
recognition on the international scene. Alongside his friends
Monet and Cézanne, he became a reference for aspiring
young painters, such as Picasso, Bonnard, Matisse, and
Maurice Denis. Inspired by Greek mythology, Provençal land-
scapes, and the great painters of the preceding centuries, in-
cluding Titian, Rubens, and Boucher, his later work was de-
voted to the female nude, scenes of domestic happiness, and
portraits that were iridescent and highly sensual. Universally
admired at the time, although much less appreciated today,
his later work is still of major importance. This work is domi-
nated by the representation of enormous odalisques (virgin
female slaves who lived in Ottoman seraglios) and was very
much a labor of love. For behind the beauty of these mag-
nificent paintings lies the fact that the painter was suffering
from excruciating pain. This pain, caused by violent rheumat-
ic attacks, eventually cost him the use of his legs and shriv-
eled up his hands.
Culmination of a life’s work: The Bathers. Oil on canvas (1.11.6 m), 1918/1919.
© RMN (Musée d’Orsay)/Hervé Lewandowski.
Late Renoir, 1892-1919 – Spaak
A TOUCH OF FRANCE
In the company of women
Dating from 1919, the year of the painter’s death, The Bathers
is regarded by Renoir himself as the true culmination of his
work. Two languid muses lie outdoors in the foreground of
the canvas offering their ample charms to the viewer.
The warm colors seem to fuse with accents of light. Further
back, three naked nymphs frolic in the water. The full shapes
of their huge figures, their contentment, and the way in which
they melt harmoniously into the landscape attest to Renoir’s
perfect pictorial mastery.
“He felt that he had epitomized the pursuits of his entire life
and prepared a good springboard for investigations to
come,” wrote the scriptwriter Jean Renoir, in a book of mem-
oirs devoted to his father.
Look at the light on the olive trees… it sparkles like diamond.
It is pink, it is blue… And the sky breaking through is enough
to drive you mad. And the mountains over there which
change with the clouds… it is a Watteau background, one
could say. Ah, this breast! Isn’t it soft and heavy! The pretty
fold beneath with its golden tone… an object of worship. Had
there not been nipples, I believe that I would never have paint-
ed faces,” Renoir intimated enthusiastically.
MEDICOGRAPHIA, Vol 31, No. 3, 2009 325
A TOUCH OF FRANCE

His words conjure up the primary source of his inspiration:

women. “He found fulfillment on both the physical and
spiritual planes when he was in their company,” recounted
his son as he painted a metaphorical portrait of his father
surrounded by women until the end of his life.

In his old age when handicapped by arthritis, it was sug-

gested that he take on a manservant. He refused. “I can-
not tolerate anyone but women around me,” he stubbornly
insisted, quite content with his not-so-conventional (an
army of young girls employed at his home for more than
30 years) domestic arrangements.

Maidservants and models

From nursemaids to nannies via the cook, all female mem-
bers of the Renoir household staff posed for the master. This
legion of beautiful countrywomen, hired for their domestic
qualities as much as for their shapes, went from domestic du-
ties to undressing with astounding naturalness and no appar-
ent problems. Neither thought nor malice ventured to trouble
their faces.

However, Renoir detested the idea that they could think. These
young, healthy girls were depicted by the painter as the fruits
and flowers of the Garden of Eden. “I came to loathe one of
my canvasses when it was christened The Thought… this

Seated Bather in a Landscape, called Eurydice (1895-1900).

Oil on canvas (11689 cm). Musée Picasso, Paris, France.
© RMN/René-Gabriel Ojéda.

young girl had never had a thought in her life. She lived like a
bird, and nothing more,” said a worked-up Renoir. “My mod-
els don’t think,” he exclaimed, more concerned with physical
flesh than with metaphysical thought. Perhaps it was the day-
to-day familiarity with these young ladies that made it possi-
ble for the models to forget him, to get carried away by their
thoughts, and for Renoir to depict them with such simplicity.

Even though he admitted to a reckless love of the female

form, preferably radiant and in full bloom, Pierre-Auguste
Renoir was, nevertheless, nothing of a womanizer. “I feel sor-
ry for men who don’t stop running after women,” he said.
“What work! On the go day and night, without a minute’s rest!
I knew painters who never completed a piece of work be-
cause, instead of painting their models, they were seducing
them”. This was far from being the case with him.

The Bather. Oil on canvas (9273 cm), circa 1903. Kunst-
historisches Museum, Vienna, Austria.
© Bridgeman-Giraudon.
Renoir was never licentious and treated his models with a lot
of respect, encouraging them to pose very freely without in-
sisting upon immobility. The young girls, in turn, would dis-
play their nudity like an offering, without prudishness. The
model “is only there to inspire me,” said the painter, “to enable
me to dare things which I would not be able to without her”.
The artist would walk around them in order to create an im-

326 MEDICOGRAPHIA, Vol 31, No. 3, 2009 Late Renoir, 1892-1919 – Spaak

Une Baigneuse. Oil on canvas (39.429.2 cm). Presented by
Sir Anthony and Lady Hornby to the National Gallery, London,
United Kingdom.
© RMN/Photographic Department.
pression of being everywhere on canvas, as Picasso would
later do when simultaneously showing the front, back, face,
and profile of his subjects.
Homage to the great masters
Pierre-Auguste Renoir, the so-called “painter of happiness,”
was 40 when he became obsessed with nudes. He had to
wait until he had finished with the shattered lines and simul-
taneous contrasts in color so dear to impressionism before
returning to the techniques of contour and line that allowed
him to portray the voluptuous pleasures of skin.
For him, it wasn’t just a question of atomizing bodies or of
reducing them to splashes of paint. When Renoir painted a
woman, he wanted to show her contours and give expres-
sion to her shape. He wanted spectators to want to touch
and caress her curves. Renoir’s nudes “come from the light
of desire,” wrote the French critic Gaëtan Picon.
From that time onward, inspired by the great masters, he nev-
er ceased trying to perfect the outline of the body, which sur-
passed individuality to attain a sort of physical ideal modeled
on the paintings of Boucher, Titian, and Rubens.
Late Renoir, 1892-1919 – Spaak
A TOUCH OF FRANCE
Seated Bather Drying Her Leg (1905). São Paulo Museum,
São Paulo, Brazil.
© Francis G. Meyer/CORBIS.
I would say with great certainty that Diana Getting out of
Her Bath by Boucher is the first painting that grabbed me
and that I have continued to love all my life, the way one al-
ways loves first loves. Boucher remains one of the painters
who best understood the body of a woman. He painted
youthful bottoms, small dimples, and only what was neces-
sary. People will say to you: I prefer a Rubens to a Boucher!
Of course, so do I! But, after all is said and done, Boucher
painted some very pretty young women.
Nearly invading the entire canvas and only hinting at green-
ery in a background reduced to a minimum, Seated Bather
Drying Her Leg (1905) is another tribute. This time, Renoir
calls forth the “genius of Rubens, the merry visual thrill that
one experiences in front of his painting”.
He modeled himself on the Flemish master in the delicate
rendering and subtlety of touch. “There’s the most dazzling
plenitude and the most beautiful color, but the painting it-
self is very thin,” he said, recalling the paintings discovered on
a journey to Munich in 1910. To give expression to the splen-
dor of the body, Renoir uses color sparingly. He brings flesh,
dominated by pinks and whites, to life by using hints of dull
shades, undulating movements of the brush to fill in a char-
MEDICOGRAPHIA, Vol 31, No. 3, 2009 327
A TOUCH OF FRANCE
Baigneuse aux cheveux longs (8265 cm), circa 1895. Musée
de l’Orangerie, Paris, France.
© RMN/Franck Raux.
A WORKSHOP IN THE COUNTRYSIDE
“Do not place too heavy a stone on me. I want to have
the strength to go for a walk in the countryside,” re-
quested Pierre-Auguste Renoir of his son Jean as a last
joke. His tomb, marked by a simple flagstone, is located
in the pretty cemetery of Essoye, a village in the Aube
where the painter lies buried with his wife, Aline Charigot,
and his three sons. It is as simple as he was in life; a life
that he dedicated entirely to his art and the depiction of
happiness. One can still visit his modest workshop at
the back of the garden of the family home that is now
occupied by Sophie Renoir, a descendant of the artist.
Empty except for a chair and a light easel, which Renoir
used when he became too handicapped to move, the
workshop is the departure point of numerous paths that
Renoir liked to take when he went for walks or bicycle
rides to paint his motifs.
The workshop is open every day from May 1 to Sep-
tember 30, from 10:00 to 12:30 and 14:00 to 18:30.
From the end of March to All Saints’ Day, it is only open
in the afternoons, except on Mondays. Essoye (10360
Essoye – Aube) is located 2 hours from Paris, 50 km
south of Troyes. Tel: 00.33.325.38.56.28.
E-mail: association.renoir@wanadoo.fr.
328 MEDICOGRAPHIA, Vol 31, No. 3, 2009
An intimate moment featuring Renoir’s main muse, Gabrielle,
with his middle son, Jean, in Gabrielle and Jean. Oil on canvas
(6554 cm), Jean Walter and Paul Guillaume Collection at the
Musée de l’Orangerie, Paris, France.
© RMN/Hervé Lewandowski.
acter’s shape, and luminous highlights to catch the eye. “He
paints like a true poet,” wrote the French novelist, poet, and
critic Camille Mauclair in 1903.
Tenderness and sensuality
The modest household employees were transfigured by
their elegiac nudity when they were represented in the inti-
macy of their washing and bathing rituals: Bather Arranging
Her Hair (1893); coming out of a bath in Large Nude (1907);
or in a rural universe before original sin, like the magnificent
Bather with Long Hair (1895), in which the ancient splendor
corresponds to a kind of female ideal sought by the artist.
All of the maidservants embodied a set of well-defined aes-
thetic attributes perfectly: gently receding shoulders; heavy
bodied; small, firm breasts; small, round heads; luminous
eyes; and full lips. Behind all the anonymous faces, there
often hides the face of a favorite model, Gabrielle Renard, a
young cousin of Mrs Renoir. Gabrielle also originated from
Essoye, a charming little village in the Aube where the Renoirs
acquired a house in 1895. Gabrielle entered into service with
the Renoir family in 1894, at the age of fourteen, and remained
with the family until 1914. She was in charge of looking after
Pierre-Auguste’s middle son, Jean, and she was an integral
part of many of the paintings of his children: Gabrielle and
Late Renoir, 1892-1919 – Spaak
 A TOUCH OF FRANCE

Jean (1895-1896); The Child and His Nanny (1895); and The
Family of the Artist (1896), which depicted radiant scenes
illustrating the maternal affection she felt for the painter’s three
sons, Pierre, Jean, and Claude, who likewise adored her. As
this new artistic freedom was dawning, Renoir was also ex-
periencing the happiness of family life. His eldest son, Pierre,
was born in 1885 to a young dressmaker, Aline Charigot. He
married her five years later in 1890, and they had two more
sons, Jean (1894) and Claude (1901).
His wife and three children contributed to his harmony and
inspired him. “I am, at this moment, painting one of Jean’s
pouts. This work is personal and only for me.” Being an at-
tentive and affectionate father fascinated by the develop-
ment of these small human beings, he gave them complete
freedom. “My child and wife behave in the same way,” he
said. “Both of them are impulsive and entirely driven by the
logic of their instincts. What makes them dangerous is the
power to charm they have at their disposal.” His children fea-
ture in many of his pieces. Claude, dressed up in a red cos-
tume and a ruff, posed for The Clown (1909), in the manner
of Gilles (1713-1721) by Watteau. While, in addition to the
innumerable portraits of his little boy with their nanny, Jean
Renoir as Hunter (1910) shows his middle son in the same
pose as that seen in the Vélazquez masterpiece.
The muse Gabrielle
Despite the love of his family, none of them was responsi-
ble for looking after their father; that role was reserved for
Gabrielle. The young girl serenely played the part of nanny
and model, posing partially clothed or completely naked. As
well as inspiring a series of reclining odalisques, she even
agreed to pose as the male figure of Paris in the 1908 paint-
ing Judgment of Paris, so uneasy was Renoir with the male
musculature of an actor he had invited to pose for him. The
works depicting Gabrielle, Renoir’s ever attentive and faithful
muse, always have an intoxicating and alluring aura that is
often lacking in the portraits of fashionable society members,
even when they include ravishing women like Mrs Gaston
Bernheim de Villers (1901).

Jean Renoir (1894-1979) as The White Pierrot.

Oil on canvas (79.161.9 cm), 1901/02. The Detroit Institute of
Arts, Detroit, USA (bequest of Robert H. Tannahill).
© Bridgeman-Giraudon.

Claude Renoir, Pierre-Auguste Renoir’s youngest son, in a clown

costume. Oil on canvas (12077 cm), 1909. Musée de l’Orangerie,
Paris, France.
© Bridgeman-Giraudon.

Late Renoir, 1892-1919 – Spaak MEDICOGRAPHIA, Vol 31, No. 3, 2009 329
A TOUCH OF FRANCE
Gabrielle with Jewellry (1910). Oil on canvas (8166 cm).
Private collection.
© Bridgeman-Giraudon.
Renoir took pleasure in making Gabrielle beautiful, by adorn-
ing her with necklaces and light fabrics, as in Gabrielle with
Jewels (circa 1910), or by putting a rose in her hair (in Ga-
brielle with a Rose [1911]). For the painter, these attributes
symbolized the female sex at its most intimate. He makes use
of these accessories many times in order to impart a charac-
teristic warmth to his commissions, including Tilla Durieux
(1914) and Mrs Colonna Roman (1913), which he continued
to accept, albeit sometimes reluctantly. Gabrielle, who was
in charge of watching over the aging painter, would prepare
his palette for him, before slipping the brush between his
bandaged hands.
The midday sun
From 1900 onward, sapped of his strength by arthritis, Renoir
began to stay in the south of France more and more frequent-
ly because the strong sun aided his condition. The Renoirs
had a house built in Cagnes-sur-Mer in 1903. Thereafter,
depending on the season, the family would move between
Essoye and the French Riviera, disregarding Paris. Having
resolved his dilemma over the choice of open air (plein air)
or workshop (atelier)—“I do open air in the workshop,” he
said—the artist concentrated on a vision of an ideal world
and a return to the roots of Mediterranean culture.
The Greeks were such an admirable race. Their existence
was so happy that they imagined the Gods came down to
330 MEDICOGRAPHIA, Vol 31, No. 3, 2009
Portrait of Renoir’s children’s nanny, Gabrielle Renard (1878-
1959), entitled, Gabrielle with a Rose. Oil on canvas (55.547.0 cm),
1911. Musée d’Orsay, Paris, France.
© RMN (Musée d’Orsay)/Hervé Lewandowski.
Earth in order to find paradise and love. Yes, the Earth was
the paradise of the Gods. That’s what I want to paint.
Renoir, obsessed by his art to the last, sought to transcend
reality. In spite of his disability, he retained total control and
mastery of his painting and sought “to render the flesh life-
like and exciting” even though he seemed to lose direction
in his last canvasses with their images of excessively soft
and passive curvaceousness. The larger his models became,
the weaker he became. “One would almost suspect that the
body of a woman contains no bones,” Boucher affirmed.
Renoir was criticized for this lasciviousness and his rejection
of academic conventions. From another point of view, one
could consider this the goal of an artist. By fleeing ugliness
and sadness and by turning his back on the social misery
prevalent at the end of the nineteenth century, he sought to
portray a fantasy of timeless humanism his whole life. The
works of his twilight years—landscapes of the Mediterranean
or bathers—are marked by a touching optimism and whirl-
wind of color, a tribute to the French joie de vivre, a love of life.
Despite the horrors of the First World War, the loss of his
wife, and the illness which weighed him down, the crippled
painter continued to perfect his voluptuous art and to strive for
a total fusion of form and color, isolated from the world in his
workshop refuge in Cagnes. “Blessed painting. Even late in
Late Renoir, 1892-1919 – Spaak
 A TOUCH OF FRANCE

LES COLLETTES EXHIBITIONS: RENOIR IN THE 20TH CENTURY

In 1908, on one of the frequent midday promenades  From September 23, 2009, to January 4, 2010, at
Renoir took to help alleviate his bouts of rheumatism, the National Galleries of the Grand Palais in Paris.
he came across and fell in love with Les Collettes. Pierre-  From February 14 to May 9, 2010, at the Los Angeles
Auguste bought the farm, which had an olive grove con- County Museum.
taining trees over one hundred years old, and had a house  From June 12, 2010, to September 5, 2010, at the
and workshop built. He would alternately spend the last Philadelphia Museum of Art.
eleven years of his life here, moments of happiness and
inspiration. The premises, which were purchased by the
life, you are still creating illusions and occasionally giving joy,”
municipality of Cagnes, boast a panoramic view of the
he wrote to his friend, the painter Albert André. When he died
coast. They continue to evoke Renoir’s paintings, thanks
on December 3, 1919, from a lung infection, the last words he
to the construction of a small museum and their superb
uttered were about a small painting that he had just complet-
garden. The garden contains orange trees and flowers,
ed: a bouquet of anemones that Nanette, a maidservant, had
including the Renoir Rose that was created especially for
gathered for him in the garden that very morning. “I am final-
him. Les Collettes, chemin des Collettes, 06800 Cagnes-
ly beginning to understand something,” he murmured as he
sur-Mer. Tel: 00.33.4.92.13.09.94
passed away. 
See Renoir chronology on page 332.

Renoir spent the last 11 years of his life at Cagnes-sur-Mer, where he painted The Vines at Cagnes. Oil on canvas (181/4 213/4 in),
1906. Gift from Colonel and Mrs E.W. Garbisch to the Brooklyn Museum, Brooklyn, New York, USA.
© Brooklyn Museum of Art /Bridgeman-Giraudon.

Late Renoir, 1892-1919 – Spaak MEDICOGRAPHIA, Vol 31, No. 3, 2009 331
A TOUCH OF FRANCE

RENOIR (1841-1919) CHRONOLOGY

1841 Birth of Pierre-Auguste Renoir in Limoges.
1860 Enters the School of Fine Arts in Paris. Joined by
Monet, Sisley, and Bazille.
1868 Shares a workshop with Bazille and meets Manet,
Degas, and Zola.
1874 First impressionist exhibition. Renoir shows six paint-
ings, including The Theatre Box.
1881 Artistic crisis. Travels to Italy. Discovers Raphael and
the frescos of Pompeii. First nude, his wife Aline in
Blonde Bather.
1885 Birth of his first son, Pierre.
1890 Marries Aline Charigot.
1892 The State acquires Young girls at the Piano. Official
recognition.
1894 Birth of his second son, Jean, and the arrival of Ga-
brielle Renard, the children’s nanny and Renoir’s prin-
cipal muse.
1895 Buys a house in Essoye (Aube), the native village of
his wife.
1897 Fall off a bicycle in Essoye, the first sign of his
rheumatism.
1900 Awarded the Legion of Honor.
1901 Birth of Claude, known as Coco, the third son of the
artist.
1907 Purchases Les Collettes in Cagnes-sur-Mer.
1910 Has to give up walking.
1912 Can only paint if a brush is placed in his hand.
1914 Two of his sons, Pierre and Jean, are wounded dur-
ing the First World War. Departure of Gabrielle Re-
nard.
1915 Death of Mrs Renoir.
1919 Completes The Bathers, his masterpiece. Dies in
Cagnes on December 3.

LA DERNIÈRE PÉRIODE DE RENOIR, 1892-1919

« Je suis dans une impasse », avouait le peintre Pierre-Auguste Renoir (1841-1919) en 1880 après avoir été une
figure emblématique du mouvement impressionniste des années 1870. « J’étais finalement arrivé à la conclusion que
je ne pourrais plus ni peindre, ni dessiner », disait l’artiste en abandonnant l’observation directe de la réalité pour
opérer un retour à « l’art des musée », au dessin et aux maîtres classiques.. Inspiré par la peinture du dix-huitième
siècle, par les œuvres de Raphaël, Titien et Rubens qu’il découvre lors de ses nombreux voyages, le peintre réalise
des nus, de plus en plus voluptueux. Bien qu’il soit déjà unanimement apprécié, Renoir inaugure un nouveau cycle
à l’orée des années 1890. « Renoir grandit continuellement, écrivait le poète Guillaume Apollinaire. Les derniers
tableaux sont toujours les plus beaux. Ce sont aussi les plus jeunes ». Le peintre concilie le plein air avec l’atelier pour
inventer un art centré autour de la représentation d’odalisques monumentales. Moins connue que sa période im-
pressionniste, cette maturité picturale est empreinte d’une grande liberté de coloris, de sujet et de facture. Des
œuvres à redécouvrir.

332 MEDICOGRAPHIA, Vol 31, No. 3, 2009 Late Renoir, 1892-1919 – Spaak
 “C hance
favors only
the prepared mind”

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