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Preface
Diabetes has become a plague upon modern America. It is the most ex-
pensive chronic illness in the country and has become a scourge of multiple
inpatient medical and surgical services. Indeed, diabetes is the fourth most
common comorbid condition in hospitals and accounts for prolonged
lengths of stay and excess costs for virtually one quarter of all hospital
admissions in the United States. More importantly, however, is the bur-
geoning number of diabetic patients. Each year, approximately 1 million
new cases of type 2 diabetes are diagnosed, and even type 1 diabetes appears
to be increasing in incidence in the United States. Because of our ability to
reduce or prevent the costly chronic complications of diabetes, as shown by
the results of recent clinical trials, newer, more aggressive standards of care
for both glucose control—as well as blood pressure, lipids, and other risk
factors for these chronic complications—have been promulgated recently
by a variety of organizations, chiefly the American Association of Clinical
Endocrinologists, The National Cholesterol Education Program, and the
American Diabetes Association. As new classes of compounds and new
agents within each class develop, thereby expanding our therapeutic options
for patients with diabetes, the potential for drug interactions and drug dif-
ficulties seems to mount geometrically.
In this issue of the Medical Clinics of North America, we have endeavored
to bring to practicing clinicians the most modern strategies by which to
0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2004.05.003
xvi A.J. Garber / Med Clin N Am 88 (2004) xv–xvi
0025-7125/04/$ - see front matter 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2004.04.013
788 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835
Fig. 1. Postabsorptive state. Glucose production and glucose use in the normal human in the
postabsorptive state. (From DeFronzo RA. Pathogenesis of type 2 diabetes mellitus: metabolic
and molecular implications for identifying diabetes genes. Diabetes 1997;5:117–9; with
permission.)
Fig. 2. (A) Whole-body rate of glucose disposal during euglycemic insulin clamps in 32 women
divided according to quartiles of insulin sensitivity. * P 0.001 for each quartile versus the
adjacent quartile. (B) Time course of plasma insulin response during the hyperglycemic clamp in
the same 32 women divided into quartiles of insulin sensitivity. Insulin secretion rose
progressively from the highest to the lowest quartile of insulin sensitivity (P 0.01). , Quartile
1; 6, quartile 2; , quartile 3; C, quartile 4. (From Diamond MP, Thornton K, Connolly-
Diamond M, Sherwin RS, DeFronzo RA. Reciprocal variations in insulin-stimulated glucose
uptake and pancreatic insulin secretion in women with normal glucose tolerance. J Soc Gynecol
Invest 1995;2:708–15.)
R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835 791
Fig. 3. Starling’s curve of the pancreas for insulin secretion. In normal-weight patients with
IGT and mild diabetes, the plasma insulin response to OGTT increases progressively until the
fasting glucose reaches 120 mg/dL. Thereafter, further increases in the fasting glucose
concentration are associated with a progressive decline in insulin secretion. (From DeFronzo
RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for
NIDDM. Diabetes 1988;37(6):667–87; with permission.)
792 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835
insulinopenic. Finally, when the fasting glucose exceeds 200–220 mg/dL, the
plasma insulin response to a glucose challenge is markedly blunted. Nonethe-
less, the fasting hyperinsulinemia persists despite FPG concentrations as high
as 250–300 mg/dL, and 24-hour integrated plasma insulin and C-peptide
profiles in lean type 2 diabetic patients remain normal. These normal day-long
values result from the combination of elevated fasting and decreased
postprandial insulin and C-peptide secretory rates [30,31].
It should be emphasized that, even though the plasma insulin response is
increased in absolute terms early in the development of type 2 diabetes (FPG
140 mg), this does not mean that beta-cell function is normal. The beta
cell responds to an increment in plasma insulin (DI) by an increment in
plasma glucose (DG) and this response is modulated by the severity of
insulin resistance, that is, the more severe the insulin resistance, the greater
the insulin response. When this index of beta-cell function is plotted against
the 2-hour plasma glucose concentration during the OGTT, the loss of
60%–70% of beta-cell function can be appreciated in individuals with
impaired glucose tolerance. In fact, normal glucose tolerant individuals in
the upper tertile of glucose tolerance (2-h plasma glucose, 120–140 mg/dL)
already have lost 50% of their beta-cell function [32].
The natural history of type 2 diabetes, starting with normal glucose
tolerance, insulin resistance, and compensatory hyperinsulinemia, with pro-
gression to impaired glucose tolerance (IGT) and overt diabetes mellitus, has
been observed in a variety of populations including whites, Native Americans,
Mexican Americans, and Pacific Islanders, and in the rhesus monkey, an
animal model that closely resembles type 2 diabetes in humans [1, 2,20–28,33–
35]. These population studies have demonstrated a strong association between
obesity and type 2 diabetes, leading to the new-world syndrome of
‘‘diabesity.’’ In high-risk populations, the progression from normal to IGT
is associated with marked increases in both fasting and glucose-stimulated
plasma insulin levels and a decrease in tissue sensitivity to insulin (Fig. 4). The
progression from IGT to type 2 diabetes with mild fasting hyperglycemia
(120–140 mg/dL, 6.7–7.8 mmol/L) is heralded by an inability of the beta cell to
maintain its previously high rate of insulin secretion in response to a glucose
challenge without further or only minimal deterioration in tissue sensitivity to
insulin. Increased basal insulin secretion and fasting hyperinsulinemia,
however, are maintained until the FPG exceeds 140 mg/dL. A similar pattern
of insulin secretion has been observed during the development of diabetes in
the rhesus monkey [33]. The aging monkey becomes obese, and a high
percentage of monkeys develop typical type 2 diabetes. The earliest detectable
abnormality (preceding the onset of diabetes mellitus) is a decrease in tissue
sensitivity to insulin, with a compensatory increase in fasting and glucose-
stimulated plasma insulin concentrations. With time, the high rate of insulin
secretion cannot be maintained, the beta cell starts on downward slope of
Starling’s curve (see Fig. 3), and fasting hyperglycemia and glucose in-
tolerance ensue. In summary, these studies are consistent in demonstrating
R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835 793
Fig. 4. Summary of the plasma insulin (top, ) and plasma glucose (bottom, C) responses
during a 100-g OGTT and tissue sensitivity to insulin (top, C) in control (CON), obese
nondiabetic (OB), obese glucose intolerant (OB-GLU INTOL), obese hyperinsulinemic diabetic
(OB-DIAB Hi INS), and obese hypoinsulinemic diabetic subjects (OB-DIAB Lo INS). See text
for a detailed discussion. (From DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell,
muscle, liver. A collusion responsible for NIDDM. Diabetes 1988;37(6):667–87; with
permission.)
Fig. 6. Dose-response curve relating the plasma insulin concentration to the rate of insulin-
mediated whole-body glucose uptake in control (C) and type 2 diabetic () subjects. * P 0.01
versus control subjects. (From Groop LC, Bonadonna RC, DelPrato S, Ratheiser K, Zyck K,
Ferrannini E, DeFronzo RA. Glucose and free fatty acid metabolism in non-insulin-dependent
diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest 1989;84(1):205–
13; with permission.)
R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835 801
Fig. 8. Dose-response curve relating the plasma insulin concentration to the suppression of
hepatic glucose production in control (C) and type 2 diabetic () subjects with moderately
severe fasting hyperglycemia. * P 0.05; ** P 0.01 versus control subjects. (From Groop LC,
Bonadonna RC, DelPrato S, Ratheiser K, Zyck K, Ferrannini E, DeFronzo RA. Glucose and
free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple
sites of insulin resistance. J Clin Invest. 1989;84(1):205–13; with permission.)
R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835 803
Fig. 9. Time course of change in leg glucose uptake in type 2 diabetic () and control (C)
subjects. In the postabsorptive state, glucose uptake in the diabetic group was significantly
greater than that in control subjects. The ability of insulin (euglycemic insulin clamp) to
stimulate leg glucose uptake, however, was reduced by 50% in the diabetic subjects. * P \ 0.05;
** P \ 0.01. (From DeFronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J. Effects
of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II)
diabetes mellitus. J Clin Invest 1985;76(1):149–55; with permission.)
R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835 805
Fig. 10. Summary of glucose metabolism during euglycemic insulin (100 lU/mL) clamp studies
performed in normal-weight type 2 diabetic and control subjects (see text for a more detailed
discussion). NIDD, non-insulin-dependent diabetes. (From DeFronzo RA. Pathogenesis of type
2 diabetes mellitus: metabolic and molecular implications for identifying diabetes genes.
Diabetes 1997;5:117–269; with permission.)
insulin sensitivity. Last, the obese diabetic group with a low insulin response
manifests the greatest glucose intolerance owing to the presence of marked
insulin deficiency without further worsening of insulin sensitivity (see Fig. 4).
The natural history of type 2 diabetes described above (see Fig. 4) is
consistent with that described by other investigators in humans and
monkeys [1,2,20,22–27,29,33–35,97–99,102,144–146]. In lean subjects span-
ning a wide range of glucose tolerance, Reaven et al [97] demonstrated that
the progression from normal glucose tolerance to IGT was signaled by the
development of severe insulin resistance, which was largely counterbalanced
by increased insulin secretion. Progression from IGT to type 2 diabetes was
associated with a marked decline in insulin secretion with no (or only slight)
further deterioration in tissue sensitivity to insulin (Fig. 11). A similar
sequence of events has been documented prospectively in Pima Indians,
Pacific Islanders, and rhesus monkeys.
In summary, insulin resistance is an early and characteristic feature of the
natural history of type 2 diabetes in high-risk populations. Overt diabetes
develops only when the beta cells are unable to appropriately augment their
secretion of insulin to compensate for the defect in insulin action. It should
be recognized, however, that there are well-described type 2 diabetic
populations in whom insulin sensitivity is normal at the onset of diabetes,
whereas insulin secretion is severely impaired. This insulinopenic variety of
type 2 diabetes appears to be more common in African Americans, elderly
subjects, and lean whites. In this latter group, it is important to exclude type
1 diabetes, because approximately 10% of white individuals with older onset
diabetes are islet cell antibody, or glutamic acid decarboxylase, positive.
Fig. 11. Insulin-mediated glucose clearance (measured with the insulin suppression test) and the
plasma insulin response (measured with an OGTT) in controls (top), in subjects with IGT
(bottom), and in type 2 diabetic individuals (top) with varying severity of glucose intolerance (see
text for a more detailed discussion). (Data from Reaven GM, Hollenbeck CB, Chen YDI.
Relationship between glucose tolerance, insulin secretion, and insulin action in non-obese
individuals with varying degrees of glucose tolerance. Diabetologia 1989;32:52–5.)
R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835 811
Fig. 12. Etiology of type 2 diabetes mellitus (T2DM). The deleterious effect of chronically
elevated plasma FFA concentrations on basal or insulin-suppressed rate of hepatic glucose
production, insulin-stimulated glucose uptake in muscle, and glucose-stimulated insulin
secretion.
812 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835
Fig. 13. Harmonious quartet. Insulin resistance in adipocytes, muscle, and liver in combination
with impaired insulin secretion by the pancreatic beta cells, represent the four major organ
system abnormalities that play a central role in the pathogenesis of type 2 diabetes mellitus.
Fig. 14. Insulin transduction system. Insulin receptor and the cascade of intracellular signaling
molecules that have been implicated in insulin action (see text for a more detailed discussion).
demonstrated in over half of type 2 diabetic subjects, and it has been difficult
to demonstrate a correlation between reduced insulin binding and the
severity of insulin resistance [179–181]. A variety of defects in insulin
receptor internalization and processing have been described in syndromes of
severe insulin resistance and diabetes. The insulin receptor gene, however,
has been sequenced in a large number of type 2 diabetic patients from
diverse ethnic populations and, with very rare exceptions, physiologically
significant mutations in the insulin receptor gene have not been observed
[182,183]. This excludes a structural gene abnormality in the insulin receptor
as a cause of common type 2 diabetes mellitus.
Fig. 15. Insulin signaling cascade in T2DM. Effect of insulin on insulin receptor (top) and IRS-
1 tyrosine phosphorylation (bottom) and the association of IRS-1 with the p85 regulatory
subunit of PI3K and PI3K activity in muscle from T2DM and control (CON) subjects. Data are
expressed as percentages of the mean insulin-stimulated values in the control groups. Open bars,
basal state; filled bars, insulin-stimulated state; * P 0.05, T2DM versus CON.
816 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835
inhibit insulin receptor tyrosine kinase activity [187]. Because insulin receptor
tyrosine kinase activity assays are performed in vitro, the results of these
assays could provide misleading information with regard to insulin receptor
function in vivo. To circumvent this problem, investigators have used the
euglycemic hyperinsulinemic clamp with muscle biopsies and anti-phospho-
tyrosine immunoblot analysis to provide a ‘‘snap shot’’ of the insulin-
stimulated tyrosine phosphorylation state of the receptor in vivo [185]. In
insulin-resistant obese nondiabetic and type 2 diabetic subjects, a substantial
decrease in insulin receptor tyrosine phosphorylation has been demonstrated;
however, when insulin-stimulated insulin receptor tyrosine phosphorylation
was examined in normal-glucose-tolerant insulin-resistant individuals (off-
spring of two diabetic parents) at high risk for developing type 2 diabetes,
a normal increase in tyrosine phosphorylation of the insulin receptor was
observed [188]. These findings are consistent with the concept that impaired
insulin receptor tyrosine kinase activity in type 2 diabetic patients is acquired
secondary to hyperglycemia or some other metabolic disturbance.
Glucose transport
Activation of the insulin signal transduction system in insulin target
tissues stimulates glucose transport through a mechanism that involves
translocation of a large intracellular pool of glucose transporters (associated
with low-density microsomes) to the plasma membrane and their subsequent
activation after insertion into the cell membrane [196,197]. There are five
major, different facilitative glucose transporters (GLUT) with distinctive
tissue distributions (Table 1) [198,199]. GLUT4, the insulin regulatable
transporter, is found in insulin-sensitive tissues (muscle and adipocytes), has
a Km of approximately 5 mmol/L, which is close to that of the plasma
glucose concentration, and is associated with HK-II [198,199]. In adipocytes
and muscle, GLUT4 concentration in the plasma membrane increases
markedly after exposure to insulin, and this increase is associated with
Table 1
Classification of glucose transport and HK activity according to their tissue distribution and
functional regulation
Organ Glucose transporter Hexokinase computer Classification
Brain GLUT1 HK-I Glucose dependent
Erythrocyte GLUT1 HK-I Glucose dependent
Adipocyte GLUT4 HK-II Insulin dependent
Muscle GLUT4 HK-II Insulin dependent
Liver GLUT2 HK-IVL Glucose sensor
Glucokinase beta cell GLUT2 HK-IVB (glucokinase) Glucose sensor
Gut GLUT3-symporter — Sodium dependent
Kidney GLUT3-symporter — Sodium dependent
Data from DeFronzo RA. Pathogenesis of type 2 diabetes mellitus: metablic and molecular
implications for identifying diabetes genes. Diabetes 1997;5:177–269.
818 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835
Glucose phosphorylation
Glucose phosphorylation and glucose transport are tightly coupled
phenomena [212]. Hexokinase isoenzymes (HK-I–IV) catalyze the first
R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835 819
Glycogen synthesis
Following phosphorylation by hexokinase II, glucose either can be
converted to glycogen or enter the glycolytic pathway. Of the glucose that
enters the glycolytic pathway, approximately 90% is oxidized, and the
remaining 10% is released as lactate. At low physiologic plasma insulin
concentrations, glycogen synthesis and glucose oxidation contribute equally
to glucose disposal; however, with increasing plasma insulin concentrations,
glycogen synthesis predominates [1,2,221]. Impaired insulin-stimulated
glycogen synthesis is a characteristic finding in all insulin-resistant states,
including obesity, IGT, diabetes, and diabesity in all ethnic groups, and
accounts for the majority of the defect in insulin-mediated whole-body
glucose disposal [1,2,12,98,210,222–224]. Impaired glycogen synthesis also
has been documented in the normal-glucose tolerant offspring of two
diabetic parents, in the first-degree relatives of type 2 diabetic individuals,
and in the normoglycemic twin of a monozygotic twin pair in which the
other twin has type 2 diabetes [65,98,225].
Glycogen synthase is the key insulin-regulated enzyme that controls the
rate of muscle glycogen synthesis [171,173,216, 226–228]. Insulin activates
glycogen synthase by stimulating a cascade of phosphorylation-dephos-
phorylation reactions (see above discussion of insulin receptor signal
transduction), which ultimately lead to the activation of PP1 (also called
glycogen synthase phosphatase). The regulatory subunit of PP1 has two
serine phosphorylation sites, called site 1 and site 2. Phosphorylation of site
2 by cAMP-dependent protein kinase inactivates PP1, whereas phosphor-
ylation of site 1 by insulin activates PP1, leading to the stimulation of
glycogen synthase. Phosphorylation of site 1 of PP1 by insulin in muscle is
catalyzed by insulin-stimulated protein kinase (ISPK)-1. Because of their
central role in muscle glycogen formation, the three enzymes, glycogen
synthase, PP1, and ISPK-1, have been extensively studied in individuals
with type 2 diabetes.
Glycogen synthase exists in an active (dephosphorylated) and an inactive
(phosphorylated) form [171–173]. Under basal conditions, total glycogen
synthase activity in type 2 diabetic subjects is reduced, and the ability of
insulin to activate glycogen synthase is severely impaired [185,229–231]. The
ability of insulin to stimulate glycogen synthase also is diminished in the
normal glucose-tolerant, insulin-resistant relatives of type 2 diabetic
individuals [232]. In insulin-resistant nondiabetic and diabetic Pima Indians,
activation of muscle PP1 (glycogen synthase phosphatase) by insulin is
severely reduced [233]. Because PP1 dephosphorylates glycogen synthase,
leading to its activation, a defect in PP1 appears to play an important role in
the muscle insulin resistance of type 2 diabetes mellitus.
R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835 821
Glycolysis/Glucose oxidation
Glucose oxidation accounts for approximately 90% of total glycolytic
flux, whereas anaerobic glycolysis accounts for the other 10%. The two
enzymes PFK and PDH play pivotal roles in the regulation of glycolysis and
glucose oxidation, respectively. In type 2 diabetic individuals, the glycolytic/
glucose oxidative pathway has been shown to be impaired [243]. Although
one study [244] has suggested that PFK activity is modestly reduced in
muscle biopsies from type 2 diabetic subjects, most evidence indicates that
the activity of PFK is normal [230,235]. Insulin has no effect on muscle PFK
activity, mRNA levels, or protein content in either nondiabetic or diabetic
individuals [235]. PDH is a key insulin-regulated enzyme with activity in
muscle that is acutely stimulated by insulin [245]. In type 2 diabetic patients,
insulin-stimulated PDH activity has been shown to be decreased in human
adipocytes and in skeletal muscle [245,246].
Obesity and type 2 diabetes mellitus are associated with accelerated FFA
turnover and oxidation [1,2,12,247], which would be expected, according to
the Randle cycle [248], to inhibit PDH activity and consequently glucose
822 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835
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* Baylor College of Medicine, 6550 Fannin Street, Suite 1045, Houston, TX 77030.
E-mail address: agarber@bcm.tmc.edu
0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2004.04.001
838 A.J. Garber / Med Clin N Am 88 (2004) 837–846
Table 1
Definition of metabolic syndrome
Risk factor Defining level
Abdominal obesity
Men Waist >40 inches
Women Waist >35 inches
Triglycerides 150 mg/dL
HDL cholesterol
Men \40 mg/dL
Women \50 mg/dL
Blood pressure 130/85 mm Hg
Fasting glucose 110 mg/dL
NCEP criteria (any 3–5 symptoms).
and tripled such risk for females with the metabolic syndrome compared
with those without the metabolic syndrome. A greater adverse cardiovas-
cular impact of the metabolic syndrome was seen by Lakka et al [4] in the
Kuoppio Study (see [4]), in which a diagnosis of the metabolic syndrome
increased coronary artery mortality and cardiovascular mortality by three-
fold and doubled total mortality in this patient population. An even greater
cardiovascular risk was noted in the Mexico City Study.
The metabolic syndrome may also be an outstanding risk predictor of
future diabetes. In the Framingham Offspring Study, a recent analysis
suggested that a diagnosis of the metabolic syndrome predicted a fivefold
8-year future risk of diabetes in males and a sixfold increase in the future
risk of diabetes in females. Although the accuracy of the metabolic syndrome
as a predictor of excess risk of cardiovascular disease is not surprising, its
robust ability to predict an excess risk of future diabetes is, in fact,
somewhat unexpected. This degree of accuracy may provide insight into the
precise nature of the ‘‘metabolic syndrome.’’ Because it is likely that the
metabolic syndrome describes at least one aspect of underlying insulin
resistance (clearly the period in which multiple metabolic abnormalities have
evolved, likely secondary to b-cell failure resulting from an underlying
insulin resistance state), then the metabolic syndrome presents a slice in time
in the evolution of the insulin resistant state into an area of gross pathology,
such as type 2 diabetes or clinical atherosclerosis.
Therefore, the metabolic syndrome likely characterizes a state in time of
latent underlying disease evolution that may be viewed as preclinical
diabetes or preclinical atherosclerosis. Based in large measure on epidemi-
ologic analyses, such a diagnosis clearly represents a high probability
transition state in the evolution from normality to gross pathology resulting
from insulin resistance. It is important to recognize a transition state
because transition states are generally more reversible than end-stage
pathology. Alternatively, one may view the high predictability of the
metabolic syndrome of future type 2 diabetes as the likelihood that the
metabolic syndrome is already type 2 diabetes. This view derives from
the observation that glucose is a continuous variable that proceeds from
completely normal to completely abnormal, with the diagnosis of diabetes
being a somewhat arbitrary event in the middle of this evolution. Prior
expert committees have set arbitrary diagnostic criteria for type 2 diabetes at
levels of 126 mg/dL, based in part on the recognized increase in the
development of the typical or classic microvascular complications of
diabetes, such as retinopathy. Nonetheless, although it is an expert opinion,
the diagnosis point for diabetes remains arbitrary. This is not to say that
diabetes may not occur at an earlier point or at lower glucose levels before
the development of very substantial rates of hyperglycemia. As seen in the
special analysis of the NHANES III database, there was a fivefold increase
in the incidence of retinopathy in the fasting glucose interval of 110 to 119
mg/dL compared with the interval of 100 to 109 mg/dL. It is therefore
A.J. Garber / Med Clin N Am 88 (2004) 837–846 841
Obesity
The foundation of the metabolic syndrome is excess deposition of
adipose tissue in visceral or abdominal compartments, which gives rise to
an underlying insulin resistant state. Although the NCEP definition of the
metabolic syndrome does not directly measure insulin sensitivity, much of
the diagnostic criteria outlined previously are associated with the dysme-
tabolism of insulin resistance. Insulin resistance may be directly addressed
by lifestyle modification. Such modifications include regular, vigorous
aerobic exercise as frequently as possible. The insulin sensitizing benefits
of exercise require, for example, five or more sessions per week of
approximately 3 to 5 miles per day, consisting of a brisk walking pace of
3 to 4 miles per hour. Light-weight training is also useful in supporting
muscle bulk and assisting with weight reduction. Of course, before
842 A.J. Garber / Med Clin N Am 88 (2004) 837–846
beginning regular daily exercise, patients with high risk of coronary disease
should undergo exercise cardiac testing to exclude subclinical or atypical
coronary ischemia.
Exercise alone without aggressive calorie restriction is usually insufficient
to produce weight loss. Indeed, exercise may increase appetite, which may
more than compensate for the increased caloric expenditure and oxygen
consumption associated with the exercise. For that reason, aggressive
dietary modification with limitation of concentrated sweets, saturated fats,
and reduction of portion sizes seems essential if weight reduction is to be
achieved. Weight reduction to achieve a body mass index (BMI) less than 30
is essential if the metabolic syndrome is to be modified. Nonobese but
overweight individuals have a substantially reduced risk of the metabolic
syndrome. Of course, reduction of overweight individuals to normal weight
(27 BMI) would be ideal, but this level may be difficult to achieve in the
markedly obese population in whom even small degrees of weight loss
would be beneficial for many of the parameters of the metabolic syndrome,
especially the hypertriglyceridemia and hyperglycemia.
Lifestyle modification with diet and exercise greatly magnifies the effect of
pharmacologic agents designed to intervene in dyslipidemia, hypertension,
or abnormal carbohydrate tolerance. Because the metabolic syndrome is
also a high-risk predictor of future diabetes, intervention to prevent the
development of overt type 2 diabetes seems appropriate. The role of diet and
exercise as part of a thorough lifestyle modification program is unsurpassed
for prevention of type 2 diabetes in patients with impaired glucose tolerance.
Although they are not strictly the same as the patient population with the
metabolic syndrome, patients in the Diabetes Prevention Program (DPP)
showed a 58% reduction in the risk of development of type 2 diabetes by
a 7% loss of body weight and regular daily exercise. Pharmacologic
therapies were also useful for the prevention of type 2 diabetes because
these therapies may have reduced the underlying insulin resistance. These
therapies, however, will be discussed later as part of future considerations in
the management of the metabolic syndrome. Pharmacologically assisted
weight loss may also be considered. Orlistat (Xenical) therapy reduces fat
absorption, produces a 3% to 8% weight loss, and reduces the development
of type 2 diabetes. It should be considered for those failing life style
modifications.
Treatment of dyslipidemia
The metabolic syndrome does not necessarily include hypercholesterol-
emia, as characterized by a markedly increased mass of low-density
lipoprotein (LDL) cholesterol. Instead, a shift in the size distribution of
LDL particles toward a smaller, denser and inherently more atherogenic
LDL particle, as the result of the underlying insulin resistance state, seems
A.J. Garber / Med Clin N Am 88 (2004) 837–846 843
Treatment of hypertension
Numerous agents have been established as excellent first-line therapies
for hypertension in patients with diabetes and in nondiabetic patients with
dyslipidemia. Ramipril, used in the HOPE Study, showed excellent
antiatherogenic effects in diabetic patients with one additional coronary
risk factor and in patients with coronary disease. Captopril and atenolol
were equally effective for macrovascular risk reduction in patients with
diabetes in the UKPDS. Calcium channel blockers such as felodipine
(Plendil) also proved effective in diabetic patients in the HOT Trial. Finally,
thiazide diuretics were found to be useful in the ALLHAT Study. Thus,
a variety of agents can be chosen for patients with diabetes. Because most
patients with type 2 diabetes evolve from a preexisting metabolic syndrome,
the use of antihypertensive agents might be expected in patients with the
metabolic syndrome, as they have been proven to be efficacious in patients
with diabetes. Because endothelial dysfunction is an important part of the
underlying insulin resistance state, which appears to be widely present in the
metabolic syndrome, angiotensin-converting enzyme inhibitors and aldo-
sterone receptor antagonists are useful in improving hypertension and
A.J. Garber / Med Clin N Am 88 (2004) 837–846 845
Summary
The metabolic syndrome is a collection of cardiovascular risk factors that
denote a high-risk multifactorial adverse cardiovascular state, which is
largely the result of obesity and the resulting insulin resistance. It is
diagnosed by the presence of multiple risk factors, such as hypertriglycer-
idemia, low HDL cholesterol, hypertension, essential hypertension, abnor-
mal fasting glucose levels, and abdominal or visceral obesity. This state also
denotes a high-risk state for the evolution to type 2 diabetes. Treatment for
the metabolic syndrome should be focused primarily on lifestyle modifica-
tion, with reduction of the underlying obesity and insulin resistance. The
treatment of individual coronary risk factors is clearly warranted in such
patients because the metabolic syndrome represents a high-risk cardiovas-
cular state equal to 20% or greater 10-year risk of coronary disease. In such
patients, it may be possible that impaired glucose tolerance also exists. This
diagnosis requires a glucose tolerance test to be performed. Chemopreven-
tion of deterioration of impaired glucose tolerance to a future diabetic state
has been successful with metformin or thiazolidinediones, as well as with
aggressive lifestyle modification. Indeed, combination of both chemo-
prevention and lifestyle modification may prevent future cases of diabetes
if instituted early in the course of diagnosis of impaired glucose tolerance.
Whether such treatments benefit the adverse cardiovascular outcomes
remain to be decided.
References
[1] Executive summary of the Third Report of the National Cholesterol Program (NCEP)
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in
Adults. JAMA 2001;285:2486–97.
[2] Lebovitz H. Diabetes Reviews 1999.
[3] Ridker PM, et al. Circulation 2003;107:391–7.
[4] Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, et al.
The metabolic syndrome and total and cardiovascular disease mortality in middle-aged
men. JAMA 2002;288:2709–16.
[5] United Kingdom Prospective Diabetes Study No. 34. Lancet 1998.
[6] Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults:
findings from the third National Health and Nutrition Examination Survey. JAMA 2002;
287:356–9.
Med Clin N Am 88 (2004) 847–863
0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2004.05.002
848 H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863
Table 1
Comparison of characteristics of adult diabetic patients 20 years and older in NHANES III
(1988–1994) and NHANES 1999–2000
NHANES III NHANES 1999–2000
Prevalence of diabetes 5.4 6.1
Age standardized (%)
Men (%) 43.2 50
BMI (kg/m2) 29.9 32.3
Age at diagnosis of diabetes 50.7 46.7
Race
Non-Hispanic white (%) 74.6 59.8
Other races (%) 25.4 40.2
Abbreviation: BMI, body mass index.
Data from Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular
disease among adults with previously diagnosed diabetes. JAMA 2004;291:335–42; and Koro
CE, Bourgeois N, Bowlin SJ, Fedder DO. Glycemic control from 1988 to 2000 among US
adults diagnosed with type 2 diabetes. Diabetes Care 2004;27:17–20.
Table 2
Causes responsible for failure to improve metabolic control in type 2 diabetic patients
Responsible cause Example
Patient Increasing obesity of the population
Difficulty in compliance with complicated regimens
Health care provider Lack of understanding importance of early aggressive control
Failure to understand significance of multiple defects
Disease Progressive beta cell failure
Therapeutic agents Inability to restore normal physiology
Side effects
H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863 849
Table 3
Comparison of the effects of thiazolidinediones and metformin on insulin resistance and the
components of the Metabolic Syndrome
Activity Metformin Thiazolidinediones
Glycemic control
FPG ## ##
HbA1c ## ##
FPI # ##
Body weight # "
Visceral fat # 0
Insulin sensitivity
Peripheral ""
Liver "" "
Dyslipidemia
LDL cholesterol "
LDL particle size 0 "
HDL cholesterol ""
Triglyceride #
Lipoprotein (a) 0 "
FFA ##
Endothelial function
Vasodilation " ""
Blood pressure 0 #
Adhesion molecules #
Muscle proliferation #
Procoagulant state
PAI-1 # #
Fibrinogen
Inflammation
C-reactive protein # ##
Mesangial function
Microalbuminuria 0 #
Abbreviations: FFA, free fatty acid; FPG, fasting plasma glucose; FPI, fasting plasma
insulin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PAI, plasminogen
activator inhibitor. 0, no effect; #, decrease; ##, marked decrease; ", increase; "", marked
increase.
Data from Lebovitz HE, Banerji MA. Treatment of insulin resistance in diabetes mellitus.
Eur J Pharmacol 2004;490:135–46.
events even though they lowered HbA1c the same 0.6% as metformin.
Clinical trials examining the effects of thiazolidinedione treatment on the
development of clinical cardiovascular events in type 2 diabetic patients are
in progress.
There are additional major differences between the effects of thiazoli-
dinediones and metformin. Metformin treatment is usually associated with
some weight loss. Most clinical studies show a mean weight loss with
metformin treatment of approximately 1 to 2 kg [29]. Thiazolidinedione
treatment is usually associated with a mean weight gain of 1.5 kg at
854 H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863
intermediate doses and 3.5 kg at high doses [30]. The side effects of
metformin include abdominal discomfort and diarrhea, which occur in
10% to 20% of patients on maximal doses, and a very rare occurrence of
lactic acidosis [29]. The gastrointestinal symptoms can be minimized by
initiating metformin therapy with 500 mg with the evening meal,
increasing the dose to 500 mg twice a day, and slowly titrating the dose
to 1000 mg twice a day with meals. The longer-acting preparations, such
as Glucophage XR, cause less gastrointestinal side effects. The few cases
of metformin-induced lactic acidosis that have been reported occurred in
individuals with decreased renal function, symptomatic heart failure on
therapy, or an underlying metabolic acidosis [31]. The major side effects
of thiazolidinedione treatment are an increase in adipose tissue and fluid
retention. The increase in adipose tissue is selective for the subcutaneous
region [32]. The visceral adipose tissue either is unchanged or decreases
slightly. The fluid retention manifests itself as mild to moderate peripheral
edema, which occurs in 4% of patients on monotherapy [33]. When
thiazolidinediones are combined with insulin, edema is seen in approxi-
mately 15% of the patients [33]. A rare type 2 diabetic patient on
thiazolidinediones develops heart failure. Such patients are usually older,
are on maximal doses of the thiazolidinedione, are also taking insulin,
and have a prior history of cardiovascular disease or renal failure [33].
The mechanism seems to be the increase in plasma volume in type 2
diabetic patients who had asymptomatic compensated heart failure.
Treatment of the fluid retention with loop diuretics is of limited benefit.
Angiotensin-converting enzyme inhibitors and aldosterone antagonists
have been used with limited success to treat the fluid retention [33].
According to a recent consensus panel convened by the American
Diabetes and American Heart Associations patients who are at risk for
developing congestive heart failure and could benefit from thiazolidine-
dione treatment should be started on very low doses, titrated up slowly,
and have careful monitoring of body weight and edema [33]. If excess
weight gain or edema is noted despite attempts to treat it, the
thiazolidinedione should be discontinued.
Metformin is administered twice a day and the maximal benefits on
glycemic control are seen at 2000 mg/d. Pioglitazone is administered once
daily in doses of 15, 30, or 45 mg/d. Rosiglitazone is administered either
once or twice a day in doses ranging from 2, 4, or 8 mg/d.
the UKPDS, which also showed that this decline in beta cell function was
not altered by treatment with diet, metformin, sulfonylureas, or insulin [10].
The decline in beta cell function is caused by a decreased ability of
glucose to cause closure of an ATP-dependent potassium channel in the
plasma membrane of beta cell [34,35]. The normal mechanism for glucose
stimulation of insulin secretion involves the following steps [34,35]. Glucose
from the plasma compartment is rapidly transported into the beta cell,
phosphorylated, and metabolized to generate ATP. Special enzymes in the
beta cell (Glut-2 glucose transporter and glucokinase) allow this process to
occur quantitatively so that the intracellular ATP:ADP ratio accurately
reflects the plasma glucose concentration. The plasma membrane of the beta
cell contains a potassium channel whose function is regulated by the
ATP:ADP ratio and a voltage-dependent calcium channel. When the plasma
glucose is low the potassium channel is open and extruding potassium from
the beta cell. The plasma membrane is appropriately polarized and the
calcium channel is closed. As the plasma glucose rises, the ATP:ADP ratio
increases, which causes the ATP-dependent potassium channels to close.
Closure of the ATP-dependent potassium channel causes depolarization of
the adjacent plasma membrane, which results in opening of the voltage-
dependent calcium channels in that portion of the depolarized membrane.
The open calcium channels allow calcium to be transported from the
extracellular compartment into the cytoplasm of the beta cell. Increases in
cytosolic calcium ion concentrations linearly increase the release of insulin
from the beta cell granule into the plasma compartment. The impaired
release of insulin, which is characteristic of the early stages of type 2
diabetes, is a delayed and impaired ability of plasma glucose fluctuations
appropriately to regulate closure of the ATP-dependent potassium channel.
As the duration of type 2 diabetes increases, the functional defect in beta
cells is compounded by an increase in apoptosis and a decrease in beta cell
mass. The mechanism responsible for the decrease in mass is unclear but the
consequence is that type 2 diabetic patients become more insulin deficient
with time.
In the first 4 or 5 years after the onset of clinical type 2 diabetes the
functional defect in insulin secretion can be ameliorated by pharmacologic
agents, which act directly on the ATP-dependent potassium channel and
augment its closure by glucose. These agents are the insulin secretagogues,
of which there are three distinct classes in clinical use: (1) sulfonylureas, (2)
meglitinides, and (3) phenylalanine derivatives. All of these agents interact
with the regulatory subunit of the ATP-dependent potassium channel and
directly stimulate its closure [34,36]. There are subtle differences in the
specific binding site and characteristics of binding among the three classes of
insulin secretagogues, which modulate differences in their pattern of insulin
release [35,37].
The commonly prescribed sulfonylureas include glyburide, glipizide, and
glimepiride. The glyburide is formulated as regular and micronized. The
856 H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863
glipizide is formulated as short acting and slow release. Table 4 lists these
formulations and their characteristics. The meglitinide that is available is
repaglinide and the phenylalanine derivative that is marketed is nateglinide.
Their characteristics are also listed in Table 4.
The clinically relevant insulin secretory defects in type 2 diabetes are (1)
a 30- to 60-minute delay in meal-mediated insulin secretion, (2) a deficient
quantity of insulin secretion, and (3) a progressive loss in beta cell function
with time [34,36,38]. Administration of sulfonylureas does not significantly
alter the delay in meal-mediated insulin secretion.
Sulfonylurea treatment augments fasting insulin secretion and the second
or late phase (after 60 minutes) of meal-mediated insulin secretion [34,36].
The consequence of these pharmacologic actions is a lowering of the fasting
plasma glucose but very little decrease in the postprandial plasma glucose
excursion. Sulfonylureas do not stimulate insulin biosynthesis. The two new
insulin secretagogues, repaglinide [39,40] and nateglinide [41,42], were
specifically designed to increase early meal-mediated insulin secretion. They
are able to do so because they are rapidly absorbed and have rapid binding
kinetics to the regulatory subunit of the ATP-dependent potassium channel
[35,37,39–42]. They can be taken at the time of the meal and are able to
facilitate early meal-mediated insulin secretion. This provides for a lower
early and a shorter duration of postprandial glucose rise. These insulin
secretagogues in contrast to sulfonylureas decrease the postprandial plasma
glucose excursions [39–43].
Table 4
Properties of commonly prescribed insulin secretagogues
Duration
Generic name Daily dose of action Comments
Glyburide 2.5–20 mg >24 h Absorption is incomplete and variable
Hypoglycemia is the most common and severe
Blocks ischemic preconditioning
Glyburide 1–8 mg >24 h More consistent absorption
micronized
Glipizide 2.5–20 mg >12 h Relatively short acting
Hypoglycemia less severe and about half as
frequent as glyburide
Glipizide- 5–20 mg 24 h Hypoglycemia and weight gain reported to be
GITS quite low
Glimepiride 1–8 mg 24 h Hypoglycemia frequency and severity \ half that
(Amaryl) of glyburide
No interference with ischemic preconditioning
Repaglinide 1–4 mg with 5–6 h Low incidence of hypoglycemia
(Prandin) each meal Weight gain less than with sulfonylureas
Nateglinide 60–120 mg 3–4 h Very low incidence of hypoglycemia
(Starlix) with each Little data on weight gain
meal
H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863 857
Table 5
Comparison of classes of insulin secretagogues
Sulfonylureas Repaglinide Nateglinide
Dosing Once or twice daily With each meal With each meal
FPG # 50 to 60 mg/dL # 50 to 60 mg/dL # 20 mg/dL
PPG excursion Slight effect Moderate effect Major effect
PP insulin secretion " late phase " early and late phases 10 min to 4 h
Hypoglycemia Fasting and late PP Less than sulfonylureas Uncommon
Weight gain 1 to 3 kg Less than sulfonylureas ?
HbA1c # 1.5% # 1.5% # 0.8%
Cost Inexpensive Expensive Expensive
Abbreviations: FPG, fasting plasma glucose; PP, postprandial; PPG, postprandial plasma
glucose excursion.
Combination therapies
Combination therapy should be the treatment of choice in most patients
with type 2 diabetes. Acceptance of the importance of combination therapy
has spawned the production of several fixed combinations, such as glyburide
and metformin (Glucovance), metformin and glipizide (Metaglip), metfor-
min and rosiglitazone (Avandemet), and glimepiride and rosiglitazone
(Avandaril). These fixed combinations provide for better compliance and
lower cost because they require one copay.
The use of metformin and a thiazolidinedione provides maximum effects
on insulin resistance with diminished side effects. This combination is quite
useful in patients in the early stages of hyperglycemia when insulin resistance
is the predominant defect and insulin secretion is still well maintained. In the
more advanced stages of hyperglycemia when insulin secretory deficiency is
more marked, a combination of an insulin secretagogue and one or more
insulin sensitizers is more appropriate. a-Glucosidase inhibitors or nategli-
nide can be added specifically to improve recalcitrant postprandial
hyperglycemia. The choice between adding a third oral agent or adding
basal insulin therapy should be dictated by the cost and the magnitude of the
HbA1c at the time the therapy change is being considered.
Summary
The appropriate management of patients with type 2 diabetes presents
many challenges to health care providers. The disease is increasing at
860 H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863
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[33] Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, et al. Thiazolidinedione
use, fluid retention, and congestive heart failure: a consensus statement from the American
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108:2941–8.
[34] Lebovitz HE, Melander A. Sulfonylureas: basic aspects and clinical use. In: DeFronzo R,
editor. International textbook of diabetes. 3rd edition. Chichester (UK): John Wiley and
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[35] Fuhlendorff J, Rorsman P, Kofod H, Brand CL, Rolin B, MacKay P, et al. Stimulation of
insulin release by repaglinide and glibenclamide involves both common and distinct
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[36] Lebovitz HE. Insulin secretogogues: sulfonylueas, meglitinides and phenylalanine deriva-
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Med Clin N Am 88 (2004) 865–895
* Corresponding author.
E-mail address: svedelman@vapop.ucsd.edu (S.V. Edelman).
0025-7125/04/$ - see front matter 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2004.04.005
866 T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895
the insulin resistance, blood glucose levels begin to rise. Over the course
of the disease, endogenous insulin levels slowly begin to decrease and,
ultimately, many patients with type 2 diabetes are unable to achieve optimal
glycemic control with oral agents [11].
In subjects with type 2 diabetes who are lean, impaired insulin secretion is
the predominant defect, and insulin resistance tends to be less severe than in
the obese variety [12]. On the other hand, insulin resistance and hyper-
insulinemia are the classical abnormalities of obese persons with type
2 diabetes [12]. In type 2 diabetes, insulin secretion is often excessive
compared with the nondiabetic situation but is still insufficient to overcome
the insulin resistance that is present. It is important to understand and
appreciate these fundamental differences when considering insulin therapy
in type 2 diabetes. Based on this knowledge, lean type 2 diabetic subjects
usually fail oral agents faster and will require considerably less insulin to
control their hyperglycemia than their obese counterparts. In contrast, large
doses of exogenous insulin are the rule in the obese form of this disorder
when euglycemia is desired [13].
The need for large amounts of exogenous insulin in obese type 2 diabetes
also raises the question of the most appropriate methods of insulin delivery.
Under normal circumstances, insulin is secreted from the pancreas into the
portal vein, going directly to the liver in which a large first-pass extraction
of portal insulin occurs [14]. When insulin is injected subcutaneously,
absorption occurs directly into the peripheral circulation, without the initial
effects of hepatic extraction. Therefore, the tissues are exposed to greater
levels of insulin than if insulin was provided by the portal route. Because the
primary target of exogenous insulin is the liver, type 2 diabetes may be
uniquely suited to delivery of insulin through the portal vein. Such a
situation occurs when insulin is delivered intraperitoneally, and the majority
of insulin is absorbed into the portal circulation [15]. Intraperitoneal insulin
delivery systems will not be discussed in this section, however, this method
holds considerable promise in type 2 diabetes because of the more
physiologic delivery of insulin and because of selective and effective
inhibition of hepatic glucose output, with less peripheral insulinemia than
occurs with subcutaneous insulin injections [16].
this situation may prove advantageous because its use is associated with
reduced weight gain.
The safety and efficacy of metformin in combination with insulin has
been demonstrated in a recent multicenter study by Yki-Jarvinen et al [35].
In this placebo-controlled study, 96 type 2 diabetics who were poorly
controlled with oral sulfonylurea therapy (mean glycosylated hemoglobin
value 9.9% 0.2%; mean fasting plasma glucose level 214 5 mg/dL) were
randomized to 1 year of treatment with bedtime intermediate-acting insulin
plus either glyburide (10.5 mg), metformin (2 g), glyburide and metformin,
or a second injection of intermediate-acting insulin in the morning. Patients
were taught to adjust the bedtime insulin dose on the basis of fasting glucose
measurements. At 1 year, body weight remained unchanged in patients
receiving bedtime insulin plus metformin (mean change 0.9 1.2 kg) but
increased by 3.9 0.7 kg, 3.6 1.2 kg, and 4.6 1.0 kg, respectively, in
patients receiving bedtime insulin plus glyburide, bedtime insulin plus both
oral drugs, and bedtime and morning insulin. In addition, the greatest
decrease in the glycosylated hemoglobin value was observed in the bedtime
insulin and metformin group (from 9.7 0.4% to 7.2 0.2%, a difference
of 2.5 0.4 percentage points) at 1 year (P 0.001 compared with
baseline and P 0.05 compared with other groups). This group also had
significantly fewer symptomatic and biochemical cases of hypoglycemia
(P 0.05) than the other groups. The authors conclude that combination
therapy with bedtime insulin plus metformin not only prevents weight gain
but also seems superior to other bedtime insulin regimens, with respect to
improvements in glycemic control and frequency of hypoglycemia.
In a more recent study [44] of approximately 390 type 2 diabetics, the
combination of insulin and metformin led to a significant improvement in
glycemic control that was greater than with insulin alone. The mean daily
glucose level decreased from 141 34 to 137 31 mg/dL in the insulin-only
group (mean decrease 0.16; 95% confidence interval [CI]; 10–4 mg/dL)
and from 141 40 to 140 31 mg/dL in the metformin group (P = 0.006
versus placebo; mean decrease 1.04; 95% CI; 27 to 9 mg/dL). The
mean daily glucose level decreased by 13 mg/dL more in the metformin
group compared with the placebo group Fig 1.
Fig. 1. (A) Blood glucose levels measured at home. (B) Change in blood glucose levels
measured at home. Data are means with SD error bars. For each time point indicated, the first
and the second bars show values at baseline and the third and the fourth show values at
16 weeks. Blood glucose levels in the metformin group compared with the placebo group are all
significantly lower at 16 weeks (P 0.05). The change in glucose values is also significantly
greater in the metformin than in the placebo group at all times during the day (P 0.05). (From
Wulffele MG, Kooy K, Lehert P. Bets D Ogterop JC, Van Der Burg BB, Donker AJM,
Stehouwer CDA. Combination of insulin and metformin in the treatment of type 2 diabetes.
Diabetes Care 2002;25(12):2133–40; with permission.)
In one 16-week study, Rubin et al [47] demonstrated that the daily addition
of 15 and 30 mg of pioglitazone to the regimen of patients receiving a median
dose of 61 units of insulin resulted in mean FPG reductions of 36 and 49 mg/
dL and HbA1c reductions of 0.7% and 1.0%, respectively, compared with
placebo. The insulin-sparing properties of rosiglitazone were shown in a 6-
month study conducted by Raskin et al [48]. They demonstrated that the
addition of 2 and 4 mg orally twice daily of rosiglitazone improved HbA1c
T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895 873
with NPH [50]. Treatment with NPH or glargine in addition to oral therapy
in type 2 diabetic patients resulted in a decrease of fasting glucose in both
groups, reaching a plateau by 12 weeks. HbA1c declined at a predictably
slower rate, stabilizing after 18 weeks (Fig. 2) [50].
Fig. 2. (A) FPG and (B) HbA1c during the study. Values in both figures are means; error bars
indicate SE. (From Riddle MC, Rosenstock J, Gerich J. The Treat-to-Target Trial: Randomized
addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes
Care 2003;26(11):3080–6; with permission.)
T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895 875
Dose adjustment
Once the fasting blood glucose concentrations are consistently in a desir-
able range, the pre-lunch, pre-dinner, and bedtime blood sugar values must
be monitored to determine if the oral hypoglycemic agents are maintaining
daylong glycemia. It is recommended that after the addition of evening
insulin patients continue to take the maximal dose of the oral sulfonylurea
agent. If the daytime blood glucose concentrations become excessively low,
the dose of oral medication must be reduced. The morning dose of sul-
fonylurea should be reduced or discontinued first. This situation is common
because glucose toxicity may be reduced because of improved glucose
control, leading to enhanced sensitivity to both oral agents and insulin. If
the pre-lunch and pre-dinner blood glucose concentrations remain exces-
sively high on combination therapy, it is likely that the oral agents are not
contributing significantly to glycemic control throughout the day. In this
situation, a more conventional or intensive regimen of two injections per
day is indicated.
Multiple-injection regimens
One of the most common insulin regimens used in type 2 diabetes mellitus
is the split-mixed regimen consisting of a pre-breakfast and pre-dinner dose
of intermediate- and fast-acting insulin. This split-mixed regimen of two
injections per day is often inadequate for patients with type 1 or lean
patients with type 2 diabetes and can result in persistent early morning
hypoglycemia and fasting hyperglycemia. Such problems do not appear to
occur as frequently in obese type 2 diabetes. This is likely caused by
pathophysiologic differences, particularly in endogenous insulin secretory
ability, insulin resistance, and counter-regulatory mechanisms in type 1 and
type 2 diabetes.
T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895 877
human insulin 70/30. The patients were randomized to receive one of two
treatment sequences: therapy twice per day with Humalog Mix 75/25 in-
jected before morning and evening meals for 3 months, after which they
were crossed over to receive human insulin 70/30 using the same dosing
frequency for an additional 3 months, or the alternate treatment sequence.
Patients performed self-monitoring blood glucose (SMBG) at scheduled
intervals during the study period (preprandial, 2-h postprandial, and
occasional 3 AM readings) and recorded this information along with any
hypoglycemic episodes in a study diary. Mean insulin doses were similar or
identical between treatments. Blood glucose values after the morning meal
were significantly lower during treatment with Humalog Mix 75/25
(Humalog Mix 75/25 8.95 2.17 versus human insulin 70/30 10.00
2.28 mmol/L, P = 0.017). Treatment with Humalog Mix 75/25 produced
similar significant blood glucose results 2 hours after the evening meal as
well (Humalog Mix 75/25 9.28 2.15 versus human insulin 70/30 10.27
2.76 mmol/L, P = 0.014). Blood glucose results at other time points, HbA1c
levels, daytime hypoglycemia, and nocturnal hypoglycemia were not sig-
nificantly different between treatments. Compared with human insulin 70/
30, twice-daily injections of Humalog Mix 75/25 in patients with type 2
diabetes resulted in improved postprandial glycemic control after the
morning and evening meals, similar overall glycemic control, and the added
convenience of administration immediately before meals.
Insulin aspart, another rapid-acting insulin analog, is available in a
premixed formulation with a protamine-retarded insulin aspart called
Novolog Mix 70/30 (70% insulin aspart protamine suspension and 30%
insulin aspart). A comparison study [58] of the pharmacokinetic and
pharmacodynamic parameters of the Novolog Mix 70/30 and human
insulin 70/30 in healthy patients showed that the faster onset and greater
peak action of insulin aspart was preserved in the aspart mixture.
Another study [59] compared premixed aspart mixture 70/30 with
premixed human insulin 70/30 administered twice daily in a randomized
12-week open-label trial in 294 patients with type 1 and type 2 diabetes.
Patients were instructed to inject the human insulin 70/30 30 minutes before
morning and evening meals and the premixed aspart mixture 10 minutes
before morning and evening meals. SMBG levels and hypoglycemia
incidence were recorded in diaries. Patients required a small increase in
the total daily aspart mixture dose compared with human insulin 70/30
(mean difference at 12 weeks [95% CI 0.01; 0.05]), P 0.01; 0.03 U/kg.
There was no significant difference in HbA1c between groups, yet the mean
blood glucose values after treatment with the aspart mixture showed
statistically significant treatment differences after breakfast, before lunch,
after dinner, and at bedtime. Blood glucose values were approximately
1.0 mmol/L lower compared with the human insulin 70/30 group at each
time point (P 0.05). The incidence of hypoglycemia was not found to be
different between the two groups, and weight gain was not significant during
880 T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895
the study period with either type of insulin. Treatment with twice-daily
premixed aspart mixture 70/30 resulted in similar overall glycemic control;
yet postprandial control improved without additional hypoglycemia and
with injections immediately before meals compared with premixed human
insulin 70/30 given 30 minutes before the meal.
In a more recent study that focused on changes in lipid levels, Schwartz
et al [60] compared insulin 70/30 mix taken twice per day plus metformin
versus triple oral therapy (secretagogues, metformin, and thiazolidine-
diones) and clearly demonstrated that insulin plus metformin are superior
in lowering total cholesterol and triglycerides levels. The baseline values for
total cholesterol, low-density lipoprotein, high-density lipoprotein, and
triglycerides indicated no differences between the triple OHA and insulin/
metformin groups. By the end of the study (week 24) significant decreases in
total cholesterol and triglycerides were evident in the insulin plus metformin
group (P = 0.038 and 0.033, respectively, compared with the triple oral
therapy group). Subjects in the triple oral therapy group showed a small
increase in cholesterol and less of a decrease in triglyceride levels [60]. For
glucose control, both groups had similar FPG values at the beginning of the
study. After 24 weeks of treatment, the changes from baseline mean FPG
values were 55 and 65 mg/dL for the triple oral therapy and insulin plus
metformin, respectively [60]. Baseline HbA1c values were 9.62 1.25% for
subjects in the triple oral therapy and 9.65 1.62% in the insulin group.
HbA1c values at weeks 2 and 6 demonstrated the efficacy of both treatments;
however, insulin plus metformin treatment achieved improvements in
HbA1c values at weeks 2 and 6 (9.03 1.35% and 8.11 1.20%,
respectively) that were significantly greater than the response to triple oral
therapy (P = 0.001 and 0.001, respectively). At weeks 12 and 24, no
statistically significant difference in HbA1c between the two groups were
observed (final values at week 24 were 7.59 1.4% for triple oral therapy
and 7.59 1.25% for insulin plus metformin [P = 0.772]) (Fig. 3) [60].
Along with SMBG, the use of rapid-acting premixed insulin analogs is
convenient and can be beneficial in reducing postprandial hyperglycemia
and in helping patients achieve glycemic control without the increased
incidence of hypoglycemia. In addition, protocols are currently underway to
assess the efficacy of using rapid-acting premixed insulin analogs three times
per day before breakfast lunch and dinner, based on HGM data. This
regimen is more related to a basal bolus strategy discussed below.
Basal–bolus strategy
The basal–bolus insulin strategy, which can be used in patients with
either type 1 or type 2 diabetes, incorporates the concept of providing
continuous basal insulin levels throughout the day and night with brief
increases in insulin levels at the time of meal ingestion by bolus doses.
T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895 881
Fig. 3. (A) Mean FPG values at screening and weeks 12 and 24 by treatment group. No
statistically significant changes were observed between the triple oral therapy (•) and insulin
plus metformin (). (B) Mean SEM changes for the total cholesterol, HDL, LDL, and
triglycerides at week 24. * Statistically significant (P 0.05) reduction in total cholesterol and
triglyceride levels in the insulin plus metformin group compared with the triple oral therapy
group. HDL, high-density lipoprotein; LDL, low-density lipoprotein; OHA, XXX. (From
Schwartz S, Sievers R, Strange P Lyness W, Hollander P. Insulin 70/30 mix plus metformin
versus triple oral therapy in the treatment of type 2 diabetes after failure of two oral drugs:
efficacy, safety, and cost analysis. Diabetes Care 2003;26(8):2598–603; with permission.)
The use of pre-meal regular insulin with bedtime NPH as the basal insulin
has been a common strategy for intensive insulin therapy in the United
States, but because regular insulin should be administered 20 to 40 minutes
before meals, a risk of hypoglycemia exists if the meal is delayed. If regular
882 T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895
insulin is given just before a meal, high postprandial glucose levels and
delayed hypoglycemia may result. A strategy that provides for some
flexibility in the mealtime administration of insulin with the use of rapid-
acting insulin analogs, lispro or aspart, administered immediately before
meals, and long-acting insulin, such as glargine, ultralente, lente, or NPH as
the basal insulin. These regimens that use multiple doses of intermediate-
acting insulin such as NPH can be associated with unpredictable nocturnal
hypoglycemia and day-to-day instability of blood glucose patterns in part
because of intrapatient variability of the effect of subcutaneous injected
insulin and the patient’s peak action profile [61]. NPH, which exhibits peak
action 5 to 7 hours after administration, has also been used in combination
with rapid-acting insulin analogs, commonly given at least twice daily,
although the disadvantages of NPH used in this manner are similar to those
associated with Ultralente [62]. Because of its time to peak action, NPH
should be given every 6 hours or 4 times per day to be effective as a basal
insulin, in many patients [63].
Improved mealtime glucose control with the rapid-acting analogs has
exposed the gaps in basal insulin coverage provided by therapy with the
traditional intermediate- and long-acting insulin preparations. Taking
a basal insulin analog with a relatively constant and flat pharmacokinetic
profile such as insulin glargine once per day will result in a more
physiologic pattern of basal insulin replacement. Insulin glargine in
combination with a rapid-acting insulin analog has demonstrated effective
glycemic control and a lower incidence of nocturnal hypoglycemia [64] than
other insulin preparations currently used for basal insulin supplementation
[64–68].
Patients on multiple-injection basal–bolus regiments should use carbo-
hydrate counting to estimate their pre-meal bolus dose of a rapid-acting
analog. In addition, a correction factor should be determined by HGM
before and after rapid-acting insulin boluses. For example, a typical
insulin-resistant subject with type 2 diabetes may need 1 unit of lispro or
aspart for every 8 g of carbohydrate compared with a 1:15 ratio for a lean
insulin-sensitive person with type 1 diabetes. A typical correction factor
would be 1 unit of lispro or aspart to bring down the blood glucose value
to 25 mg/dL compared with a person with type 1 diabetes whose cor-
rection factor is 1 unit of lispro or aspart to bring down the blood glucose
value to 50 mg/dL. The carbohydrate to insulin ratio and correction factor
may be different depending on the time of the day and degree of
hyperglycemia.
The availability of mealtime and basal insulin analogs, combination
therapy with oral agents, and the use of insulin regimens comprising
basal and mealtime (bolus) insulin components that better simulate
normal insulin secretion represent important advances in insulin therapy.
All of these approaches can have a significant impact on treatment
outcomes.
T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895 883
uptake increased from 12.7 5.7 to 22.4 8.8 lmol/kg/min (P 0.0005), and
in 1 month of intensive therapy, the HbA1c dropped to 8.9% 1.2% with no
significant change in the patients’ body weight. After 6 and 12 months of CSII
therapy, the mean HbA1c values were 7.1 0.6% and 8.3 1.4%, respectively
(P 0.001 versus pretreatment values for all time points) [71].
In another recent study [72], 132 CSII naıı̈ve type 2 diabetics were
randomized to the pump or multiple daily injections (MDI). This study
showed that pump therapy provided efficacy and safety equivalent to MDI
therapy. Lower 8-point blood glucose values were shown by the CSII group at
most time points (values were only significant 90 min after breakfast; 167
47.5 mg/dL versus 192 65.0 mg/dL for CSII and MDI, respectively;
P = 0.019) (Fig. 4).
In summary, insulin pump therapy has not been fully evaluated in
patients with type 2 diabetes. From published studies, however, it is
apparent that CSII therapy can safely improve glycemic control while
limiting hypoglycemia. CSII may be particularly useful in treating patients
with type 2 diabetes who do not respond satisfactorily to more conventional
insulin treatment strategies.
Fig. 4. Baseline and end-of-study 8-point blood glucose profiles (mean SEM) for the intent-
to-treat population. Dashed lines represent baseline profiles; solid lines represent end-of-study
profiles; •, means for CSII; n, means for MDI therapy. Number of patients at each time point:
CSII, 56–63; MDI, 54–59. *P, 0.02. BB, before breakfast; B90, 90 minutes after breakfast;
BL, before lunch; L90, 90 minutes after lunch; BD, before dinner; D90, 90 minutes after dinner;
BE, at bedtime. (From Raskin P, Bode BW, Marks JB, Hirsh IB, Weinstein RL, McGill
JB, Peterson GE, Mudaliar SR, Reinhardt RR. Continuous subcutaneous insulin infusion and
multiple daily injection are equally effective in type 2 diabetes: a randomized, parallel-group,
24-week study. Diabetes Care 2003;26(9):2598–603; with permission.)
886 T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895
Fig. 5. Glucose infusion rate (GIR) registered following administration of inhaled insulin (¤,
80 units; n,160 units; •, 240 units) and subcutaneous injection (}, 8 units; , 16 units; , 24
units) in patients with type 2 diabetes. GIRs have been averaged over 30-minute periods. Data
points are means SE (n = 16) at each time point for low, medium, and high doses for inhaled
and injected insulin. (From Kim D, Mudaliar S, Chinnapongse S, Chu N, Boies SM, Davis T,
Perera AD, Fishman RS, Shapiro DA, Henry R. Dose-response relationships of inhaled insulin
delivered via the Aerodose insulin inhaler and subcutaneously injected insulin in patients with
type 2 diabetes. Diabetes Care 2003;26(10):2842–7; with permission.)
peak excursion. The HIM2 and subcutaneous insulin curves remain nearly
indistinguishable for at least another hour. During the fourth hour
postdose, the HIM2 curve clearly separates from the subcutaneous insulin
curve, becoming nearly identical to the placebo curve, as the glucose
excursion values in all three groups decline toward baseline. Peripheral
plasma insulin revealed an initial peak in peripheral plasma insulin
concentrations following administration of HIM2; however, this initial
insulin peak was caused by one patient who had a rapid peak of insulin. The
median insulin Cmax values, following administration of HIM2 and sub-
cutaneous regular insulin, were nearly identical (Fig. 6) [76].
=
Fig. 6. 0.5 mg/kg and 1.0 mg/kg HIM2 dose groups; pooled data. (A) Mean plasma glucose
excursion versus time profiles and (B) mean plasma insulin concentration versus time profiles.
At time 0, patients received 0.5 or 1.0 mg/kg oral HIM2, 8 units subcutaneous regular insulin or
oral placebo. At 30 min, patients began ingesting the standardized meal (Boost Plus). Patients
ingested the entire meal over a 10-minute period. Postprandial plasma glucose excursions and
insulin concentrations were determined from blood samples collected a the time points
indicated. Data are expressed as means SE (n = 12 patients). , oral HIM2 (0.5) and 1.0 mg/kg
dose groups combined); , 8 units of subcutaneous regular insulin; , oral placebo. (From Kipnes
M, Dandona P, Tripathy D, Still JG, Kosutic G. Control of postprandial plasma glucose by an
oral insulin product (hexyl-insulin monoconjugate 2 [HIM2]) in patients with type 2 diabetes.
Diabetes Care 2003;26(2):421–6; with permission.)
890 T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895
Fig. 7. Change from baseline in mean HbA1c (A) and weight (B) (intent-to-treat population).
* P 0.05 for treatment arm versus placebo. , placebo; n, 90 lg twice daily; •, 120 lg. (From
Hollander PA, Levy P, Fineman MS, Maggs DG, Shen LZ, Strobel SA, et al. Pramlintide as
an adjunct to insulin therapy improves long-term glycemic and weight control in patients with
type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care 2003;26(3):784–90; with
permission.)
Summary
Type 2 diabetes is a common disorder often accompanied by numerous
metabolic abnormalities leading to elevated rates of cardiovascular morbid-
ity and mortality. Improved glycemia will delay or prevent the development
of microvascular disease and reduce many or all of the acute and subacute
complications that worsen the quality of daily life. Exogenous insulin is
T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895 891
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Med Clin N Am 88 (2004) 897–909
0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2004.04.004
898 R.M. Krauss, P.W. Siri / Med Clin N Am 88 (2004) 897–909
been identified (Fig. 1) [14]. Plasma VLDL levels correlate positively with
increased density and decreased size of LDL [15,16], and increased
concentrations of small, dense LDL in turn have been shown to be
associated with reduced plasma HDL levels [17]. Importantly, the residence
time of small, dense LDL in plasma may be prolonged, given their relatively
reduced affinity for the LDL receptor [14].
LPL
IDL 2 LDL I
Liver
TG
TG
CETP
LPL LPL HL Smaller
1 2 VLDL 2 IDL 1 LDL II LDL
TG TG
CETP
LPL LPL/HL HL
VLDL 1 Remnants LDL III Smaller
LDL
TG
CETP
larger LPL
Remnants LPL/HL HL
VLDL 1 LDL IV Smaller
LDL
Fig. 1. Hypothetical metabolic scheme incorporating proposed pathways for the production of
major LDL subclasses I, II, III, and IV. The properties of triglyceride-rich lipoproteins secreted
by the liver are determined by the operation of multiple pathways (1 and 2) and by hepatic TG
availability. In pathway 1, triglyceride-rich VLDL-1 and triglyceride-poor IDL-2 particles are
coordinately produced. VLDL-1 production results from a discrete quantity of lipid on
a precursor particle. Lipolysis of VLDL-1 yields remnants, which in turn yield LDL-III by
hepatic lipase. Further remodeling of these particles may occur by CETP-mediated triglyceride
enrichment and hepatic lipase-mediated lipolysis. Pathway 2, which results in the production of
VLDL-2, is distinct from pathway 1 and gives rise to IDL-1 and LDL-II by lipolysis. Further
processing by CETP-mediated transfer of triglycerides into LDL-II and lipolysis by hepatic
lipase yields smaller and denser LDL products. CE, cholesteryl esters; LPL, lipoprotein lipase.
(From Berneis KK, Krauss RM. Metabolic origins and clinical significance of LDL
heterogeneity. J Lipid Res 2002;43:1363–79; with permission.)
900 R.M. Krauss, P.W. Siri / Med Clin N Am 88 (2004) 897–909
lipoprotein particles are reduced in core volume and surface and are either
cleared through remnant removal pathways or moved along the delipidation
pathway where they are converted into less buoyant LDL particles. HL is
responsible for the hydrolysis of phospholipids in LDL and HDL particles;
its increased activity in the setting of insulin resistance has been associated
with smaller and denser LDL particles and a decrease in HDL2 particles
because the latter are more rapidly cleared from plasma.
Lipid-lowering agents
Statins (HMG-CoA reductase inhibitors)
Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in choles-
terol biosynthesis, thereby increasing LDL receptor activity and stimulating
the clearance of lipoprotein particles from plasma. Statins also inhibit the
secretion of lipoprotein particles from the liver. In addition to lowering
LDL, statins have been shown to lower plasma TG levels and to raise HDL
cholesterol, albeit to varying degrees. All subclasses of LDL and IDL are
reduced to an equivalent extent, although there have been reports of greater
lowering of small LDL in conjunction with TG reduction [52]. Most studies,
however, have not demonstrated a reversal of the small, dense LDL
phenotype with statin treatment.
Niacin
Niacin, or nicotinic acid, has been shown to significantly reduce TG
concentrations, increase HDL cholesterol levels, and increase LDL particle
size and buoyancy. Niacin reduces FFA release from adipose tissue and
suppresses the hepatic production of VLDL. These changes effectively
decrease plasma TG levels and reduce the number of small, dense LDL
R.M. Krauss, P.W. Siri / Med Clin N Am 88 (2004) 897–909 903
particles. The effect of niacin on HDL cholesterol levels has been shown to
be mediated by reduced activity of the receptor responsible for the intra-
hepatic degradation of HDL [60]. Reducing the uptake of HDL elongates
the half-life of these particles in plasma.
Concern regarding the adverse effects of niacin on glycemic control has
discouraged its use in type 2 diabetics. However, a recent clinical trial [61]
indicates that the worsening of glycemic control with niacin treatment may
be limited to high doses. Extended-release niacin administered at 1000 and
1500 mg/d was effective in significantly increasing HDL cholesterol levels
and decreasing TG levels, relative to placebo treatment. Only the group of
patients receiving 1500 mg/d of niacin showed adverse changes in glycemic
control; concentrations of glycosylated hemoglobin increased from 7.2% at
baseline to 7.5% after 16 weeks of niacin therapy (P = 0.048, relative to
controls). Although four patients discontinued therapy because of inadequate
glycemic control, most patients were able to tolerate niacin therapy.
Antidiabetic agents
Thiazolidinediones
TZDs (PPAR-c agonist) have been shown to lower glucose concen-
trations in type 2 diabetes by improving peripheral insulin sensitivity and
thereby promoting glucose uptake. TZDs have also been shown to reduce
hepatic glucose production [62] and decrease plasma FFA levels [63]. As an
agonist of PPAR-c, TZD stimulates genes involved in adipocyte differen-
tiation. Although not indicated for the treatment of dyslipidemia, these
agents have been shown to improve lipid abnormalities associated with type
2 diabetes. Use of rosiglitazone and pioglitazone has been shown to increase
HDL cholesterol levels in patients with diabetes. Although TZDs tend to
increase total and LDL cholesterol, they induce favorable changes in LDL
particle size and susceptibility to oxidation [64]. Plasma TG levels are
generally decreased with pioglitazone therapy [65–67] and have also been
shown to be reduced with rosiglitazone in hypertriglyceridemic patients [68].
In a randomized controlled clinical trial, treatment with rosiglitazone for 8
weeks led to significant increases in HDL cholesterol (6%) and HDL2 levels
(13%) and a shift of 71% of patients initially presenting with small, dense LDL
to a phenotype of more buoyant and, thus, less atherogenic LDL particles.
Combination therapy with atorvastatin led to an even greater increase in HDL
(5%) as well as significant decreases in LDL cholesterol (ÿ30%) and TG
(ÿ27%) [69]. Pioglitazone has also been shown to be effective in ameliorating
the syndrome of dyslipidemia in several studies conducted in patients with
type 2 diabetes [70,71]. A recent study [72] in nondiabetic patients with arterial
hypertension shows a significant reduction in small, dense LDL after 16 weeks
of pioglitazone treatment. At baseline, 66% of the study group had elevations
in small, dense LDL; and treatment with pioglitazone resulted in a 22%
reduction in the levels of small, dense LDL particles.
904 R.M. Krauss, P.W. Siri / Med Clin N Am 88 (2004) 897–909
Metformin
Metformin is a biguanide that has been proven to be an effective
hypoglycemic agent [73]. The drug lowers fasting glucose and insulin levels
by improving insulin sensitivity, inhibiting hepatic gluconeogenesis, and
stimulating peripheral glucose uptake [74]. Importantly, this agent has been
shown to decrease cardiovascular disease risk in type 2 diabetics, in-
dependently of its effects on glycemic control [75]. Studies have shown that
metformin improves lipoprotein profiles in patients with type 2 diabetes and
insulin resistance [76]. It decreases plasma FFA as well as TG[77], decreases
total and LDL cholesterol [78,79], and maintains [78] or increases [77,79]
HDL cholesterol levels. Improvements in the components of type 2 diabetes-
associated dyslipidemia likely contribute to the cardioprotective effect of
metformin.
Summary
Abnormal lipid metabolism often presents in patients with type 2
diabetes. Resistance to insulin likely underlies the changes that occur in
lipid parameters. Increased FFA availability can drive the secretion of TG-
rich lipoproteins from the liver, and this increased TG substrate can lead to
reductions in HDL cholesterol as well as the conversion of LDL particles
into particles that are smaller and denser. The combination of elevated TG,
reduced HDL cholesterol, and smaller and denser LDL particles typifies the
dyslipidemia associated with type 2 diabetes and insulin resistance. Each of
these lipid changes has been independently associated with increased
cardiovascular disease risk. A variety of treatment options exist, and
changes in lifestyle and behaviors known to adversely alter lipid metabolism
should be key components of any program designed to manage atherogenic
dyslipidemia. Effective pharmacologic therapies include lipid-lowering
agents, such as statins, fibrates, and niacin, as well as antidiabetic agents,
such as the thiazolidinediones and metformin. Treatment with these agents
alone or in combination has been shown to correct the lipid abnormalities
associated with type 2 diabetes and reduce the risk of cardiovascular disease.
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Med Clin N Am 88 (2004) 911–931
* Corresponding author.
E-mail address: pdandona@kaleidahealth.org (P. Dandona).
0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2004.04.006
912 P. Dandona et al / Med Clin N Am 88 (2004) 911–931
still not totally clear, however, what the specific mediator of hypertension in
diabetes is.
Table 1
Benefits of blood pressure control; placebo-controlled trials
Eligibility BP difference
(mm Hg)
Step therapy (BP at entry Duration
Trial vs placeboa mm Hg) (yrs) Sy Di CVDb Microb
SHEP 1. Chlorthalidone
2. Atenolol HTN (170/77) 5 9.8 2.2 # 34% N/A
3. Reserpine
Syst-Eur 1. Nitrendipine HTN (175/85) 2 8.6 3.9 # 69% N/A
2. Enalapril
3. Hctz
HOPE Ramipril CVD/CVDRF 4.5 2.4 1 # 25% #16%c
(142/80)
RENAAL Losartan DM, nephro 3.4 2 0 # 10% (NS) # 21%d
(152/82)
IPDM Irbesartan HTN, DM, 2 3 0 N/A # 70%e
microalbumin
(153/91)
Abbreviations: BP difference, difference in BP between the treated and placebo groups; Di,
diastolic; DM, diabetes mellitus; HOPE, Heart Outcomes and Prevention Evaluation; HTN,
hypertension; IPDM, Irbesartan in Patients with type 2 Diabetes and Microalbuminuria;
nephro, nephropathy; NS, nonsignificant; N/A, not available; RENAAL, Reduction of
Endpoints in NIDDM with Angiotensin II Antagonist Losartan; RF, risk factor; SHEP,
Systolic Hypertension in the Elderly Program; Syst-Eur, Systolic Hypertension in Europe; Sy,
systolic.
a
Agents added sequentially if BP goal was not achieved.
b
Reduction in CVD (cardiovascular disease) and Micro (microvascular complications) in
the treated group compared with placebo.
c
Reduction in overt nephropathy albumin/creatinine >36 mg/mmol, laser therapy, dialysis.
d
Nephropathy, albumin/creatinine >300 mg/g, creatinine 1.3–3 mg/dl, 21% decrease in
doubling of serum creatinine and end-stage renal disease.
e
70% reduction in the risk of overt nephropathy for irbesartan 300 mg.
channel blocker (CCB) agents were safe and effective in reducing blood
pressure and in reducing CV complications.
In a subgroup analysis of the Heart Outcomes and Prevention Evaluation
(HOPE) study [80], subjects with diabetes and an additional risk factor for
atherosclerosis or a history of CV disease were randomized to ramipril,
10 mg or placebo. Subjects had a baseline BP of 142/80 mm Hg, the ramipril
treated group had a BP fall of 2.4/1 mm Hg at the end of the study
compared with the placebo-treated group. Ramipril-treated patients had
a 25% reduction in CV outcomes, 24% reduction in total mortality, and
a 16% reduction in microvascular endpoints. This effect of ramipril was
significant even after adjusting for the blood pressure differences. Another
arm of this study demonstrated a significant ramipril-induced decrease in
progression of carotid intimal-media thickness [81].
In the Reduction of Endpoints in NIDDM with the Angiotensin II
Antagonist Losartan (RENAAL) study [82], 1500 subjects with type 2
916 P. Dandona et al / Med Clin N Am 88 (2004) 911–931
Table 2
Trials targeting different levels of BP control
Achieved BP
Target BP
(mm Hg)
(mm Hg)
Trial Step therapya control Active Control Active CVDb Microb
HOT 1. Felodipine 5 mg
2. b-Blocker or Diastolic BP Diastolic BP 144/85 140/81 # 51% N/A
ACE inhibitor
3. " Felodipine
to 10 mg
4. " step2 drug \90 \80
5. Diuretic
UKPDS 1. Captopril
or atenolol
2. Furosemide
3. Nifedipine SR \180/105 \150/85 154/87 144/82 # 34%c # 37%d
4. Methyldopa
5. Prazosin
ABCD 1. Nisolodipine Diastolic BP Diastolic BP 138/86 132/78 NSe NS
or enalapril
2. Metoprolol
3. Hctz \75 80–90
Abbreviations: ABCD, Apropriate Blood Pressure Control in Diabetes; HOT, Hypertension
Optimal treatment; UKPDS, United Kingdom Prospective Diabetes Study.
a
Agents added sequentially if BP goal was not achieved.
b
Reduction in CVD (cardiovascular disease) and Micro (microvascular complications) in
the active group compared with the control group.
c
Included a # diabetes related death by 32%, stroke by 44%, heart failure by 56%.
d
Included a 47% reduction in deterioration of visual acuity.
e
Reduction in mortality by 49%.
endpoint, deaths related to diabetes, stroke, and heart failure. There was
also a 37% decrease in microvascular complications, primarily because of
a decrease in retinal photocoagulation, and an improvement in visual acuity.
It was estimated that for every 10 mm Hg of decrease in systolic blood
pressure, there is a 12% reduction in a diabetes related endpoint, a 15%
reduction in death because of diabetes, an 11% reduction in myocardial
infarction, and a 13% decrease in microvascular complications [86]. There
was no threshold of risk, and the best outcomes were seen in subjects with
a systolic BP of less than 120 mm Hg. The benefits of better blood pressure
control were greater than that of improvement in glycemic control
(glycosylated hemoglobin 7.9% versus 7.0%), with a 2- to 5-fold greater
absolute risk reduction and much lower numbers needed to treat [87]. The
benefits of blood pressure lowering, however, were seen in both the
conventional and intensively treated groups, and the benefits of glycemic
control were seen in the aggressively and conservatively targeted blood
pressure groups [85]. Thus, treatment of a single risk factor does not
eliminate the risk of complications, and all risk factors need to be
918 P. Dandona et al / Med Clin N Am 88 (2004) 911–931
Table 3
Trials comparing specific anti-hypertensive therapies on cardiovascular outcomes
Trial Reference Active CVDa Microa
ACE I vs calcium channel blockers
FACET Amlodipine Fosinopril # 51% N/A
ABCD Nisolidipine Enalapril # 57% N/A
STOP-2 Isradipine/felodipine Enalapril/lisinopril NSb N/A
ACE I vs b-blocker/diuretic
STOP-2 b-Blocker diuretic Enalapril/lisinopril NS N/A
CAPP b-Blocker diuretic Captopril # 41%c N/A
UKPDS Atenolol Captopril NS NS
ALLHAT Chlortahlidone Lisinopril NSd NS
Calcium channel blocker vs b-blocker/diuretic
NORDIL b-Blocker diuretic Diltiazem NSe N/A
INSIGHT Coamilozide Nifedipine GITS NS N/A
ALLHAT Chlorthalidone Amlodipine NSf N/A
STOP-2 b-Blocker diuretic Enalapril/lisinopril NS N/A
ARB vs b-blocker
LIFE Atenolol Losartan # 24% N/A
ARB vs calcium channel blocker
IDNT Amlodipine Irbesartan NS # 23%
Abbreviations: ABCD, Appropriate Blood pressure Control in Diabetes; ALLHAT, Anti-
hypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial; CAPP, Captopril
Prevention Project; FACET, Fosinopril versus Amlodipine Cardiovascular Events Trial;
IDNT, Irbesartan Diabetic Nephropathy trial; INSIGHT, International Nifedipine GITS
Study: Intervention as a Goal in Hypertension Treatment; LIFE, Losartan Intervention for
Endpoint reduction; NORDIL, Nordic Diltiazem; NS, non significant; N/A, not available;
STOP-2, Swedish Trial in Old Patients with Hypertension-2; UKPDS, United Kingdom
Prospective Diabetes Study.
a
Reduction in CVD (cardiovascular disease) and Micro (microvascular complications) in
the active group compared to the reference group.
b
Reduction in myocardial infarction by 49% in ACE I group.
c
Reduction in myocardial infarction by 66%.
d
22% increase in heart failure in lisinopril group.
e
20% reduction in stroke with diltiazem.
f
42% increase in heart failure with amlodipine.
enalapril [88]. Blood pressure reduction was similar in both arms, but by the
end of the trial, half the subjects were not taking the initially assigned
treatment. In an intention-to-treat analysis, the subjects in the nisoldipine
group had a 5 times higher risk of myocardial infarction (a secondary
endpoint) that was attributed to a beneficial effect of ACE inhibition rather
than an adverse effect of nisoldipine.
In the Fosinopril versus Amlodipine Cardiovascular Events Trial
(FACET) [97], 380 diabetic subjects were randomly assigned to Fosinopril
or Amlodipine. Although the Amlodipine group had a lower systolic blood
pressure than the Fosinopril group, combined CV events were significantly
lower in the fosinopril group primarily because of a difference in the number
920 P. Dandona et al / Med Clin N Am 88 (2004) 911–931
of subjects with hospitalized angina (0 versus 4). The trial was designed to
study treatment-related differences in serum lipids and diabetes control, with
CV endpoints as secondary outcomes. This was also an open-label study,
and if the blood pressure goal was not attained on the assigned study drug,
the other study drug was added. The best outcomes were seen in the subjects
receiving both drugs (108 subjects).
In the Swedish Trial in Old Patients with Hypertension (STOP)-2 [98],
CCB, ACE I, and diuretics plus b-blockers were compared with each other.
Blood pressure lowering was similar between the groups with no difference
in combined CV events or total mortality. However, myocardial infarction
was significantly lower and strokes non-significantly higher in patients
treated with ACE I compared with CCB.
The largest hypertension trial to date, the Antihypertensive and Lipid
Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [99],
compared the effectiveness of a thiazide diuretic (chlorthalidone), an ACE
I (lisinopril), a CCB (Amlodipine), and an a1-blocker (Doxazosin) as an
initial treatment for hypertension in patients at high risk for a CV event. The
doxazosin arm was suspended early because of an increase in the incidence
of heart failure. The primary outcome was combined nonfatal and fatal
myocardial infarction. Secondary outcomes were all-cause mortality, stroke,
combined coronary heart disease (primary outcome, coronary revascular-
ization or angina with hospitalization), and combined CVD (combined
coronary heart disease, stroke, angina without hospitalization, heart failure,
and peripheral arterial disease). Systolic blood pressure was the lowest in the
diuretic group whereas diastolic blood pressure was the lowest in the
Amlodipine group. In a pre-specified subgroup analysis of 12,063 type 2
diabetics, the incidence of heart failure was the lowest in the diuretic group
compared with lisinopril (RR 1.22 [confidence interval {CI}, 1.05–1.42]) and
Amlodipine (RR 1.42 [CI, 1.23–1.64]). Combined CVD was higher in the
ACE I group compared with the diuretic group (RR 1.08 [CI, 1.00–1.17])
primarily because of a higher risk of heart failure and stroke in the black
population; systolic blood pressure was 4 mm Hg higher than the diuretic
group in this population. There was no difference between the groups with
regard to other outcomes in the diabetic population. Forty percent of the
patients required two medications and one third did not reach the BP goal
of 140/90 mm Hg. Microvascular endpoints are also being evaluated, but
they have not yet been reported. There have been numerous explanations of
the results of the ALLHAT. One explanation is the withdrawal of diuretics
in patients receiving this treatment in the ACE inhibitor and Amlodipine
arm at the beginning of the study, which may have unmasked heart failure
in these patients and therefore resulted in the higher incidence of this
complication in these groups. The other explanation is the inability to use
diuretics in the ACE inhibitor arm, a combination that is commonly used in
clinical practice to enhance the BP-lowering effects of ACE I in blacks. On
the basis of these arguments, it has been suggested that ALLHAT should be
P. Dandona et al / Med Clin N Am 88 (2004) 911–931 921
captopril on slowing the progression of renal disease [106]. There was a 50%
reduction in the endpoints of death, dialysis, transplantation, and doubling
of serum creatinine with captopril, compared with placebo. Although mean
arterial blood pressure was lower by 2 mm Hg in the captopril group, this
effect was shown to be independent of the BP lowering. Studies in type 1
diabetics with microalbuminuria in both hypertensive and normotensive
populations have also shown a reduction in progression to macroalbumi-
nuria and in regression to normoalbuminuria [107]. A recent trial [108] has
also shown an improvement in microalbuminuria unrelated to ACE
inhibition in type 1 diabetics. In this trial, one of the factors associated
with regression of microalbuminuria was a systolic BP less than 115 mm Hg.
ACE I has also been shown to reduce the risk of retinopathy and
neuropathy in type 1 diabetes [109,110].
In type 2 diabetes, ACE I, ARB, b-blockers and nondihydropyridine
CCBs have been shown to reduce the progression to nephropathy and
decline in renal function in micro- and macroalbuminuric normotensive and
hypertensive subjects [82,83,102,106,107,111]. Data regarding a renoprotec-
tive effect in overt nephropathy, however, are most convincing for ARBs
because they have been tested in large placebo-controlled clinical trials in
which the benefit has been shown to be independent of their BP-lowering
effect. Small trials [112–114] have also shown a beneficial effect of combining
ACE I and ARB, and thiazolidinediones and spironolactone on proteinuria.
Although there is little evidence regarding the prophylactic use of ACE I or
ARBs to prevent microalbuminuria, there was a nonsignificant decrease in
the development of albuminuria in the type 2 diabetics in the HOPE and
LIFE studies [80,98].
heart failure, the risks of which are high in a diabetic; and they limit the side
effects of diuretics (hypokalemia) and CCBs (edema). Moreover, therapy
with ACE I or ARB is well tolerated. Presently the only indication for
choosing an ARB over an ACE I is in patients with overt nephropathy and
those with left ventricular hypertrophy in view of the observations in
RENAAL, IDNT, and LIFE studies. Therapies with the two agents are
interchangeable if there are side effects, most commonly a cough with ACE
I. In blacks, there is also a higher incidence of angioedema with these agents.
With the initiation of ACE I therapy, a noncontinuous increase in creatinine
of up to 30% from baseline can be expected, and this should not prompt
discontinuation of this therapy [116]. Although it is associated with an
increase in the incidence of hyperkalemia, ACE I therapy in subjects with
creatinine levels greater than 3 mg/dL can delay the time to dialysis and
confer CV protection in these high-risk patients [116,117].
Combination therapy with a diuretic and ACE I or ARB should be
considered if blood pressure lowering of greater than 15 mm Hg systolic or
10 mm Hg diastolic is required; however, it should be initiated carefully in
subjects at a risk for orthostatic hypotension. In subjects with coronary
artery disease (CAD) and heart failure, b-blockers should be instituted
along with ACE I or ARB because they are known to improve prognosis in
these conditions [118]. If BP is inadequately controlled with a combination
of ACE I or ARB and diuretic, the present authors still favor the use of b-
blockers as the third-line agent, even in the absence of CAD or heart failure.
This recommendation is based on the increased prevalence of asymptomatic
heart disease and autonomic neuropathy in diabetics, the increased risk of
CAD and heart failure in this population, and the evidence of equal efficacy
to ACE inhibition in the UKPDS. b-blockers, however, have been shown to
be less efficacious in the elderly, less tolerated in clinical studies, and
associated with mild weight gain in the UKPDS trial.
In subjects with proteinuria, there is evidence that suggests a beneficial
effect of nondihydropidine CCB, and in the National Kidney Foundation
guidelines, these agents are the preferred third-line agents in the treatment of
hypertension. There is also evidence regarding a synergistic effect of CCBs
when combined with ACE I. In both the HOT and HOPE trials,
approximately 45% of the subjects were taking this combination therapy,
and the best outcomes in FACET were seen in the group taking this
combination. CCBs are also more effective than b-blockers and ACE I in
lowering BP in the elderly. CCBs have a neutral effect on metabolic
parameters, and there are no contraindications to dihydropyridine CCBs;
however, dihydropyridine CCBs should be used in combination with ACE I
in the presence of nephropathy, and nondihydropyridine CCB should be
combined cautiously with b-blockers in the elderly because b-blockers might
lead to bradyarrhythmias. If further BP lowering is required, any other
agent can be used; however, clonidine should not be used with b-blockers
for numerous reasons including an increased likelihood of bradycardia.
924 P. Dandona et al / Med Clin N Am 88 (2004) 911–931
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OR (95% Cl)
Fig. 1. Association of endogenous sex hormones with incident diabetes by multiple logistic
regression, adjusted for baseline age, BMI, and systolic blood pressure among older men (solid
box) and women (open box) without diabetes. Sex hormone differences were analyzed as the
lowest quartile versus the top three quartiles in men and the highest quartile versus the bottom
three quartiles in women (*P 0.05). (From Oh JY, Barrett-Connor E, Wedick NM, Wingard
DL; Rancho Bernardo Study. Endogenous sex hormones and the development of type 2
diabetes in older men and women: the Rancho Bernardo Study. Diabetes Care 2002;25:55–60;
with permission.)
and each 1 standard-deviation fall in SHBG (16 nmol/L) increased the risk
by 1.89-fold (P 0.02). The latter study, however, did not have baseline
glucose and insulin levels but relied on self-reporting of diabetes.
Low testosterone levels are common in type 2 diabetics, but this could be
because of aging or caused by the high prevalence of obesity in this
population. The Rancho Bernardo study evaluated 985 men, aged 40 to 79
years, between 1972 and1974 [17]. The 110 diabetic men had significantly
lower levels of testosterone and SHBG compared with 875 nondiabetic men.
A significant difference remained after adjustment for age (Table 1).
Twenty-one percent of diabetic men compared with 13% of nondiabetic
men had testosterone levels below 350 ng/mL. The same investigator
identified 44 men with untreated type 2 diabetes mellitus over a 15-month
period. Thirty-two of these men were identified with a 75-g oral glucose
tolerance test [18]. The diabetics were compared with 44 age- and BMI-
matched men. Total testosterone levels were lower in the diabetics (P 0.05)
when compared with each of the control groups. Bioavailable testosterone
levels were lower than controls that were not matched for BMI but were
936 R.A. Hijazi et al / Med Clin N Am 88 (2004) 933–945
Table 1
Crude, age-adjusted, and age- and BMI-adjusted mean testosterone and SHBG levels by
diabetic status
Nondiabetic Diabetic
(n = 875) (n = 110) P value
Testosterone (ng/mL) 5.41 4.97
Age-adjusted 5.45 4.85 0.01
Age- and BMI-adjusted 5.35 5.10 0.08
Percentage with 21% 13% 0.05
testosterone 3.5 ng/mL
SHBG (10ÿ8 M) 329 285
Age-adjusted 327 282 0.01
Age- and BMI-adjusted 326 291 0.05
Data from Barrett-Connor E, Khaw KT, Yen SS. Endogenous sex hormone levels in older
adult men with non-insulin-dependent diabetes mellitus. Ann Intern Med 1992;117:807–11.
SHBG
SHBG levels are affected by several conditions. There is a strong
association between increased total body fat, subcutaneous and visceral
adiposity, and decreased plasma levels of SHBG [21,22]. SHBG levels were
similar in diabetic and nondiabetic men with similar fat content, but SHBG
levels vary inversely with hyperinsulinism in nondiabetic subjects [23].
SHBG levels seem to be an indicator of general adiposity rather than an
index of altered insulin-glucose homeostasis in morbidly obese subjects.
Hyperinsulinism also decreases SHBG synthesis as found by testing cultured
hepatic cells [24]. These observations have been interpreted to show that
obesity causes insulin resistance and hyperinsulinism, and hyperinsulinism
decreases SHBG levels. Hypothyroidism and the nephrotic syndrome also
reduce SHBG levels. In addition to aging, factors that are known to increase
SHBG include estrogen [25], hyperthyroidism [26], some anticonvulsants
[27], a high phytoestrogen diet [28], and hepatic cirrhosis [29].
R.A. Hijazi et al / Med Clin N Am 88 (2004) 933–945 937
Other hormones
Leptin is a peripheral hormone that has a role in energy balance and
energy stores. In animal models it has been shown to reflect total adipose
mass [35]. Leptin levels are directly related to total body fat but are highly
variable among individuals [36]. Inter-individual and age differences in
serum leptin levels may be related more to testosterone levels than to BMI
[37]. Leptin levels increase with age regardless of changes in body fat,
possibly because of the fall in testosterone levels. The negative correlation
between leptin and testosterone in men is consistent with the hypothesis that
testosterone may inhibit adipocyte ob gene transcription.
Adiponectin is an adipose-specific secretory protein, with antidiabetic
and antiatherogenic properties. Androgens appear to decrease plasma
adiponectin [38]. The hypoadiponectinemia induced by androgens may
increase insulin resistance and atherosclerosis in men. In mice, castration
but not ovariectomy increases adiponectin levels, and treatment with
testosterone reduced adiponectin levels in the castrated mice.
938 R.A. Hijazi et al / Med Clin N Am 88 (2004) 933–945
Epidemiology
It is estimated that 40% to 60% of men with diabetes have erectile
dysfunction. Typically, ED affects middle-aged or older diabetic males. In
one survey [39] of 541 diabetic men aged 20 to 59 years, the prevalence of
ED was 6% for diabetic men age 20 to 24 years and 52% for those 55 to 59
years old. The prevalence of ED was evaluated in 365 men, age 21 years or
older, with a minimum duration of diabetes of 10 years, and whose diabetes
was diagnosed before age 30 [40]. Most of these patients had type 1 diabetes.
The prevalence was 1.1% in the 21 to 30-year-old group and 47.1% in those
43 years old or older (Fig. 2). In addition to increasing age, ED was
associated with smoking, obesity, poor glycemic control, low HDL,
neuropathy, and retinopathy.
100
Prevalence of Erectile Dysfunction (%)
75
50
25
0
21-30 >30-40 >40-50 >50-60 >60
Age (yr)
Causes of ED
Normal erections are mediated by an increase in parasympathetic tone
and a reduction in sympathetic tone [41,42]. These neural pathways are
modulated by visual, auditory, olfactory, tactile, and psychologic stimuli.
Nonadrenergic, noncholinergic nerve endings release nitric oxide, which
stimulates cyclic guanosine monophosphate (cGMP) in the smooth muscle
of arterioles supplying the corpora cavernosa and of smooth muscle cells
lining the sinusoids of the corpora cavernosa. cGMP stimulates processes
that cause intracellular calcium levels to fall, resulting in smooth muscle
relaxation. The combination of increased blood flow to and the engorge-
ment of the corpora cavernosa causes compression of the veins that drain
the corpora cavernosa against the inelastic tunica albuginea. This essentially
prevents venous drainage of the corpora and causes penile rigidity.
ED in diabetics often is multifactorial. It can result from nerve damage
(eg, neuropathy), impaired blood flow (eg, vasculopathy), or psychological
factors. Some factors that can affect cavernosal smooth muscle relaxation
have been assessed in animal models. For instance, streptozotocin-induced
diabetic rats have increased penile cGMP and cyclic adenosine mono-
phosphate (cAMP) levels [43]. This suggests that defective relaxation or
increased contraction of cavernosal smooth muscle is the cause of impaired
erections in this model. Although an increase in connective tissue in the
corpora cavernosa has been observed in diabetic men with ED, many
diabetic men respond to PDE5 inhibitor, which acts by increasing cGMP.
Other diabetic men respond to intracavernosal injections of prostaglandin
(PG)E1, which increases cAMP in the corpora cavernosa and causes penile
erection. These observations indicate that the smooth muscle is able to relax
and fibrosis is not the limiting condition, at least in the earlier stages of ED.
Evaluation
Many patients with diabetes will not volunteer information about their
sexual function. Thus, it is very important for the clinician to inquire about
ED in all diabetic patients. If detected, one should not assume that it is only
caused by neuropathy or vasculopathy.
The provider should conduct a comprehensive history and physical
examination, trying to identify other possible causes of ED, such as med-
ications, substance abuse, alcohol, hypogonadism, thyroid dysfunction, pel-
vic trauma, Peyronie’s disease, or psychogenic causes. Laboratory workup
should include a complete blood count and screening chemistries to rule out
systemic disease, lipid profile, glycosylated hemoglobin, total testosterone,
LH, and a thyroid-stimulating hormone level. If the total testosterone is less
than 300 ng/dL, a second specimen should be obtained between 7 and 10 AM,
and total testosterone LH and prolactin should be determined. Measure-
ment of bioavailable or free testosterone by equilibrium dialysis should be
considered for borderline values or when there is reason to believe that
940 R.A. Hijazi et al / Med Clin N Am 88 (2004) 933–945
Treatment
There are numerous modalities of therapy for ED, none of which is
specific for diabetes. To our knowledge, there are no studies that
demonstrate tight glycemic control improves ED in diabetics. In fact,
a Veterans Affairs cooperative study [44] involving 153 men who received
standard versus intensive treatment of their diabetes actually found that
erectile dysfunction increased from 53% to 73% in the standard treatment
group and from 51% to 73% in the intensive treatment group, over 2 years.
There are studies, however, showing that tight control can improve
endothelial function, and in the early stages, endothelial dysfunction may
be the cause of ED. In view of the other potential benefits, good glycemic
control is imperative.
Oral PDE5 inhibitors are the most prescribed drugs used to treat ED. These
agents inhibit PDE5, which metabolizes cGMP to inactive 59-GMP. cGMP
causes a reduction in intracellular calcium levels and relaxation of the smooth
muscle in the arterioles supplying the corpora cavernosa and the trabecular
smooth muscle lining the sinusoids of the corpora cavernosa. Sildenafil, the
first PDE5 inhibitor to receive approval for clinical use, inhibits degradation
of cGMP, thereby facilitating and prolonging penile erections. Unlike PGE1,
it does not cause penile erection; thus, sexual stimulation is necessary. In
a double blind, flexible dose, placebo-controlled trial involving 268 diabetics
men with ED, 56% of the men taking sildenafil reported improved erections
compared with 10% in the placebo arm [45]. Head-to-head comparisons in
this population are limited at this time; however, randomized, placebo-
controlled studies have been conducted in diabetics in different patient
populations with three PDE5 inhibitors (Table 2) [46,47].
R.A. Hijazi et al / Med Clin N Am 88 (2004) 933–945 941
Table 2
PDE5 inhibitors efficacy in diabetes based on the responses to ‘‘Has treatment improved your
erections after 12 weeks?’’
Answering ‘‘yes’’ Answering ‘‘yes’’
Drug [Ref.] Dose placebo (%) therapy (%)
Sildenafil [43] 100 mg 10 (n = 121) 56 (n = 131)
Vardenafil [44] 10 mg 13 (n = 133) 57 (n = 137)
Vardenafil [44] 20 mg 13 (n = 133) 72 (n = 131)
Tadalafil [45] 10 mg 25 (n = 71) 56 (n = 73)
Tadalafil [45] 20 mg 25 (n = 71) 64 (n = 72)
These studies were performed on different patient groups and are not head-to-head
comparisons.
Table 3
Sildenafil: most common side effects
Placebo Sildenafil
Event (%) (n = 725) (%) (n = 734)
Flushing 1 10
Dyspepsia 2 7
Nasal congestion 2 4
Abnormal vision 0 3
Headache 4 16
Available at http://www.viagramd.wm/pi/proPackInsert.asp.
942 R.A. Hijazi et al / Med Clin N Am 88 (2004) 933–945
Summary
We now have a variety of treatments for the diabetic with ED. If
hypogonadism is present and there are no contraindications, testosterone
replacement therapy should be considered. In addition to the effects of
testosterone replacement therapy on libido and erections, testosterone
improves body composition, bone density, and mood. The hematocrit,
digital rectal examination, and prostate-specific antigen level, however, must
be monitored carefully in men 60 and older and in men 50 and older if they
are African American or have a family history of prostate cancer because
R.A. Hijazi et al / Med Clin N Am 88 (2004) 933–945 943
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Med Clin N Am 88 (2004) 947–999
Diabetic neuropathies
A.I. Vinik, MD, PhD*, Anahit Mehrabyan, MD
Departments of Internal Medicine and Pathology/Neurobiology, The Strelitz
Diabetes Institutes, Eastern Virginia Medical School, 855 West Brambleton Avenue,
Norfolk, VA 23510, USA
* Corresponding author.
E-mail address: vinikai@evms.edu (A.I. Vinik).
0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2004.04.009
948 A.I. Vinik, A. Mehrabyan / Med Clin N Am 88 (2004) 947–999
Classification
Diabetic neuropathy is not a single entity but a number of different
syndromes, ranging from subclinical to clinical manifestations depending on
the classes of nerve fibers involved. According to the San Antonio
Convention [12], the main groups of neurologic disturbance in diabetes
mellitus include (1) subclinical neuropathy, determined by abnormalities in
electrodiagnostic and quantitative sensory testing, (2) diffuse clinical neu-
ropathy with distal symmetric sensorimotor and autonomic syndromes, and
(3) focal syndromes.
Subclinical neuropathy is diagnosed on the basis of (1) abnormal elec-
trodiagnostic tests with decreased nerve conduction velocity (NCV) or de-
creased amplitudes; (2) abnormal quantitative sensory tests (QST) for
vibration, tactile, thermal warming, and cooling thresholds; and (3) quan-
titative autonomic function tests revealing diminished heart rate variation
with deep breathing, Valsalva’s maneuver, and postural testing. The different
clinical presentations of diabetic neuropathy are schematically illustrated in
Fig. 1.
Natural history
The natural history of neuropathies separates them into two very
distinctive entities: those that progress gradually with increasing duration
of diabetes, and those that remit usually completely. Sensory and autonomic
neuropathies generally progress, whereas mononeuropathies, radiculopa-
thies, and acute painful neuropathies, although symptoms are severe, are
short-lived and tend to recover [13]. Progression of DN is related to
glycemic control in both type 1 and type 2 diabetes [14,15]. It seems that the
most rapid deterioration of nerve function occurs soon after the onset of
type 1 diabetes and within 2 to 3 years there is a slowing of the progress with
a shallower slope to the curve of dysfunction. In contrast, in type 2 diabetes,
A.I. Vinik, A. Mehrabyan / Med Clin N Am 88 (2004) 947–999 949
Motor deficit: 0
Motor deficit: 0 → +++
Pathogenesis
Fig. 2 summarizes the current view of the pathogenesis of DN. This figure
depicts multiple etiologies including metabolic, vascular, autoimmune,
oxidative stress, and neurohormonal growth-factor deficiency.
Detailed discussion of the different theories is beyond the scope of this
article; the reader is referred to several excellent recent reviews [26–28]. DN
is a heterogeneous disease with widely varying pathology, however,
suggesting differences in pathogenic mechanisms for the different clinical
GENETIC Glucotoxicity
APoE4 and
AR Z2 alleles
ACE polymorphism Lipotoxicity Epigenetic
Toll rec polymorphism AGEs PARPs etc
Endothelial Functional Progressive
Initiating
Injury Changes Pathological
Event Changes
INFLAMMATION
Oxidative/Nitrative
Stress months to years
PKC
Selectins
VCAMS
IL6, TNFα, NFκB
ROS, nitrotyrosines
Clinical presentation
An international consensus meeting on the outpatient diagnosis and
management of DN agreed on a simple definition of DN as ‘‘the presence of
symptoms or signs of peripheral nerve dysfunction in people with diabetes
after the exclusion of other causes’’ [12]. It was also agreed that neuropathy
cannot be diagnosed without a careful clinical examination: absence of
symptoms cannot be equated with absence of neuropathy because asymp-
tomatic neuropathy is common. The importance of excluding nondiabetic
causes was emphasized in the Rochester Diabetic Neuropathy Study in
which up to 10% of peripheral neuropathy in diabetic patients was deemed to
be of nondiabetic causation [29]. A more detailed definition of neuropathy
had previously been agreed at the San Antonio Consensus Conference:
‘‘diabetic neuropathy is a descriptive term meaning a demonstrable disorder,
either clinically evident or sub-clinical, that occurs in the setting of diabetes
mellitus without other causes for peripheral neuropathy. The neuropathic
disorder includes manifestations in the somatic or autonomic parts of the
peripheral nervous system’’ [12]. It is generally agreed that DN should not be
diagnosed on one symptom, sign, or test alone: a minimum of two
abnormalities (from symptoms, signs, nerve conduction abnormalities,
quantitative sensory tests, or quantitative autonomic tests) is recommended
by Dyck [30]. It is, however, woefully underdiagnosed by endocrinologists
and nonendocrinologists. In the GOAL A1c study [31] identification of the
absence of neuropathy in 7000 patients was fairly adequate but was only
accurate in the presence of mild neuropathy one third of the time and reached
75% only if neuropathy was severe. Clearly, there is a need for education of
the means whereby neuropathy may be diagnosed.
The spectrum of clinical neuropathic syndromes described in patients with
diabetes mellitus includes dysfunction of almost every segment of the somatic
peripheral and autonomic nervous system [32]: it has been said that ‘‘knowing
952 A.I. Vinik, A. Mehrabyan / Med Clin N Am 88 (2004) 947–999
Focal neuropathies
Mononeuritis and entrapment syndromes
Mononeuropathies occur primarily in the older population; their onset is
generally acute, associated with pain; and their course is self-limiting, re-
solving within 6 to 8 weeks. These are caused by vascular obstruction after
which adjacent neuronal fascicles take over the function of those infarcted by
the clot [28]. Mononeuropathies must be distinguished from entrapment syn-
dromes that start slowly, progress, and persist without intervention (Table 1).
Common entrapment sites in diabetic patients involve median, ulnar,
radial, femoral, lateral cutaneous nerves of the thigh, peroneal, and medial
and lateral plantar nerve. Carpal tunnel syndrome occurs three times as
frequently in a people with diabetes compared with a normal healthy
population [33,34], and its increased prevalence in diabetes may be related to
diabetic cheiroarthropathy [35], repeated undetected trauma, metabolic
changes, or accumulation of fluid or edema within the confined space of the
carpal tunnel [32]. It is found in up to one third of patients with diabetes
[36]. If recognized, the diagnosis can be confirmed by electrophysiologic
study and therapy is simple with surgical release. The mainstays of
nonsurgical treatment are resting the wrist aided by the placement of a wrist
splint in a neutral position for day and night use, and the addition of anti-
inflammatory drug medications. Surgical treatment consists of sectioning
the volar carpal ligament [37]. The decision to proceed with surgery should
be based on several considerations, including severity of symptoms,
appearance of motor weakness, and failure of nonsurgical treatment.
Diffuse neuropathies
Proximal motor neuropathies (diabetic amyotrophy, femoral neuropathy)
For many years proximal neuropathy has been considered as a compo-
nent of DN. Its pathogenesis was ill understood [38], and its treatment was
Table 1
Mononeuritis versus entrapment
Mononeuritis Entrapment
Onset sudden Onset gradual
Usually single nerve but may be multiple Single nerves exposed to trauma
Common nerves: CN III, VI, VII, ulnar, Common nerves: median, ulnar, peroneal,
median, peroneal medial, and lateral plantar
Not progressive and resolves spontaneously Progressive
Treatment symptomatic Treatment, rest, splints, diuretics,
steroid injections, and surgery for paralysis
A.I. Vinik, A. Mehrabyan / Med Clin N Am 88 (2004) 947–999 953
neglected with the anticipation that the patient would eventually recover,
albeit over a period of some 1 to 2 years, suffering considerable pain, weak-
ness, and disability. The condition has a number of synonyms: proximal
neuropathy, femoral neuropathy, diabetic amyotrophy, and diabetic neu-
ropathic cachexia. Proximal motor neuropathy can be clinically identified
based on recognition of these common features: (1) primarily affects the
elderly; (2) gradual or abrupt onset; (3) begins with pain in the thighs and
hips or buttocks; (4) followed by significant weakness of the proximal
muscles of the lower limbs with inability to rise from the sitting position
(positive Gower’s maneuver); (5) begins unilaterally and spreads bilaterally;
(6) coexists with distal symmetric polyneuropathy (DSPN); and (7)
spontaneous muscle fasciculation, or provoked by percussion. The condi-
tion is now recognized as being secondary to a variety of causes unrelated to
diabetes, but which have a greater frequency in patients with diabetes than
the general population. It includes patients with chronic inflammatory
demyelinating polyneuropathy, monoclonal gammopathy, circulating GM1
antibodies, and antibodies to neuronal cells and inflammatory vasculitis
[39,40]. It was formerly thought to resolve spontaneously in 1.5 to 2 years,
but now, if found to be immune-mediated, can resolve within days on
immunotherapy. The condition is readily recognizable clinically with pre-
vailing weakness of the iliopsoas, obturator, and adductor muscles, together
with relative preservation of the gluteus maximus and minimus and
hamstrings [41]. Those people affected have great difficulty rising out of
chairs unaided and often use their arms to assist themselves. Heel or toe
standing is surprisingly good. In the classic form of diabetic amyotrophy,
axonal loss is the predominant process and the condition coexists with
DSPN [42]. Electrophysiologic evaluation reveals lumbosacral plexopathy
[41]. In contrast, if demyelination predominates and the motor deficit affects
proximal and distal muscle groups, the diagnosis of chronic inflammatory
demyelinating polyneuropathy, monoclonal gammopathy of unknown
significance, and vasculitis should be considered [43,44]. It seems probable
that these conditions occur more commonly in people with diabetes [45–47].
Vinik [48] (Fig. 3) pointed out that almost half the patients with proximal
neuropathies have a vasculitis and all but 9% have chronic inflammatory
demyelinating polyneuropathy or monoclonal gammopathy of unknown
significance or a ganglioside antibody syndrome [49]. Sharma et al [46]
examined over 1000 patients with neurologic disorders and found that
chronic inflammatory demyelinating polyneuropathy was 11 times more
frequent among their diabetic than nondiabetic population.
Biopsy of the obturator nerve reveals deposition of immunoglobulin,
demyelination, and inflammatory cell infiltrate of the vasa nervorum [50].
Cerebrospinal fluid protein content is high and there is an increase in the
lymphocyte count. Treatment options include intravenous immunoglobulin
for chronic inflammatory demyelinating polyneuropathy, plasma exchange
for monoclonal gammopathy of unknown significance, steroids and
954 A.I. Vinik, A. Mehrabyan / Med Clin N Am 88 (2004) 947–999
Vasculitis
9% CIDP
17% MGUS
Diabetes
22% 52%
Fig. 3. Disabling peripheral neuropathies in older adults. (From Vinik A. Diagnosis and
management of diabetic neuropathy. Clin Geriatr Med 1999;15:293–320; with permission.)
azathioprine for vasculitis, and withdrawal from drugs or other agents that
may have caused a vasculitis. It is important to divide proximal syndromes
into these two subcategories, because the chronic inflammatory demyelin-
ating polyneuropathy variant responds dramatically to intervention [43,51],
whereas amyotrophy runs its own course over months to years. Until more
evidence is available, they should be considered separate syndromes.
These conditions need to be distinguished from spinal stenosis syn-
dromes. There is encroachment on nerve roots as they emerge from the
spinal cord, osteophytes may cause compression, with aging there is
hypertrophy of the ligamentum flavum and disk dehydration, and there
may even be some form of arachnoiditis. When the compression involves the
vascular system claudication typical occurs walking downhill, is relieved by
bending forward, and occurs at the watershed level between T12 and L1/2.
Nerve root compression is more typical at L5/S1 and in difficult cases it may
be necessary to obtain an MRI of the lumbosacral spine. Diagnosis is
critical because therapy may be simple physical therapy or surgical decom-
pression if symptoms are severe or there is motor paralysis.
Large Small
Neuropathy
Motor Pain
Vibration Autonomic
Position sense Thermal
Touch/pressure Produces symptoms
Interferes with QOL and ADL and leads to
morbidity and mortality
Fig. 6. Loss of cutaneous nerve fibers that stain positive for the neuronal antigen PGP 9.5 in
sensory neuropathy. (A) Normal density of epidermal nerve fibers (arrows) in back. (B) Slightly
reduced density and abnormal nerve fiber swellings (arrows) in proximal thigh. (C) Complete
clearance of nerve fibers in calf.
Table 2
Sensory signs and symptoms of stimulus-independent and stimulus-evoked pain
Stimulus-independent pain Stimulus-evoked pain
Patient expresses symptoms Physician elicits signs after mechanical, thermal,
on presentation or chemical stimulation
Involves continuous burning sensation; Includes hyperalgesia or allodynia
also may include:
Intermittent shooting, lancinating
sensations
Electric-shock–like pain
Dysesthesias
pins and needles, tingling, and sharp knife-like or stabbing pain) derive from
C-fiber dysfunction and may have a different origin and respond differently
to different medications (eg, gabapentin [62] and the PKC-inhibitor LY
333531) [63]. These differences have led to the development of improved
tools for the quantitation of symptoms of DNs [64].
Even more hazardous to the interpretation of pain relief is the fact that
drugs used for treatment (eg, nerve growth factor) induce local sensitivity at
the site of injection, which is construed as pain. Other drugs (eg, topiramate)
cause paresthesias interpreted as pain, leading to the apparent failure of two
trials and the success of a third that specifically defined the nature of pain
and the site to exclude the nonneuropathic pain syndromes listed later
(Table 3) [48].
Pain tolerance is uniquely individual. Quantifying pain is subjective and
can be quite variable, depending on the terminology used to define pain, the
instrument used to measure pain, and the patient’s ability to describe his or
her pain. Moreover, few patients can discern whether their pain is
neuropathic or nonneuropathic in origin, and careful clinical evaluation is
critical for devising suitable management strategies.
Table 3
Common pain syndromes similar to painful diabetic neuropathy
Condition Key characteristics and differentiating features
Claudication Doppler ultrasonography confirms clinical diagnosis of arterial
occlusion
Patients with diabetes may present with normal extremities and
absent foot pulses
Peripheral arterial occlusion with underlying atherosclerosis
Usually intermittent, worsened by walking; remits with rest;
other signs or symptoms suggest arterial insufficiency
Morton’s neuroma Benign neuroma formation on third plantar interdigital nerve
Generally unilateral
More frequent in women
Pain elicited when pressure is applied with the thumb between
the first and fourth metatarsal heads
Osteoarthritis Can be secondary to diabetes mellitus, but pain is usually
gradual in onset and in one or two joints
Differential diagnosis based on x-ray
Morning stiffness, diminished joint motion, and flexion
contractures are characteristic
Pain worsens with exercise and improves with rest
Radiculopathy can result
Radiculopathy Can be caused by diabetes, but can also result from arthritis
or metastatic disease
Neurologic examinations and imaging can localize lesion site
Pain can occur in thorax, extremities, shoulder, or arm,
depending on site of lesion
Charcot’s May result from osteopenia caused by increased blood flow
neuroarthropathy following repeated minor trauma in individuals
with diabetic neuropathy
Warm to hot foot with increased blood flows
Decreased warm sensory perception, vibration detection
Plantar fasciitis Pain in the plantar region of the foot
Tenderness along the plantar fascia when ankle is dorsiflexed
Shooting or burning in the heel with each step
Worsening pain with prolonged activity
Often associated with calcaneal spur on radiography
Tarsal tunnel syndrome Caused by entrapment of the posterior tibial nerve
Pain and numbness radiate from beneath the medial
malleolus to the sole
Clinical examination includes percussion, palpation for
possible soft tissue matter, nerve conduction studies, MRI
Fig. 7. Clinical presentation of the large and small neuropathies. (From Vinik AI, Erbas T,
Stansberry K, Pittenger G. Small fiber neuropathy and neurovascular disturbances in diabetes
mellitus. Exp Clin Endocrinol Diabetes 2001;109(Suppl 2):S451–73, Ó J.A. Barth Verlag in
Georg Thieme Verlag KG; with permission.)
even basic daily activities, such as sitting at a desk may be disrupted. Pain
often occurs at the onset of the disease and is often worsened by initiation of
therapy with insulin or sulfonylureas [65].
It may be associated with profound weight loss and severe depression
that has been termed ‘‘diabetic neuropathic cachexia’’ [66]. This syndrome
occurs predominantly in male patients and may occur at any time in the
course of both type 1 and type 2 diabetes. It is self-limiting and invariably
responds to simple symptomatic treatment. Such conditions as Fabry’s
disease, amyloid, HIV infection, heavy metal poisoning (eg, arsenic), and
excess alcohol consumption should be excluded. It does overlap with the
idiopathic variety of acute painful small-fiber neuropathy that is also
a diagnosis by exclusion [67].
Sympat
+
_
NA
C Aβ C Aβ /Aδ C Aβ C Aβ
Fig. 8. Schematic representation of the generation of neuropathic pain. In this simplified
scheme, the spinal cord is illustrated as an oval.
Neuropharmacology of pain
The neuropharmacology of pain is also becoming better understood. For
example, recent data suggest that c-aminobutyric acid, voltage-gated sodium
channels, and glutamate receptors may be involved in the pathophysiology
of neuropathic pain. Many of the newer agents (called antineuropathic
agents) have significant effects on these neurophysiologic mechanisms.
The growing knowledge about the neural and pharmacologic basis of
neuropathic pain is likely to have important treatment implications, including
development and refinement of a symptom-mechanism-based approach to
neuropathic pain, and implementation of novel treatment strategies using the
newer antiepileptic agents, which may address the underlying neurophysio-
logic aberrations in neuropathic pain, allowing the clinician to increase the
likelihood of effective management.
The mechanism for pain in small-fiber neuropathy is not well understood.
Hyperglycemia may be a factor in lowering the pain threshold. The
condition may appear soon after initiation of therapy [65]. A striking
amelioration of symptoms with the intravenous administration of insulin
can be achieved [68]. There is a sequence in DN, beginning when nerve
function (A beta and C fiber) is intact and there is no pain. With damage to
C fibers there is sympathetic sensitization and peripheral autonomic
symptoms are interpreted a painful. With death of C fibers there is
nociceptor sensitization and A beta-fibers conduct all varieties of peripheral
stimuli, such as touch, and these are interpreted as painful (eg, allodynia).
With time there is reorganization at the cord level and the patient
experiences clod hyperalgesia and ultimately even with the death of all
fibers pain is registered in the cerebral cortex, whereupon the syndrome
becomes chronic without the need for peripheral stimulation (see Fig. 8 for
explanation of the stages of pain). Disappearance of pain may not
necessarily reflect nerve recovery but rather nerve death. When patients
volunteer the loss of pain, progression of the neuropathy must be excluded
by careful examination.
A.I. Vinik, A. Mehrabyan / Med Clin N Am 88 (2004) 947–999 963
Large-fiber neuropathies
Large-fiber neuropathies may involve sensory or motor nerves. These
tend to be the neuropathies of signs rather than symptoms. Large fibers
subserve motor function, vibration perception, position sense, and cold
thermal perception. Unlike the small nerve fibers these are the myelinated,
rapidly conducting fibers that begin in the toes and have their first synapse
in the medulla oblongata. They tend to be affected first because of their
length and the tendency in diabetes for nerves to ‘‘die back.’’ Because they
are myelinated, they are the fibers represented in the EMG, and subclinical
abnormalities in nerve function are readily detected. The symptoms may be
minimal: sensation of walking on cotton, floors feeling ‘‘strange,’’ inability
to turn the pages of a book, or inability to discriminate among coins.
Clinical presentation of large-fiber neuropathies includes the following:
Impaired vibration perception (often the first objective evidence) and
position sense
Depressed tendon reflexes
A delta-type deep-seated gnawing, dull, like a toothache in the bones of
the feet, or even crushing or cramp-like pain
Sensory ataxia (waddling like a duck)
Wasting of small muscles of feet with hammertoes (intrinsic minus feet
and hands) with weakness of hands and feet
Shortening of the Achilles tendon with pes equinus
Increased blood flow (hot foot)
Most patients with DSPN, however, have a mixed variety of neuropathy
with both large and small nerve fiber damages. In the case of DSPN, a ‘‘glove
and stocking’’ distribution of sensory loss is almost universal [32]. Early in
the course of the neuropathic process, multifocal sensory loss also might be
found. In some patients, severe distal muscle weakness can accompany the
sensory loss resulting in an inability to stand on the toes or heels. Some
grading systems use this as a definition of severity.
sensitivity from 60% to 90% [72]. Sensory function must be evaluated on both
sides of the feet and hands if one wants to be sure not to miss entrapment
syndromes. A Tinel’s sign is not only useful for carpal tunnel problems, but
can be applied to the ulnar notch, the head of the fibula, and below the medial
tibial epicondyle for ulnar, peroneal, and medial plantar entrapments,
respectively. The 1988 San Antonio conference on DN and the 1992
conference of the American Academy of Neurology [12] recommended that
at least one parameter from each of the following five categories are measured
to classify DN: (1) symptom profiles, (2) neurologic examination, (3) QST, (4)
nerve conduction study, and (5) autonomic function testing. A number of
simple symptom screening questionnaires are available to record symptom
quality and severity. A simplified neuropathy symptom score that was used in
the European prevalence studies could also be useful in clinical practice [6,73].
The Michigan Neuropathy Screening Instrument is a brief 15-item question-
naire that can be administered to patients as a screening tool for neuropathy
[74]. Other similar symptom scoring systems have also been described [6].
Simple visual analog or verbal descriptive scales may be used to follow
patients’ responses to treatment of their neuropathic symptoms [71,75,76]. It
must always be remembered, however, that identification of neuropathic
symptoms is not useful as a diagnostic or screening tool in the assessment of
DN, as shown by Franse et al [77].
The QST and quantitative autonomic function tests are objective indices
of neurologic functional status. Combined, these tests cover vibratory,
proprioceptive, tactile, pain, thermal, and autonomic function. An in-
ternational group of experts in DN held a consensus meeting to develop
guidelines for the management of diabetic peripheral neuropathy by the
practicing clinician [12]. This clinical staging is in general agreement with
that proposed by Dyck [78] for use in both clinical practice and
epidemiologic studies or controlled clinical trials. The clinical ‘‘no neurop-
athy’’ is equivalent to Dyck’s N0 or N1a; ‘‘clinical neuropathy’’ is equivalent
to N1b, N2a, or N2b; and ‘‘late complications’’ is equivalent to Dyck N3.
There have been a number of other relevant reports, including two on
measures for use in clinical trials to assess symptoms [75] and QST [79]. The
strengths of QST are well documented [80], but the limitations of QST are
also clear. No matter what the instrument or procedure used, QST is only
a semiobjective measure, which is affected by the subject’s attention,
motivation, and cooperation, and by anthropometric variables, such as
age, gender, body mass, and history of smoking and alcohol consumption.
Expectancy and subject bias are additional factors that can exert a powerful
influence on QST findings. Further, QST is sensitive to changes in structure
or function along the entire neuraxis from nerve to cortex; it is not a specific
measure of peripheral nerve function [80].
The American Academy of Neurology reported on the use of QST for
clinical and research purposes [79] suggesting that these tests could be used
as an ancillary but were not sufficiently robust for routine clinical use.
A.I. Vinik, A. Mehrabyan / Med Clin N Am 88 (2004) 947–999 965
Management of neuropathy
Once neuropathy is diagnosed, therapy can be instituted with the goal of
ameliorating symptoms and preventing the progression of neuropathy.
Successful management of these syndromes must be geared to the individual
pathogenic processes (Fig. 10).
Control of hyperglycemia
Retrospective and prospective studies have suggested a relationship
between hyperglycemia and the development and severity of DN. Pirart
[7] followed 4400 diabetic patients over 25 years and showed an increase in
prevalence of clinically detectable DN from 12% of patients at the time of
diagnosis of diabetes to almost 50% after 25 years. The highest prevalence
occurred in those people with poorest diabetes control. The DCCT research
Group [14] reported significant effects of intensive insulin therapy on
prevention of neuropathy. The prevalence rates for clinical or electrophys-
iologic evidence of neuropathy were reduced by 50% in those treated by
intensive insulin therapy during 5 years. At that stage of the study, only 3%
of the patients in the primary prevention cohort treated by intensive insulin
therapy showed minimal signs of DN, compared with 10% of those treated
968 A.I. Vinik, A. Mehrabyan / Med Clin N Am 88 (2004) 947–999
Diabetes
Dyslipidemia EFA dysmetabolism
Hyperglycemia
Polyol
pathway DAG
flux Free transition metal PKC β PKC
ions Inhibitor
ARIs
Autoxidation AII
AGE formation ET
Endogenous scavengers
Antioxidants NO
Reactive Oxygen Species
α-Lipoic acid PGI 2
Ischemia/ ONOO- EDHF
A-V shunting reperfusion
Vascular
Nerve and ganglion dysfunction
NEUROPATHY blood flow
Endoneurial hypoxia
Cameron et al., Diabetologia, 2001; 44:1973–88
Fig. 10. Management aimed at pathogenetic mechanisms. (From Cameron NE, Eaton SE,
Cotter MA, Tesfaye S. Vascular factors and metabolic interactions in the pathogenesis of
diabetic neuropathy. Diabetologia 2001;44(11):1973–88; with permission.)
array of new aldose reductase inhibitors. It is also becoming clear that aldose
reductase inhibition may be insufficient in its own right to achieve the
desirable degree of metabolic enhancement in patients with a multitude of
biochemical abnormalities. Combinations of therapy with aldose reductase
inhibitors and antioxidants may become critical if the relentless progress of
DN is to be abated.
a-Lipoic acid
Lipoic acid (1,2-dithiolane-3-pentanoic acid), a derivative of octanoic
acid, is present in food and is also synthesized by the liver. It is a natural
cofactor in the pyruvate dehydrogenase complex where it binds acyl groups
and transfers them from one part of the complex to another. a-Lipoic acid,
which is also known as thioctic acid, has generated considerable interest as
a thiol replenishing and redox modulating agent. It has been shown to be
effective in ameliorating both the somatic and autonomic neuropathies in
diabetes [111–113]. It is currently undergoing extensive trials in the United
States as both an antidiabetic agent and for the treatment of DN.
c-Linolenic acid
Linoleic acid, an essential fatty acid, is metabolized to dihomo-c-linolenic
acid, which serves as an important constituent of neuronal membrane
phospholipids, and also serves as a substrate for prostaglandin E formation,
seemingly important for preservation of nerve blood flow. In diabetes,
conversion of linoleic acid to c-linolenic acid and subsequent metabolites is
impaired, possibly contributing to the pathogenesis of DN [114]. A recent
multicenter double-blind placebo-controlled trial using c-linolenic acid for
1 year demonstrated significant improvements in both clinical measures and
electrophysiologic testing [115].
Aminoguanidine
Animal studies using aminoguanidine, an inhibitor of the formation of
advanced glycosylation end-products, show improvement in nerve conduc-
tion velocity in streptozotocin-induced DN in rats. Controlled clinical trials
to determine its efficacy in humans [116,117] have been discontinued because
of toxicity. There are, however, successors to aminoguanidine that hold
promise for this approach [118].
Neurotrophic therapy
There is now considerable evidence in animal models of diabetes that
decreased expression of nerve growth factor and its receptors, trk A, reduces
retrograde axonal transport of nerve growth factor and diminishes support
of small unmyelinated neurons and their neuropeptides, such as substance P
and calcitonin gene-related peptide, both potent vasodilators [120,121].
Furthermore, recombinant human nerve growth factor administration
restores these neuropeptide levels toward normal and prevents the mani-
festations of sensory neuropathy in animals [122]. In a 15-center, double-
blind, placebo-controlled study of the safety and efficacy of recombinant
human nerve growth factor in 250 subjects with symptomatic small-fiber
neuropathy [18], recombinant human nerve growth factor improved the
neurologic impairment score of the lower limbs, and improved small nerve
fiber function cooling threshold (A delta-fibers) and the ability to perceive
heat pain (C fiber) compared with placebo. These results were consistent
with the postulated actions of nerve growth factor on trk A receptors
present on small-fiber neurons. This led to two large multicenter studies
conducted in the United States and the rest of the world. Results of these
two studies were presented at the American Diabetes Association meetings
in June 1999 [19]. Regrettably, recombinant human nerve growth factor was
not found to have beneficial effects over and above placebo. The reason for
this dichotomy has not been resolved, but this has somewhat dampened the
enthusiasm for growth factor therapy of DN.
C-fiber pain
Initially, when there is ongoing damage to the nerves, the patient
experiences the pain of the burning, lancinating, dysesthetic type often
accompanied by hyperalgesia and allodynia. Because the peripheral sympa-
thetic nerve fibers are also small unmyelinated C fibers, sympathetic blocking
agents (clonidine) may improve the pain. Loss of sympathetic regulation of
sweat glands and arteriovenous shunt vessels in the foot creates a favorable
environment for bacteria to penetrate, multiply, and wreak havoc with the
foot. These fibers use the neuropeptide substance P as their neurotransmitter,
and depletion of axonal substance P (capsaicin) often leads to amelioration
of the pain. When the destructive forces persist, however, the individual
becomes pain free and develops impaired warm temperature and pain
thresholds. Disappearance of pain in these circumstances should be hailed as
a warning that the neuropathy is progressing.
A delta-fiber pain
A delta-fiber pain is a more deep-seated, dull, and gnawing ache, which
often does not respond to the previously described measures. A number of
different agents have been used for the pain associated with these fibers with
varying success.
not mistaken for pain was successful [136]. What has emerged from all the
studies is that the drug lowers blood pressure, improves lipid profiles,
decreases insulin resistance, and increases nerve fiber regeneration in the
skin [97]. It has the potential to relieve pain by altering the biology of the
disease and has now been shown to increase intraepidermal nerve fibers.
Further trials are being done. One must start with no more than 15 mg/d,
preferably at night, and then increase the dose only after the patient can
tolerate the drug. A maximum of 200 mg was sufficient to induce nerve fiber
recovery.
Patients must exercise care with exposure to heat (no falling asleep in
front of fires)
Emollient creams should be used for the drying and cracking
After bathing feet should be thoroughly dried and powdered between
the toes
Nails should be cut transversely, preferably by a podiatrist
Autonomic neuropathies
The autonomic nervous system supplies all organs in the body and
consists of an afferent and an efferent system, with long efferents in the
vagus (cholinergic) and short postganglionic unmyelinated fibers in the
sympathetic system (adrenergic). A third component is the neuropeptidergic
system with its neurotransmitters substance P, vasoactive intestinal poly-
peptide, and calcitonin gene-related peptide among others. Diabetic auto-
nomic neuropathy can cause dysfunction of every part of the body. Diabetic
autonomic neuropathy often goes completely unrecognized by patient and
physician alike because of its insidious onset and protean multiple organ
involvement. Alternatively, the appearance of complex and confusing
symptoms in a single organ system because of diabetic autonomic neurop-
athy may cause profound symptoms and receive intense diagnostic and
therapeutic attention. Subclinical involvement may be widespread, whereas
clinical symptoms and signs may be focused within a single organ. The
organ systems that most often exhibit prominent clinical autonomic signs
and symptoms in diabetes include the ocular pupil, sweat glands, genito-
urinary system, gastrointestinal tract system, adrenal medullary system, and
the cardiovascular system (Box 1).
A.I. Vinik, A. Mehrabyan / Med Clin N Am 88 (2004) 947–999 977
Table 4
Differential diagnosis of diabetic autonomic neuropathy
Clinical manifestations Differential diagnosis
Cardiovascular Cardiovascular disorders
Tachycardia, exercise intolerance Idiopathic orthostatic hypotension,
Cardiac denervation, painless multiple system atrophy with
myocardial infarction Parkinsonism, orthostatic tachycardia,
Orthostatic hypotension hyperadrenergic hypotension
Shy-Drager syndrome
Panhypopituitarism
Pheochromocytoma
Hypovolemia
Congestive heart disease
Carcinoid syndrome
Gastrointestinal Gastrointestinal disorders
Esophageal dysfunction Obstruction
Gastroparesis diabeticorum Bezoars
Diarrhea Secretory diarrhea (endocrine tumors)
Constipation Biliary disease
Fecal incontinence Psychogenic vomiting
Medications
Genitourinary Genitourinary
Erectile dysfunction Genital and pelvic surgery
Retrograde ejaculation Atherosclerotic vascular disease
Cystopathy Medications
Neurogenic bladder Alcohol abuse
Neurovascular Other causes of neurovascular dysfunction
Heat intolerance Chagas’ disease
Gustatory sweating Amyloidosis
Dry skin Arsenic
Impaired skin blood flow
Metabolic Metabolic
Hypoglycemia unawareness Other causes of hypoglycemia,
Hypoglycemia unresponsiveness intensive glycemic control and
Hypoglycemiassociated autonomic failure drugs that mask hypoglycemia
Pupillary Pupillary
Decreased diameter of dark adapted pupil Syphilis
Argyll-Robertson–type pupil
Table 5
Diagnostic tests of cardiovascular autonomic neuropathy
Test Method and parameters
Resting heart rate; beat-to-beat >100 beats/min is abnormal. With the patient at rest
heart rate; variation and supine (no overnight coffee or hypoglycemic
episodes), breathing 6 breaths/min, heart rate
monitored by EKG or ANSCORE device, a
difference in heart rate of [15 beats/min is normal
and \10 beats/min is abnormal, R-R inspiration/
R-R expiration [1.17. All indices of HRV are
age-dependent.
Heart rate response to standing During continuous EKG monitoring, the R-R
interval is measured at beats 15 and 30 after
standing. Normally, a tachycardia is followed by
reflex bradycardia. The 30:15 ratio is normally
[1.03.
Heart rate response to The subject forcibly exhales into the mouthpiece of
Valsalva’s maneuver a manometer to 40 mm Hg for 15 seconds during
EKG monitoring. Healthy subjects develop tachy
cardia and peripheral vasoconstriction during
strain and an overshoot bradycardia and rise in
blood pressure with release. The ratio of longest
R-R shortest R-R should be [1.2.
Systolic blood pressure Systolic blood pressure is measured in the supine
response to standing subject. The patient stands and the systolic blood
pressure is measured after 2 min. Normal response
is a fall of \10 mm Hg, borderline is a fall of
10–29 mm Hg, and abnormal is a fall of
[30 mm Hg with symptoms.
Diastolic blood pressure response The subject squeezes a handgrip dynamometer to
to isometric exercise establish a maximum. Grip is then squeezed at
30% maximum for 5 min. The normal response for
diastolic blood pressure is a rise of [16 mm Hg in
the other arm.
EKG QT-QTc intervals The QTc (corrected QT interval on EKG) should
be \440 ms.
Spectral analysis VLF peak # (sympathetic dysfunction)
LF peak# (sympathetic dysfunction)
HF peak # (parasympathetic dysfunction)
LH/HF ratio # (sympathetic imbalance)
Neurovascular flow Using noninvasive laser Doppler measures of
peripheral sympathetic responses to nociception.
Postural Dizziness
Measure Blood Pressure and
heart rate supine and
standing
Diagnosis =Vaso-Vagal
Evaluate Heart Rate Decrease Syncope
Presentation
Nausea,vomiting,
bloating, satiety,
brittle diabetes
Drug therapy. Some patients with postural hypotension may benefit from
treatment with 9-flurohydrocortisone (Table 6). Unfortunately, symptoms
do not improve until edema occurs, and there is a significant risk of
developing congestive heart failure and hypertension. If fluorohydrocorti-
sone does not work satisfactorily, various adrenergic agonists and antago-
nists may be used. If the adrenergic receptor status is known, then therapy
can be guided to the appropriate agent. Metoclopramide may be helpful in
patients with dopamine excess or increased sensitivity to dopaminergic
stimulation. Patients with a2-adrenergic receptor excess may respond to the
a2-antagonist yohimbine. Those few patients in whom b-receptors are
increased may be helped with propranolol. a2-Adrenergic receptor deficiency
can be treated with the a2-agonist clonidine, which in this setting may
paradoxically increase blood pressure. One should start with small doses and
gradually increase the dose. If the preceding measures fail, midodrine, a a1-
adrenergic agonist, or dihydroergotamine in combination with caffeine may
help. A particularly refractory form of postural hypotension occurs in some
patients postprandially and may respond to therapy with octreotide given
subcutaneously in the mornings.
Gastropathy
Gastrointestinal motor disorders are frequent and widespread in type 2
diabetic patients regardless of symptoms [155] and there is a poor correlation
Table 6
Pharmacologic treatment of autonomic neuropathy
Clinical status Drug Dosage Side effects
983
984 A.I. Vinik, A. Mehrabyan / Med Clin N Am 88 (2004) 947–999
Enteropathy
Enteropathy involving the small bowel and colon can produce both
chronic constipation and explosive diabetic diarrhea, making treatment of
this particular complication difficult.
Diet. Patients with poor digestion may benefit from a gluten-free diet.
Beware of certain fibers in the neuropathic patient that can lead to bezoar
formation because of bowel stasis in gastroparetic or constipated patients.
Cystopathy
In diabetic autonomic neuropathy, the motor function of the bladder is
unimpaired, but afferent fiber damage results in diminished bladder
sensation. The urinary bladder can be enlarged to more than three times its
normal size. Patients are seen with bladders filled to their umbilicus, yet they
feel no discomfort. Loss of bladder sensation occurs with diminished voiding
frequency, and the patient is no longer able to void completely. Conse-
quently, dribbling and overflow incontinence are common complaints. A
A.I. Vinik, A. Mehrabyan / Med Clin N Am 88 (2004) 947–999 985
Sexual dysfunction
Erectile dysfunction occurs in 50% to 75% of diabetic men, and it tends to
occur at an earlier age than in the general population. The incidence of
erectile dysfunction in diabetic men aged 20 to 29 years is 9% and increases to
95% by age 70. It may be the presenting symptom of diabetes. More than
50% notice the onset of erectile dysfunction within 10 years of the diagnosis,
but it may precede the other complications of diabetes. The etiology of
erectile dysfunction in diabetes is multifactorial. Neuropathy, vascular
disease, diabetes control, nutrition, endocrine disorders, psychogenic factors,
and drugs used in the treatment of diabetes and its complications play a role
[161,162]. The diagnosis of the cause of erectile dysfunction is made by
a logical stepwise progression [161,162] in all instances. An approach to
therapy has recently been presented to which the reader is referred (Fig. 14)
[161].
A thorough work-up for impotence includes medical and sexual history;
physical and psychologic evaluations; blood test for diabetes and a check of
levels of testosterone, prolactin, and thyroid hormones; test for nocturnal
erections; tests to assess penile, pelvic, and spinal nerve function; and test to
assess penile blood supply and blood pressure. The flow chart provided is
intended as a guide to assist in defining the problem (see Fig. 14).
The health care provider should initiate questions that help distinguish
the various forms of organic erectile dysfunction from those that are
psychogenic in origin. Physical examination must include an evaluation of
the autonomic nervous system, vascular supply, and the hypothalamic-
pituitary-gonadal axis.
Autonomic neuropathy causing erectile dysfunction is almost always
accompanied by loss of ankle jerks and absence or reduction of vibration
sense over the large toes. More direct evidence of impairment of penile
autonomic function can be obtained by demonstrating normal perianal
sensation, assessing the tone of the anal sphincter during a rectal examination,
986 A.I. Vinik, A. Mehrabyan / Med Clin N Am 88 (2004) 947–999
Trauma
Vascular status
Sexual development
Penis, testes, scrotum, visual fields, breasts, hair
Testosterone, prolactin
Physicial
Somatic and autonomic nerve function
Perianal sensation
Anal wink
Bulbocavernous reflex
Expiration/ inspiration ratio
Trial of oral Vascular status
agents Pulses
Penile / brachial index
Response No response
sildenafil,
vardenafil
and
tadalafil Abnormal NPT Normal
Erection No erection
Neuropathic Vascular
and ascertaining the presence of an anal wink when the area of the skin
adjacent to the anus is stroked or contraction of the anus when the glans penis
is squeezed (ie, the bulbo-cavernosus reflex). These measurements are easily
and quickly done at the bedside and reflect the integrity of sacral para-
sympathetic divisions.
Vascular disease is usually manifested by buttock claudication but may
be caused by stenosis of the internal pudendal artery. A penile-brachial
index of less than 0.7 indicates diminished blood supply. A venous leak
manifests as unresponsiveness to vasodilators and needs to be evaluated by
penile Doppler sonography.
To distinguish psychogenic from organic erectile dysfunction nocturnal
penile tumescence can be done. Normal nocturnal penile tumescence defines
psychogenic erectile dysfunction, and a negative response to vasodilators
implies vascular insufficiency. Application of nocturnal penile tumescence is
not so simple. It is much like having a sphygmomanometer cuff inflate over
the penis many times during the night while one is trying to have a normal
night’s sleep and the rapid eye movement sleep associated with erections.
The individual may have to take the device home and become familiar with
it over several nights before one has a reliable estimate of the failure of
nocturnal penile tumescence.
and uncomfortable for some patients. The inflatable type is three times more
expensive and subject to mechanical failure, but it avoids the embarrassment
caused by other devices.
Sweating disturbances
Hyperhidrosis of the upper body, often related to eating (gustatory
sweating), and anhidrosis of the lower body is a characteristic feature of
autonomic neuropathy. Gustatory sweating accompanies the ingestion of
certain foods, particularly spicy foods, and cheeses. Gustatory sweating is
more common than previously believed and topically applied glycopyrrolate
(antimuscarinic compound) is very effective treatment in reducing both the
severity and frequency [165,166]. Symptomatic relief can be obtained by
avoiding the specific inciting food. Loss of lower body sweating can cause
dry, brittle skin that cracks easily, predisposing one to ulcer formation that
can lead to loss of the limb. Special attention must be paid to foot care
(Table 7).
Metabolic dysfunction
Hypoglycemia unawareness
Blood glucose concentration is normally maintained during starvation or
increased insulin action by an asymptomatic parasympathetic response with
bradycardia and mild hypotension, followed by a sympathetic response with
glucagon and epinephrine secretion for short-term glucose counterregula-
tion and growth hormone and cortisol in long-term regulation. Blood
glucose concentration is normally maintained during starvation or increased
insulin action by an asymptomatic parasympathetic response with brady-
cardia and mild hypotension, followed by a sympathetic response with
glucagon and epinephrine secretion for short-term glucose counterregula-
tion and growth hormone and cortisol in long-term regulation. The release
of catecholamine alerts the patient to take the required measures to prevent
coma caused by low blood glucose. The absence of warning signs of
impending neuroglycopenia is known as ‘‘hypoglycemic unawareness.’’ The
failure of glucose counterregulation can be confirmed by the absence of
glucagon and epinephrine responses to hypoglycemia induced by a standard,
controlled dose of insulin [167].
In patients with type 1 diabetes mellitus, the glucagon response is
impaired with diabetes duration of 1 to 5 years, and after 14 to 31 years
A.I. Vinik, A. Mehrabyan / Med Clin N Am 88 (2004) 947–999 989
Table 7
Evidenced-based summary of major recommendations for evaluation of diabetic autonomic
neuropathy
Recommendations Evidence grading
Baseline determination of HRV should be performed E
for individuals with type 2 diabetes
Baseline determination of HRV should be performed within E
5 years of diagnosis for those with type 1 diabetes
HRV tests should be repeated annually in type 1 and type E
2 individuals
HRV should be performed before developing an exercise B
program for individuals with diabetes
Preoperative HRV should be performed when planning C
the anesthetic management of diabetic patients
Asymptomatic individuals found to have cardiac E
autonomic dysfunction should undergo additional
cardiac evaluation, particularly if additional cardiovascular
risk factors are present
Testing of cardiac autonomic function after a C
myocardial infraction can provide risk stratification,
identifying a subgroup of patients who are at high
risk for cardiovascular death
Testing of HRV can be used to indicate the presence of B
autonomic neuropathy in patients with symptoms that
may derive from autonomic neuropathy (eg,
erectile dysfunction, gastroparesis, and orthostasis)
Abbreviation: HRV, heart rate variability.
Summary
Diabetic neuropathy is a common complication of diabetes that often is
associated with considerable morbidity and mortality. The epidemiology
and natural history of DN is clouded with uncertainty, largely because of
confusion regarding the definition and measurement of this disorder.
The recent resurgence of interest in the vascular hypothesis, oxidative
stress, the neurotrophic hypothesis, and the possibility of the role of
autoimmunity has opened up new avenues of investigation for therapeutic
intervention. Paralleling an increased understanding of the pathogenesis of
DN, there must be refinements in the ability to measure quantitatively the
different types of defects that occur in this disorder, so that appropriate
therapies can be targeted to specific fiber types. These tests must be validated
and standardized to allow comparability between studies and a more
meaningful interpretation of study results. The ability to manage success-
fully the many different manifestations of DN depends ultimately on success
in uncovering the pathogenic processes underlying this disorder.
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* Corresponding author.
E-mail address: vfonseca@tulane.edu (V.A. Fonseca).
0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2004.04.012
1002 A. Jawa et al / Med Clin N Am 88 (2004) 1001–1036
Historical perspective
In 1936, Kimmelstiel and Wilson described the renal histology at autopsy
in eight cases of which seven had diabetes, together with hypertension,
albuminuria, edema, and renal failure and had the characteristic nodular
lesions of diabetes mellitus. These findings were extended by other workers,
[3,4] who confirmed the existence of a specific histopathology of the kidney
in diabetes mellitus. Diffuse glomerulosclerosis was subsequently described
and distinguished from the nodular form of Kimmelstiel and Wilson [5].
The introduction of percutaneous renal biopsies and electron microscopy
in the 1950s rapidly led to a greater understanding of the disease. Studies
confirmed that the earliest changes in the kidney in diabetes consisted of the
accumulation of basement membrane–like material in the mesangium
together with basement membrane thickening [6].
The most striking advances in DR relates to its treatment with retinal
photocoagulation. The first use of photocoagulation in humans for retinal
photocoagulation using the xenon arc lamp was by Meyer-Schwickerath in
1946. Several large clinical trials have helped define the epidemiology,
natural history, and management strategies in DR [7–16].
Epidemiology
The epidemiology of DN has been best studied in patients with type 1
diabetes, because the time of clinical onset is usually known. Approximately
25% to 45% of these patients develop clinically evident disease during their
lifetime [17–19]. The peak time to development of nephropathy in type 1
diabetes is between 10 and 15 years after the onset of disease. Importantly,
patients who do not develop proteinuria after 20 to 25 years of diabetes have
a very low subsequent risk of developing overt renal disease of only about 1%
per year [17]. In patients with type 2 diabetes, the prevalence of progressive
renal disease has previously been reported to be lower. Nephropathy develops
in up to 50% of type 2 diabetic Pima Indians 20 years after diagnosis of
type 2 diabetes, however, and 15% have progressed to ESRD by this time
[20,21]. Importantly, proteinuria is a risk factor for cardiovascular disease
and it is possible that previous studies underestimate the prevalence of DN
in type 2 diabetes because many patients died of cardiovascular disease
before developing ESRD.
Recent data suggest that the risk of nephropathy is equivalent in the two
types of diabetes. Evidence in support of this hypothesis in one report were
the observations that the time to proteinuria from the onset of diabetes and
the time to ESRD from the onset of proteinuria were similar in type 1 and
type 2 disease [22].
Diabetic retinopathy is more prevalent among patients with type 1
diabetes than type 2. Within 5 and 10 years of diagnosis, about 58% and
A. Jawa et al / Med Clin N Am 88 (2004) 1001–1036 1003
Table 1
Stages of diabetic nephropathy
Stage Characteristics
Normoalbuminuria Normal albumin excretion rate (AER \20 lg/min)
Microalbuminuria Increased albumin excretion rate (AER 20–200 lg/min)
Incipient diabetic Persistent microalbuminuria (in at least two of three
nephropathy collections over 6 mo) hyperfiltration; blood
pressure elevation
Early overt diabetic Clinical-grade proteinuria (AER [200 lg/min in
nephropathy two of three collections within 6 mo or
dipstick-positive proteinuria); hypertension
Advanced diabetic Progressive proteinuria; hypertension; declining
nephropathy glomerular filtration rate (decreased creatinine
clearance, increased blood urea nitrogen and creatinine)
End-stage renal disease Uremia; nephrotic syndrome; need for renal
replacement therapy (transplantation or dialysis)
Abbreviation: AER, albumin excretion rate in a timed specimen.
1004 A. Jawa et al / Med Clin N Am 88 (2004) 1001–1036
with the highest GFR early in the course of their disease may be those most
likely to develop DN [27,28]. There have been no prospective studies,
however, demonstrating that patients with hyperfiltration progress to
chronic renal failure at a greater or faster fashion than patients without
hyperfiltration.
Diabetic retinopathy
In contrast, the natural history of DR is not as clearly defined, although
the condition can be easily classified clinically (Table 2). The early stage of
DR is characterized by loss of pericytes around capillaries in the retina. This
is followed by development of weakness in the capillary wall that leads
to capillary aneurysm formation (microaneurysm) and fluid leakage from
capillaries as their walls become more permeable. Impaired vascular
function gradually develops leading to areas of ischemia and infarction.
In response to these changes local growth factors are secreted that con-
tribute to new vessel proliferation.
Pathology
There are three major histologic changes in the glomeruli in DN: (1)
mesangial expansion, (2) glomerular basement membrane thickening, and
(3) glomerular sclerosis (Figs. 1–3) [36]. Glomerular sclerosis may have
a nodular appearance called the ‘‘Kimmelstiel-Wilson lesion’’ and is often
associated with hyaline deposits in the glomerular arterioles reflecting the
insudation of plasma proteins, such as fibrin, immunoglobulins, and
complement into the vascular wall [36,37].
The mesangial expansion and glomerulosclerosis do not always develop
in parallel, suggesting that they may have somewhat different pathogenesis
[37]. Mesangial expansion may be directly induced by hyperglycemia, by
increased matrix production, or glycosylation of matrix proteins. In vitro
studies have demonstrated that hyperglycemia stimulates mesangial cell
matrix formation [37,38].
Nonproliferative DR is characterized by structural abnormalities of the
retinal vessels (capillaries primarily, although venules and arterioles also
Table 2
Classification of diabetic retinopathy
Classification Characteristics Impact on vision
Background (nonproliferative) Microaneurysms; venous None
retinopathy dilatation; hemorrhages; exudates
Background retinopathy Macular edema May impair vision
with maculopathy
Proliferative retinopathy Neovascularization Vision already
(pathognomonic feature); affected at this stage
fibrous proliferation;
preretinal hemorrhage;
vitreous hemorrhage
Advanced diabetic Vitreous opacities (hemorrhage and Vision already
eye disease fibrous tissues) Retinal detachment affected at this stage
Involutional retinopathy Residual scarring from previously Vision already
active proliferative retinopathy affected at this stage
1006 A. Jawa et al / Med Clin N Am 88 (2004) 1001–1036
Fig. 2. Diffuse and nodular glomerulosclerosis (Kimmelstiel-Wilson lesion; Periodic acid Schiff
stain, 40).
A. Jawa et al / Med Clin N Am 88 (2004) 1001–1036 1007
Fig. 3. Advanced diabetic nephropathy with diffuse and nodular mesangial expansion and
hyaline thickening of arterioles (Periodic acid Schiff stain, 100).
Pathogenesis
The pathogenesis of both DN and DR is complex and multiple factors
are involved in the process. Major risk factors for DN include the following:
Hypertension
Poor glycemic control
Ethnicity (African American, Mexican American, and Pima Indians)
Genetic susceptibility
Increased glomerular filtration rate
Increased plasma prorenin activity
Increased sodium-lithium and sodium-hydrogen countertransport
Furthermore, there is a complex interaction of these factors and the
presence of one may exacerbate the effects of another factor. First outlined
are factors that are common to both conditions and then discussed are
factors that may be specific to any one of the complications (Fig. 8).
Fig. 5. Microaneurysms.
Glucose
=angiotensin
AT 1 receptor
Increased Efferent
glomerular arteriolar
pressure constriction
Ang I l
Ang I l
Fig. 8. Pathologic processes leading to glomerular injury and proteinuria. AGE, advanced
glycation end-product; Ang, angiotensin.
1010
+ +
NADPH NADP NAD NADH
Glucose
Sorbitol Fructose
Polyol pathway
GFAT
Glucosamine-6-P UDP - GlcNAc
Fructose-6-P
Gln Glu
Hexosamine pathway
Pentose-5-phosphates
TK
+ +
Erythrose-4-phosphate Thiamine NADH NAD
DHAP α-Glycerol - P DAG PKC
Diacylglycerol pathway
Glyceraldehyde-3-P
+ Methylglyoxal AGEs
NAD
GAPDH O2 AGE pathway
NADH
1, 3-Diphosphoglycerate
A. Jawa et al / Med Clin N Am 88 (2004) 1001–1036 1011
=
Fig. 9. Potential mechanism by which hyperglycemia can cause tissue damage. Hyperglycemia-
induced mitochondrial superoxide overproduction partially inhibits the glycolytic enzyme
GAPDH, thereby diverting upstream metabolites from glycolysis into glucose-driven signaling
pathways of glucose overuse. AGE, advanced glycation end-product; DAG, diacylglycerol;
DHAP, dihydroxyacetone phosphate; GAPDH, glyceraldehyde phosphate dehydrogenase;
GFAT, glutamine fructose-6-phosphate amidotransferase; PKC, protein kinase C; UDP, uridin
diphosphate. (Adapted from Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q,
et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents
experimental diabetic retinopathy. Nat Med 2003;9:294–9; with permission.)
1012 A. Jawa et al / Med Clin N Am 88 (2004) 1001–1036
In the kidney, growth hormone has been implicated in the early stage
of hypertrophy and hyperfiltration. As discussed later, other growth factors
stimulated by angiotensin II may play a role in the increase in intra-
glomerular matrix hypertrophy. Angiotensin II itself has direct and potent
cellular growth-promoting actions [63]. In addition, it stimulates production
of important growth factors, such as TGF-b. The latter plays a key role in
extracellular matrix formation in the mesangium of the kidney.
Activation of the renin-angiotensin system also leads to a selective
constriction of the efferent arteriole (compared with the afferent one). This
leads to an increase in intraglomerular pressure, an important contributor to
renal damage. Indeed, the selective dilatation of the efferent arterioles has
been suggested as a major factor in the greatly beneficial effects of ACE
inhibitors and angiotensin receptor blockers in DN.
Furthermore, there is a decreased prevalence and possibly a regression of
DR in patients with growth hormone deficiency. Growth hormone may play
a causative or at least an important supportive role in the development and
progression of diabetic vascular complications. Poulsen noted reversal of
florid DR in a woman who had postpartum hemorrhagic necrosis of the
pituitary gland (panhypopituitarism). More recently, growth hormone
deficiency was found to be somewhat protective against retinopathy [64].
Administration of insulin-like growth factor also has been associated with
retinal changes, although these are not entirely specific for DR.
It has been recently recognized that vasoproliferative factors, released by
the retina itself, retinal vessels, or the retinal pigment epithelium, which may
induce neovascularization. Vascular endothelial growth factor, which
inhibits the growth of retinal endothelial cells in vitro, has recently been
implicated in DR [65] and has also been found to be increased in the vitreous
fluid of patients with DR [66].
Duration of disease
In various randomized controlled trials, the total duration of disease has
been found to be the strongest predictor of development and progression of
DR [72]. In the Wisconsin epidemiologic study of DR, prevalence in
younger-onset patients with diabetes was 8%, 25%, 60%, and 80% at 3, 5,
10, and 15 years after diagnosis, respectively [10].
Blood pressure
Some research indicates that elevated systolic blood pressure is a moder-
ate risk factor for both DN and DR, more so for the latter [72]. In UKPDS
trial tight blood pressure control was shown to cause 34% reduction in
progression of retinopathy and a 47% reduced risk of deterioration in visual
A. Jawa et al / Med Clin N Am 88 (2004) 1001–1036 1015
Genetics
The increased synthesis of angiotensin II plays an important role in
initiation and progression of DN by affecting hemodynamic and non-
hemodynamic mechanisms [74]. Studies have shown that an inversion (I)-
deletion (D) polymorphism of the ACE gene (ACE/ID) is associated with
the level of circulating ACE and with an increased risk of coronary heart
disease in nondiabetic patients [75]. Yoshida et al [76] followed 168
proteinuric patients with type 2 diabetes for 10 years and found in an
analysis of the clinical course of the three ACE genotypes that most patients
with the DD genotypes (95%) progressed to ESRD within 10 years. Two
recent studies have confirmed that the D allele has a deleterious effect on
renal function in patients with type 2 diabetes [77,78].
Several studies have shown that the likelihood of developing DN is
markedly increased in patients with a diabetic sibling or parent who has
DN; these observations have been made in both type 1 and type 2 diabetes
[79–81]. One report, for example, evaluated Pima Indians in which two
successive generations had type 2 diabetes [79]. The likelihood of the
offspring developing overt proteinuria was 14% if neither parent had
proteinuria, 23% if one parent had proteinuria, and 46% if both parents
had proteinuria.
One component of the genetic risk may be the ACE gene genotype. In
patients with type 2 diabetes, the DD polymorphism has been associated
with an increased risk for the development of DN, more severe proteinuria,
a greater likelihood of progressive renal failure, and enhanced mortality on
dialysis [76,82,83]. A critical review of 19 studies examining a possible link
between the ACE gene genotype and DN failed to confirm an association
among whites with either type 1 or type 2 diabetes, but could not exclude
a possible association in Asians [84]. Unfortunately, because of poor
methodology, no definite conclusions could be drawn.
An enhanced risk may also be caused by inheritance of one allele of the
aldose reductase gene, the rate-limiting enzyme for the polyol pathway. In
a controlled study of patients with type 1 diabetes, homozygosity for the Z-2
allele was significantly associated with an odds ratio of 5.25 for the presence
of nephropathy [85].
Many patients with salt-sensitive essential hypertension have an elevation
in red cell sodium-lithium countertransport; increased sodium-hydrogen
1016 A. Jawa et al / Med Clin N Am 88 (2004) 1001–1036
Ethnicity
The incidence and severity of DN are increased in blacks (threefold to
sixfold compared with whites), Mexican-Americans, and Pima Indians with
type 2 diabetes [20,96,97]. This observation in such genetically disparate
populations suggests a primary role for socioeconomic factors, such as diet,
poor control of hyperglycemia, hypertension, and obesity [98].
As an example, there seems to be an important association between
hypertension and disease progression in black patients with type 2 diabetes.
A cross-sectional study found that GFR was normal in patients who were
A. Jawa et al / Med Clin N Am 88 (2004) 1001–1036 1017
Pregnancy
In women who begin a pregnancy without retinopathy, the risk of
developing nonproliferative DR is about 10%. Further, those with non-
proliferative DR at the onset of pregnancy and those who have or who
develop systemic hypertension tend to show progression, with increased
hemorrhages, cotton wool spots, and macular edema [105]. Fortunately,
usually some regression occurs after delivery. About 4% of pregnant
women who have nonproliferative DR progress to PDR. Those with
untreated PDR at the onset of pregnancy frequently do poorly unless they
are treated using panretinal photocoagulation. Finally, patients who have
1018 A. Jawa et al / Med Clin N Am 88 (2004) 1001–1036
Diagnosis
Diagnosis of diabetic nephropathy
Guidelines for systematic screening have been developed because patients
with nephropathy are often asymptomatic and because a number of effective
intervention strategies can slow disease progression (Table 3).
Screening for DN needs to be a routine component of diabetes care.
The American Diabetes Association recommends yearly screening for
individuals with type 2 diabetes and yearly screening for those with type 1
diabetes after 5 years’ duration of disease (but not before puberty). Several
screening techniques are available: the albumin:creatinine ratio from
a random spot urine collection, a 24-hour urine collection for albuminuria
and creatinine (allowing calculation of creatinine clearance as well), or
a timed (eg, overnight or 3- to 4-hour) urine collection are all acceptable.
Positive results need to be confirmed with a second measurement because of
the high variability in albumin excretion in people with diabetes. Use of
urine dipsticks for microalbuminuria (on fresh morning specimens) is
reasonable for initial screens, but these findings are semiquantitative, and
positive tests should be followed-up by a 24-hour or timed urine collec-
tion. Microalbuminuria is considered to be present if urinary albumin
excretion is 30 to 300 mg per 24 hours (equivalent to 20–200 lg/min on
a timed specimen or 30–300 mg/g creatinine on a random sample) (Fig. 10).
Short-term hyperglycemia, exercise, urinary tract infections, marked hy-
pertension, heart failure, and acute febrile illness can cause transient
A. Jawa et al / Med Clin N Am 88 (2004) 1001–1036 1019
Table 3
Interpretation of urinary albumin excretion (based on different assessment methods)
Urine albumin: Morning urine
Urinary AER Urinary AER creatinine ratio albumin
Finding (mug/min) (mg/24 hr) (mg/g) concentration (mg/L)
Normal \20 \30 \30 \30
Microalbuminuria 20–200 30–300 30–300 30–300
Macroalbuminuria >200 >300 >300 >300
Abbreviation: AER, albumin excretion rate in a timed specimen.
From American Diabetes Recommendations 2003. Diabetic nephropathy. Diabetes Care
2003;26(Suppl 1); with permission from The American Diabetes Association.
No
+ for albumin
Yes
Condition that may invalidate
urine albumin excretion?
Yes No
Yes
Repeat microalbuminuria
test twice within 3-6 month period.
Rescreen No
2 of 3 tests positive?
in one year
Yes
Fig. 10. Screening for microalbuminuria. (From Molith M, Franz M, Keane W, Megensen CE,
Parring H, Steffes M. Clinical practice recommendations: diabetic nephropathy. Diabet Care
2003;26(Suppl 1):S96; with permission.)
Patients who progress are more likely to have higher hemoglobin A1c values
and a higher blood pressure than nonprogressors [133,134]. A retrospective
study measured both albumin excretion and glycemic control in 1613 patients
with type 1 diabetes [134]. The risk of having microalbuminuria increased
abruptly at hemoglobin A1c value above 8.1%. In a prospective report,
multivariate analysis of 1134 patients with type 1 diabetes found that higher
values for hemoglobin A1c were independent risk factors for progression to
microalbuminuria [135]. Progressors also had higher systolic and diastolic
blood pressures (123/75 mm Hg versus 118/73 mm Hg for nonprogressors).
Progression from microalbuminuria to overt nephropathy within a 10-year
period occurs in 20% to 40% of white patients with type 2 diabetes [136,137].
Risk factors contributing to progression include hyperglycemia, hyperten-
sion, and cigarette smoking. Other studies of Pima Indians and Israeli patients
with type 2 diabetes have found a 4- to 5-year rate of progression to overt
proteinuria of 37% to 42% [138,139]. A 4-year follow-up of 34 patients with
overt proteinuria found a mean loss in GFR of 0.93 mL/min/mo, a rate similar
to that observed in patients with type 1 diabetes [138].
Management
Prevention
Strong clinical trial data suggest that both DN and DR can be prevented
by good glycemic control. In addition to glycemic control data suggest
that good blood pressure control may also decrease the onset of DR and
DN. Furthermore, the development of microalbuminuria is delayed by
ACE inhibitors [140,141].
The DCCT, a randomized, multicenter, controlled clinical trial, demon-
strated that intensive treatment of type 1 diabetes-decreased the progression
of nephropathy and retinopathy. The incidence of microalbuminuria was
significantly reduced by 39% in three combined cohorts, by 34% in the
primary-prevention cohort, and by 43% in the secondary-intervention
cohort [68].
The UKPDS, a randomized, multicenter, controlled clinical trial, demon-
strated that a policy of intensive treatment with goal of meticulous glycemic
control could decrease complications of type 2 diabetes. Patients assigned to
the intensive policy A1c of 7% had a significant 25% risk reduction in
microvascular end points (P \ .01) compared with those in the conventional
policy A1c of 7.9%. At 9, 12, and 15 years follow-up the risk reduction in the
appearance of microalbuminuria was 24%, 33%, and 30%, respectively [67].
The benefit of antihypertensive therapy with an ACE inhibitor in type 1
diabetes can be demonstrated early in the course of the disease when
microalbuminuria is the only clinical manifestation. In one study, the
administration of an ACE inhibitor to normotensive type 1 diabetics
with microalbuminuria decreased both albumin excretion and at 2 years
A. Jawa et al / Med Clin N Am 88 (2004) 1001–1036 1023
Surgical therapy
Several multicenter, prospective, randomized, controlled studies have
demonstrated that intervention with laser photocoagulation surgery or
vitrectomy may preserve vision in certain patients with DR. These studies
are discussed next.
Panretinal photocoagulation
Panretinal photocoagulation is the treatment of choice for high-risk
retinopathy. The Diabetic Retinopathy Study first established the benefit in
treatment of eyes with high-risk criteria with proliferative retinopathy. Laser
panretinal photocoagulation significantly reduced the likelihood that an eye
with high-risk characteristics progresses to severe visual loss, up to greater
than a 50% reduction in visual loss [7]. Eyes with high-risk characteristics
are defined as those with neovascularization of the disk greater than half the
disk area, those with any neovascularization of the disk and vitreous
hemorrhage, or those with neovascularization elsewhere greater than half
the disc area and vitreous or preretinal hemorrhage.
1026 A. Jawa et al / Med Clin N Am 88 (2004) 1001–1036
control eyes [164]. The ETDRS also showed that panretinal photocoagulation
should not be given to eyes with clinically significant macular edema unless
high-risk criteria are present [165]. An acceptable alternative treatment to the
ETDRS strategy is a grid treatment [166].
Panretinal photocoagulation has significant complications: it often causes
decreased visual acuity by increasing macular edema [167] or by causing
macular pucker. Fortunately, the edema frequently regresses spontaneously
over 6 months, but the visual field is usually moderately, yet permanently,
decreased. Color vision and dark adaptation, which are often already
impaired, are worsened by panretinal photocoagulation [168]. For this
reason, panretinal photocoagulation is not recommended for patients with
background DR, who should nevertheless be followed-up closely to detect
any disease progression.
Vitrectomy
Vitrectomy, introduced by Machemer et al [169], plays a vital role in the
management of severe complications of DR. The major indications are
nonclearing vitreous hemorrhage, macular involving or threatening traction
retinal detachment, and combined traction-rhegmatogenous retinal detach-
ment. Less common indications are macular edema with a thickened and taut
posterior hyaloid [170], macular heterotopia, epiretinal membrane, severe
preretinal macular hemorrhage, and neovascular glaucoma with cloudy
media.
Summary
There has been much progress in the understanding of the pathogenesis and
pathophysiology of DN and DR. This has resulted in significant advances in
treatment. In particular the blockade of the renin-angiotensin system for DN
and laser photocoagulation for DR has resulted in decreasing long-term
morbidity. Nevertheless, the impact of these complications remains significant
and clinicians should remain vigilant. Regular screening as recommended by
guidelines and prompt institution of treatment lead to further reductions in
morbidity and mortality.
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Med Clin N Am 88 (2004) 1037–1061
* Corresponding author.
E-mail address: tangw@ccf.org (W.H.W. Tang).
0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2004.04.008
1038 W.H.W. Tang et al / Med Clin N Am 88 (2004) 1037–1061
100
80
Survival (%)
60
40
Nondiabetic subjects without prior MI
Diabetic subjects without prior MI
Nondiabetic subjects with prior MI
20 Diabetic subjects with prior MI
0
0 1 2 3 4 5 6 7 8
Year
Fig. 1. Kaplan–Meier estimates of the probability of death from coronary heart disease in 1059
subjects with type 2 diabetes and 1378 nondiabetic subjects with and without previous
myocardial infarction. I bars indicate 95% confidence intervals. Thin line, nondiabetic subject
without prior MI; medium line, diabetic subjects without prior MI; gray line, nondiabetic
subjects with prior MI; heavy line, diabetic subjects with prior MI. (From Haffner et al.
Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic
subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229, Ó
Massachusetts Medical Society. All rights reserved; with permission.)
Pathophysiology
Ischemic heart disease results from progressive or unstable coronary
atherosclerosis. Atherosclerotic coronary artery disease in diabetic patients
is often a diffuse process, affecting proximal and distal coronary segments.
Diabetic patients frequently suffer from microvascular coronary disease
and a reduction in vasodilatory reserve. Hyperinsulinemia and the insulin
resistance syndrome are believed to have several adverse metabolic
consequences that may promote atherogenesis [3–5]. For example, hyper-
insulinemia may impair endothelial function by inhibition of nitric oxide
synthesis and increased production of endothelin-1 [6]. Advanced glycosyla-
tion end products and elevated levels of free fatty acids, which are products of
the hyperinsulinemic and hyperglycemic states, increase the production of
reactive oxygen species, leading to increased oxidative stress and inflamma-
tion [7,8]. In addition, hyperglycemia is associated with an increase in
chemoattractant cytokines and cell adhesion molecules such as E-selectin,
vascular cell adhesion molecule-1, and intracellular cell adhesion molecule [9].
Diabetic patients are subject to a range of serum lipid abnormalities,
including elevated levels of total cholesterol, very-low-density lipoprotein
cholesterol, and triglycerides and reduced levels of high-density lipoprotein
(HDL) cholesterol [10,11]. In diabetic patients, diminished activity of
W.H.W. Tang et al / Med Clin N Am 88 (2004) 1037–1061 1039
flow reserve may mediate silent ischemic episodes, which occur primarily at
rest or with minimal exertion [26].
The decision to perform screening in asymptomatic diabetic individuals is
a difficult one because a lack of symptoms in the diabetic patient is not
reassuring. Indeed, multiple studies [27,28] have shown that asymptomatic
ischemia predicts multivessel coronary disease, increased adverse clinical
outcomes, and poor survival. Nevertheless, there is a wide variability in risk
profiles for CVD in diabetic patients. Because efforts to screen all diabetic
individuals for CVD are not cost-effective, the American Diabetes Associ-
ation and the American College of Cardiology/American Heart Association
(ACC/AHA) have recommended screening diabetic patients at high risk for
CVD who are about to embark on a moderate- to high-intensity exercise
program. [29,30] ‘‘High risk’’ features are shown in Box 2.
There are multiple modalities available for CVD screening. The reported
accuracies of these tests in diabetic patients are shown in Table 1. The test most
commonly used to screen for ischemia is the exercise treadmill test. The
exercise treadmill test is easy to perform, relatively inexpensive, and is capable
of generating several types of prognostic information, including ischemic ST–
T wave abnormalities, exercise capacity, and heart rate recovery. The exercise
treadmill test, however, is unable to localize ischemia and has diminished
accuracy in the setting of baseline electrocardiograph abnormalities such as
left ventricular hypertrophy, digoxin effect, resting ST-segment abnormalities,
conduction abnormalities, and ventricular-paced rhythms.
Stress myocardial perfusion imaging (eg, stress single photon emission
computed tomography [SPECT]) can be used for risk stratification and
diagnosis of CVD in patients with diabetes when the standard exercise
treadmill test is inadequate. Several studies [31,32] have shown that SPECT
has similar prognostic value in patients with and without diabetes. In
symptomatic patients with diabetes, abnormalities on stress SPECT imaging
independently predict the subsequent occurrence of cardiac death and MI
[33]. Although data on the use of SPECT imaging in asymptomatic patients
with diabetes are limited, preliminary studies have demonstrated that
Table 1
Characteristics of tests used for noninvasive assessment for CVD in diabetic patients
Symptomatic Positive Negative
patients Sensitivity Specificity predictive predictive
Test n included? (%) (%) value (%) value (%)
Exercise tolerance 190 Yes 47 81 85 41
testing [141]
SPECT [31] 138 Yes 86 56 89 48
Dobutamine stress 52 Yes 82 54 84 50
echocardiography
[142]
Table 2
Medical therapies for ischemic heart disease
Drug Starting dosage Major side effects
Nitrates
Sublingual 0.3–0.4 mg Headache, lightheadedness,
Oral 10 mg 3 times/d/ flushing, orthostasis
30 mg 4 times/da
Transdermal 0.2 mg/h
b-Blockers
b1 Selective 25 mg 4 times/d Bradycardia, atrioventricular
Metoprolol succinate 25 mg 2 times/d block, heart failure, fatigue,
Metoprolol tartrate 25 mg 4 times/d depression, erectile dysfunction,
Atenolol then 2 times/d exacerbation of claudication,
Nonselective 40 mg 2 times/d bronchospasm, increased insulin
Propranolol then 4 times/d induced hypoglycemia
Calcium channel blockers
Verapamil 80 mg 4 times/d/ Bradycardia, atrioventricular
Amlodipine 240 mg 4 times/da block, heart failure, flushing,
Nifedipine 5 mg 4 times/d headache, constipation,
Diltiazem 20 mg 4 times/d pedal edema
60 mg 4 times/d/
240 mg 4 times/da
ACE inhibitors
Captopril 6.25–12.5 mg 3 times/d Hypotension, renal insufficiency,
Enalapril 2.5–5 mg 4 times/d hyperkalemia, cough,
Lisinopril 2.5–5 mg 4 times/d angioneurotic edema,
Ramipril 1.25–2.5 mg 4 times/d anaphylaxis
Aspirin 81–325 mg 4 times/d Gastrointestinal ulcers, renal
dysfunction, bronchospasm,
rash
Clopidogrel 75 mg 4 times/d Gastrointestinal ulcers,
rash, thrombocytopenia,
throbocytopenic
thrombotic purpura (rare)
a
Sustained release preparation.
of this trial, 3866 patients with diabetes were randomized to treatment with
either clopidogrel or aspirin. After multivariable adjustment, clopidogrel
was associated with a 13.1% relative risk reduction in the composite
endpoint compared with aspirin (P = 0.032) [48].
Clopidogrel may also benefit patients presenting with acute ischemic
heart disease (unstable angina or non–Q-wave MI). In the Clopidogrel in
Unstable Angina to Prevent Recurrent Events (CURE) trial, the composite
outcome of CV death, nonfatal MI, or stroke occurred in 9.3% of patients
treated with a combination of clopidogrel plus aspirin, compared with
11.4% of patients treated with aspirin alone, after a mean of 9 months’
follow-up (P 0.001). A trend toward benefit with the combination therapy
was maintained in the subgroup analysis of the 2840 diabetic patients in the
trial (14.2% event rate in the combination group versus 16.7% in the group
taking aspirin alone, P = not significant) [49]. As a result, updated guide-
lines from the ACC/AHA task force have recommended that clopidogrel be
added to aspirin early in the treatment of patients presenting with unstable
angina or non–Q-wave MI [50]. In clinical practice, the addition of
clopidogrel is often deferred until after the patient’s cardiologist has chosen
a revascularization strategy (percutaneous coronary intervention [PCI]
versus coronary artery bypass graft surgery [CABG] versus medical ther-
apy). Often, clopidogrel is not administered to patients who are scheduled to
undergo CABG because of the recommendation that CABG be delayed for
a minimum of 5 days after the last dose to prevent complications from
bleeding. This recommendation is controversial, and several trials eval-
uating the optimal timing and dosage of clopidogrel administration are
underway.
GP IIb/IIIa inhibitors are intravenous antiplatelet drugs used during
medical therapy for acute coronary syndromes or as adjunctive therapy
during PCI. In the general population, the use of GP IIb/IIIa inhibitors has
been associated with a reduction of up to 65 acute ischemic events per 1000
patients treated during elective and urgent PCI and with 15 to 32 events per
1000 patients treated for acute coronary syndromes [51]. One agent
particularly, abciximab, has been associated with the long-term benefit of
reduced mortality [52]. Several contemporary trials in PCI have shown that
treatment with GP IIb/IIIa inhibitors is associated with a reduction in the
combined 30-day endpoint of death, MI, and urgent revascularization in
both diabetic and nondiabetic subpopulations [53]. It is presently unclear if
the magnitude of benefit varies among the three available GP IIb/IIIa
inhibitors. The effect of GP IIb/IIIa inhibitors on 6-month target vessel
revascularization (TVR), a surrogate measure of clinical restenosis, is less
certain. Rates of TVR varied markedly between trials and within the
diabetic and nondiabetic subgroups. A substantial body of evidence has
demonstrated that treatment with abciximab during PCI is associated with
a marked reduction in 1-year mortality [52,54,55], a benefit that is
particularly apparent for diabetic patients [56]. The benefit of GP IIb/IIIa
W.H.W. Tang et al / Med Clin N Am 88 (2004) 1037–1061 1045
absolute benefits of ACE inhibitor treatment were greater for diabetic versus
nondiabetic patients (17.3 lives saved per 1000 versus 3.2 live saved per 1000,
respectively).
ACE inhibitor therapy is also beneficial in diabetic patients with at least one
cardiovascular risk factor but no history of cardiovascular disease. The Heart
Outcomes Prevention Evaluation (HOPE) study and the Microalbuminuria,
Cardiovascular, and Renal Outcomes (MICRO) HOPE substudy demon-
strated that ramipril therapy was associated with a 25% reduction in the
combined endpoint of MI, stroke, or cardiovascular death (95% CI 12–36,
P = 0.0004) [67]. This benefit was seen irrespective of a history of cardiovas-
cular disease. Additionally, recent results from the Efficacy of Perindopril in
Reduction of Cardiovascular Events among Patients with Stable Coronary
Artery Disease (EUROPA) study [68] demonstrate the benefit of ACE
inhibitor therapy in diabetic patients with stable CVD.
Calcium channel blockers (CCB) induce coronary and peripheral vasodi-
latation, decrease heart rate, and reduce cardiac contractility. As a group,
CCBs are effective antianginal agents. Although CCBs are generally used in
hypertensive diabetic patients who require multiple drugs for blood pressure
control, CCBs may also be used for therapy of angina in the presence of
contraindications or significant side effects to BBs [69]. In addition, CCBs may
be added to BBs or nitrates if these drugs provide inadequate symptom relief.
The dihydropyridine class of drugs (eg, amlodipine) produces more peripheral
vasodilatation and less negative chronotropic and inotropic effects than CCBs
such as diltiazem and verapamil. Use of short-acting CCBs (eg, nifedipine) is
discouraged because of data suggesting an increased risk of MI [70,71]. On the
other hand, CCBs are the treatment of choice for Prinzmetal’s (or variant)
angina.
In addition to pharmacotherapy for angina, diabetic patients with ischemic
heart disease should undergo intensive cardiac risk factor modification to
prevent progression of atherosclerosis. These therapies include treatment of
hypertension (target blood pressure 130/85 mm Hg), lipid-lowering thera-
pies (target LDL cholesterol 100 mg/dl, triglycerides 150 mg/dl, HDL 40
mg/dl), smoking cessation, glycemic control (target hemoglobin A1c 6.5%),
and weight control. For patients with chronic stable angina that is refractory
to conventional antianginal medications and CVD that is not amenable to
further surgical or percutaneous revascularization, enhanced external coun-
terpulsation is a mechanical therapeutic option that may provide symptom
relief [72].
Coronary revascularization
Despite maximal medical therapy, many diabetics require coronary artery
revascularization, using methods such as percutaneous transluminal coronary
angioplasty (PTCA), PCI with coronary stenting, or CABG for treatment of
ischemic heart disease. It is clear that diabetic patients have a higher risk
W.H.W. Tang et al / Med Clin N Am 88 (2004) 1037–1061 1047
randomized trial were not seen in the BARI registry, raising some questions
about generalizing the results to diabetic patients outside of controlled clinical
trials [89].
Two major trials, the Arterial Revascularization Therapies Study (ARTS)
and Stent or Surgery (SOS) study, were designed to compare PCI with
coronary stenting versus CABG [90,91]. Both trials found no significant
difference in death or MI between the PCI and CABG groups in long-term
follow-up; however, the need for repeat TVR was increased in the PCI groups
compared with the CABG groups (21% versus 3.8% in ARTS, P \ 0.001).
The diabetic patients in ARTS (n = 208) had a higher 1-year event-free
survival with CABG, compared with PCI (84.4% versus 63.4%, P \ 0.001)
[92]. Most of this difference resulted from the increased need for repeat TVR
following PCI. Despite these data favoring selection of CABG in diabetic
patients, advances in adjunctive therapies during PCI and the recent in-
troduction of drug-eluting stents leave the question about the optimal
revascularization strategy for diabetic patients unanswered. Further studies
are ongoing to help guide clinical decision making. In addition, the BARI 2D
study has been designed to evaluate strategies for glycemic control during
revascularization [93].
Table 3
Common heart failure drugs with special considerations for diabetic patients
Drug class Start dose Target Special considerations
(examples) (mg) dose (mg) in diabetics
ACE inhibitors
Captopril 6.25–12.5 50 3 times/d Indicated for all HF patients
Enalapril 2.5–5 10 2 times/d unless contraindicated (#
Lisinopril 2.5–5 10–20 4 times/d blood pressure, "potassium,
Ramipril 1.25–2.5 5 2 times/d "creatinine (use hydralazine/
isosorbide dinitrate if
creatinine 3 mg/dL,
angioedema/cough)
b-Blockers
Carvedilol 3.125–6.25 25 2 times/d Indicated for all systolic HF
Metoprolol 12.5–25 100 4 times/d patients unless contraindicated
succinate (#pulse rate, #blood pressure,
Bisoprolol 2.5–5 20 4 times/d heart block, reactive airway
disease)
Spironolactone 12.5–25 N/A Indicated for advanced systolic HF
(NYHA class III-IV), need to
closely watch for "potassium,
"creatinine in diabetic patients;
no need for up-titration
Hydralazine/ 25 3 times/d 100 3 times/d Indicated for ACE-inhibitor/ARB-
isosorbide 10 4 times/d 40 4 times/d intolerant patients and those
dinitrate with advanced renal insufficiency
Diuretics
Furosemide 20–40 Titrate to Indicated for symptomatic relief
Bumetanide 1–2 euvolemia from fluid retention; thiazides
Torsemide 1–10 (but not loop diuretics) may
Metolazone 2.5–5 attenuate insulin sensitivity
Digoxin 0.125 N/A Indicated for advanced HF to
prevent morbidity, particularly
with concomitant atrial
fibrillation; watch for toxicity
especially with amiodarone and
renal insufficiency; prefer a lower
dose (0.125 4 times/d or 4 times
every other day) especially in
elderly and in women; no need
for up-titration
ARBs
Losartan 25 50 4 times/d Indicated for ACE-inhibitor
Valsartan 80 160 4 times/d intolerant HF patients; appears
Candesartan 4 32 4 times/d to be beneficial when added to
ACE-inhibitor in HF patients
(CHARM) and possibly in CHF
patients with preserved LVEF
1052 W.H.W. Tang et al / Med Clin N Am 88 (2004) 1037–1061
Summary
Ischemic heart disease and HF are major contributors to morbidity and
mortality in patients with diabetes mellitus. Although we have made great
progress in our understanding of the pathophysiology of cardiovascular
disease and diabetes mellitus, cooperation between cardiologists, diabetol-
ogists, and internists is needed to optimize and balance therapies for these
disorders.
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Med Clin N Am 88 (2004) 1063–1084
* Corresponding author. Joslin Diabetes Center, Beth Israel Deaconess Medical Center,
1 Joslin Place, Boston, MA 02215.
E-mail address: martin.abrahamson@joslin.harvard.edu (M.J. Abrahamson).
0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2004.04.010
1064 J.L. Gaglia et al / Med Clin N Am 88 (2004) 1063–1084
Precipitating causes
The commonest precipitating cause of hyperglycemic crises is infection,
which accounts for 20% to 55% of cases, with the most common infections
being pneumonia and urinary tract infections [5]. Omission of diabetes
therapy or inadequate treatment has been recognized as another common
cause of hyperglycemic crises, accounting for 20% to 40% of cases [5]. Up
to 40% of older patients who present with hyperglycemic crises do not have
a previous diagnosis of diabetes [6], with the strongest risk factor in the
general population for undiagnosed diabetes being increasing age [7]. Other
acute medical illnesses that may contribute as precipitating factors include
cerebral vascular accidents, myocardial infarctions, pancreatitis, trauma,
and alcohol intoxication; combined, these account for about 10% of all
cases (Box 1) [5]. Various medications including diuretics, b-blockers,
Clinical presentation
The symptoms of uncontrolled diabetes often precede acute metabolic
decompensation. Symptoms may include malaise, blurred vision, polyuria,
polydipsia, and weight loss. Typically, DKA evolves rapidly over a period of
hours, whereas HHS tends to evolve over days leading to the more severe
hyperosmolality. Dehydration may be worsened by concomitant use of
diuretics [2]. Typical signs of dehydration include dry mucous membranes,
decreased skin turgor, hypotension, and tachycardia. Guidelines have been
established for the determination of volume status based on physical
examination and orthostasis (Table 1). In elderly patients, however, it may
be difficult to judge skin turgor, and patients with long-standing neuropathy
may have impaired response to intravascular volume depletion. A fruity odor
on the breath indicates the presence of acetone from ketogenesis. Kussmaul’s
Table 1
Clinical assessment of dehydration
Clinical finding % dehydration Estimated volume
Decreased tissue turgor 5 1L
Orthostatic change in
pulse alone 10 2L
Orthostatic change in
pulse and blood pressure
([15/10 mm Hg) 15–20 3–4 L
Supine hypotension or sepsis >20 >4 L
Pathophysiology
In all hyperglycemic crises, insulin deficiency, absolute or relative, against
a background of increased insulin resistance is the principle underlying
defect. Insulin levels are not adequate to maintain normal serum glucose
and suppress ketogenesis. Hyperglycemia itself can further compromise
insulin secretory capacity and increase insulin resistance causing a vicious
cycle of worsening hyperglycemia and decreasing insulin production [13]. In
elderly individuals with decreased baseline secretory reserve, this effect may
be quite pronounced.
J.L. Gaglia et al / Med Clin N Am 88 (2004) 1063–1084 1067
Laboratory findings
Initial evaluation of elderly patients presenting with hyperglycemic crisis
should include plasma glucose, electrolytes, bicarbonate, blood urea
nitrogen (BUN), creatinine, creatinine kinase, phosphate, urine and serum
1068 J.L. Gaglia et al / Med Clin N Am 88 (2004) 1063–1084
Fig. 1. Insulin deficiency, relative or absolute, leads to increased hepatic glucose production
and decreased peripheral use of glucose, which results in hyperglycemia, osmotic diuresis, and
dehydration. In severe insulin deficiency, ketone body production is augmented leading to
ketonemia and eventual ketoacidosis. GFR, glomerular filtration rate.
ketones, calculation of the anion gap, arterial blood gas, complete blood
count with differential, urinalysis, pregnancy test in all women of re-
productive age, and electrocardiogram. Measurement of hemoglobin A1C
may provide useful information about the underlying degree of metabolic
control. If clinically indicated, components of an infectious work-up
including culture of blood, urine, and throat and a chest radiograph and
possible abdominal imaging should be performed. If pneumonia is suspected
without evidence of infiltrate on the admission radiograph, chest radiogra-
phy should be repeated after adequate hydration. If myocardial infarction is
suspected, cardiac enzymes should be evaluated.
Leukocytosis with elevated granulocytes is commonly seen and white cell
counts of 12 to 20 K are not unusual. Mild leukocytosis by itself does not
imply infection, but instead is a response to stress and dehydration. White
cell counts above 30 K, however, are highly suggestive of infection.
J.L. Gaglia et al / Med Clin N Am 88 (2004) 1063–1084 1069
Fluids
Fluid replacement is one of the mainstays of treatment. Fluid re-
placement lowers blood sugars independent of insulin; reduces the levels of
counter-regulatory hormones (which improves insulin sensitivity); and
restores intravascular volume. Although not recommended, it is possible
to treat HHS without the administration of insulin, but with fluids alone
[20,24,25]. This approach is discouraged, because there have been case
reports of patients becoming acidemic if insulin is withheld [20]. Fluid
1070 J.L. Gaglia et al / Med Clin N Am 88 (2004) 1063–1084
Table 2
Suggested replacement fluids
Time Volume
1st h 1–2 L normal saline
2nd h 1 L normal saline
3rd h 500 mL to 1 L normal saline
4th h 500 mL to 1 L normal or half normal saline
5th h 500 mL to 1 L normal or half normal saline
Total first 5 h 3.5–5 L
6th–12th h 250–500 mL/h half normal saline
Administer normal saline or colloid as indicated to maintain hemodynamic stability. Once
corrected sodium approaches normal consider changing to half normal saline (usually about
4 h). Change to D5 half normal saline when blood glucose reaches 250 mg/dL. Patients with
a prolonged antecedent period may require additional fluid replacement and caution must be
used with patients who are elderly, with a history of congestive heart failure, or renal failure.
Insulin therapy
Before the introduction of insulin in 1922, diabetic coma was almost
uniformly fatal. The primary goals of insulin therapy are to reverse
ketogenesis (if present); suppress lipolysis; and inhibit hepatic gluconeogen-
esis. Insulin also decreases the effective plasma osmolality by increasing
cellular permeability to glucose. There are several cautions, however, to the
use of insulin therapy in hyperglycemic crises. Insulin therapy should not be
initiated in patients with hypotension and severe hyperglycemia until
volume resuscitation has occurred. Insulin enhances intracellular transport
of glucose with a resultant fluid shift from the extracellular to the
intracellular compartment. As much as 2 to 3 L may shift out of the
intravascular compartment [26], increasing the risk of hypovolemic shock
and thromboembolism in the setting of inadequate volume resuscitation.
Because insulin also mediates the re-entry of potassium into the intracellular
compartment, insulin administration can lead to life-threatening hypokale-
mia, and should also be withheld in patients who are hypokalemic at
presentation (potassium less than 3.3) until potassium replacement therapy
is given (potassium greater than 3.5) [27]. Insulin therapy in these situations
may result in arrhythmias, impaired cardiovascular function, or muscle
weakness and respiratory failure. Ultimately, it is the adequacy of fluid and
electrolyte repletion that determines the effectiveness of insulin therapy.
During hyperglycemic crises there is usually profound insulin resistance
requiring supraphysiologic doses of insulin to prevent ketogenesis, gluco-
neogenesis, and lipolysis [28,29] and resolution of hyperglycemia and
hyperosmolality [30]. Intravenous administration is the preferred initial
route of administration because it leads to a more rapid initial fall in glucose
and ketones when compared with subcutaneous or intramuscular adminis-
tration [31]. After the first 2 hours of treatment, the rate of decline of
ketonemia and hyperglycemia is comparable between all three routes of
1072 J.L. Gaglia et al / Med Clin N Am 88 (2004) 1063–1084
accidental insulin omission later in the day. For patients in whom total
insulin requirements are not known, an initial dose of 0.5 to 1 U/kg/d total
is usually given in a mixed regimen including both short- or rapid-acting and
intermediate- or long-acting insulins.
Bicarbonate
Although the use of alkali therapy may seem an attractive method to
correct the metabolic acidosis seen in DKA, it is usually not necessary
because the metabolic acidosis tends to correct with insulin administration
as protons are consumed and bicarbonate is regenerated during ketoanion
metabolism. The administration of bicarbonate may actually lead to
rebound alkalosis, worsened hypokalemia, paradoxical central nervous
system acidosis, increase in intracellular acidosis, and prolongation of
ketosis. Joslin [34] was one of the first to recognize the pitfalls of bicarbonate
therapy writing in 1917 that, ‘‘The dangers attendant upon the use of alkalis
in the treatment of acid intoxication far outweigh their advantages.’’ Joslin’s
avoidance of bicarbonate therapy may have contributed to the decreased
mortality seen in his treatment protocol compared with other major clinical
centers. When studied in a randomized prospective manner, there is no
benefit to bicarbonate therapy in patients with a pH between 6.9 and 7.14
[35,36]. The groups reported with pH less than 7 have been very small,
however, and there have been no prospective randomized studies evaluating
the use of bicarbonate when the arterial pH is less than 6.9. Severe acidemia
has been associated with vascular refractoriness to adrenergic action, central
nervous system depression, and impaired myocardial contractility. Bicar-
bonate therapy is reserved for those patients with clinical manifestations of
acidemia or a pH less than 7. Usually 1 to 2 ampules of sodium bicarbonate
(50–100 mEq) is added to a liter of half normal saline to make a nearly
isotonic solution, which is administered over a period of 1 to 2 hours. If
potassium is also low, 10 to 20 mEq of potassium chloride may be added.
The venous pH should be rechecked 30 minutes after administration and
treatment repeated if the corrected pH is below 7.
Potassium
In 1946 Holler [37] first recognized the importance of potassium reple-
tion in the treatment of hyperglycemic crises. Before his publication, it was
not uncommon for patients to die after apparent treatment and resolution
of diabetic coma. One such description taken from a 1944 report is as
follows: ‘‘...after considerable hours of therapy and improvement, they
suddenly fail rapidly and die. Analyses show that the serum sodium,
chloride, carbon dioxide and the blood sugar were satisfactory. The urine
sugar and ketones had cleared up’’ [38]. Potassium is important for muscle
function, and hypokalemia has been associated with arrhythmias, cardiac
J.L. Gaglia et al / Med Clin N Am 88 (2004) 1063–1084 1075
Phosphate
Total body phosphate depletion is common in DKA and HHS. Like
potassium, phosphate shifts from the intracellular to the extracellular
compartment in hyperglycemic crises and serum levels of phosphate at
presentation are typically normal or elevated. Osmotic diuresis, however,
leads to enhanced urinary phosphate losses and total body depletion.
During insulin therapy phosphate reenters the intracellular compartment
with resultant hypophosphatemia. Because of the prolonged duration of
symptoms in HHS and frequent comorbid conditions, phosphate levels
are often lower than those seen in DKA. Potential complications of
severe hypophosphatemia include decreased cardiac output, respiratory
muscle weakness, rhabdomyolysis, central nervous system depression, sei-
zures and coma, acute renal failure, and hemolytic anemia [39]. In theory,
phosphate depletion may also contribute to decreased concentrations of
Table 3
Guidelines for potassium replacement
Serum K (mEq/L) Additional K in IVFs
\3.5 40 mEq/L
3.5–4.5 20 mEq/L
4.5–5.5 10 mEq/L
>5.5 Stop K infusion
Do not administer K if K is [5.5 or patient is anuric.
Abbreviation: IVFs, intravenous fluids.
1076 J.L. Gaglia et al / Med Clin N Am 88 (2004) 1063–1084
Complications
Pancreatitis
Nonspecific elevations of amylase and lipase may occur in both DKA
and HHS. In one recent series, nonspecific elevations in amylase and lipase
occurred in 16% to 25% of cases of DKA. Serum amylase and lipase may be
elevated to more than three times normal without clinical or CT evidence of
actual pancreatitis [45]. The cause of nonspecific hyperamylasemia in
hyperglycemic crises is thought to be multifactorial including salivary
hyperamylasemia, reduced renal clearance of amylase, and increased
leakage from the pancreas. Much less is known about the causes of
hyperlipasemia but it is postulated that the reduced glomerular filtration
seen in hyperglycemic crises may result in decreased renal clearance and that
nonpancreatic lipases may be measured in the current assay generating false-
positive results [45].
Coexisting acute pancreatitis, however, may occur in 10% to 15% of
cases of DKA [46]. Acute pancreatitis in hyperglycemic crises is often
associated with transient severe hypertriglyceridemia. Insulin deficiency
promotes lipolysis, which releases free fatty acids. With the inhibition of
lipoprotein lipase in peripheral tissues and increased delivery of free fatty
acids to the liver, severe hypertriglyceridemia may ensue. In a recent series
by Nair et al [46] of 100 consecutive patients admitted with DKA, 22 had
mild hypertriglyceridemia (greater than 500 mg/dL) and 8 had severe
hypertriglyceridemia (greater than 1000 mg/dL). Half of the patients with
severe hypertriglyceridemia were diagnosed with pancreatitis based on CT
findings. In these patients, the hypertriglyceridemia was transient with
triglyceride levels decreasing to less than 300 mg/dL with resolution of
J.L. Gaglia et al / Med Clin N Am 88 (2004) 1063–1084 1077
ketosis. Acute pancreatitis was seen more often in patients with more severe
metabolic acidosis (pH 7.15 versus 7.31, P = .0001) and higher serum glucose
(934 mg/dL versus 714 mg/dL, P = .02) at the time of presentation [46].
Rhabdomyolysis
Rhabdomyolysis is a clinical and biochemical syndrome resulting from
the destruction of myocytes and leakage of their cellular contents into the
plasma. It is a frequently unrecognized feature of hyperglycemic crises with
an incidence of 17% in one large series (defined as creatinine kinase levels
greater than 1000 IU/L) [47]. Patients who presented with rhabdomyolysis
had significantly higher blood glucose levels and serum osmolality on
admission. Patients with rhabdomyolysis also had evidence of decreased
renal function with significantly higher concentration of BUN, creatinine,
and b2-microglobulin [47,48]. In a series of 265 patients with hyperglycemic
crises, 44 of which had evidence of rhabdomyolysis, the mortality within 1
week of presentation was significantly higher in those with rhabdomyolysis
(38.5% for DKA, 35.5% for HHS) than those without (9.7% for DKA,
26.7% for HHS, P \ .05) [47]. In this series by Wang et al [47] there was not
a significant age-related difference in the incidence of rhabdomyolysis. The
mean age was higher in those with ketoacidosis and rhabdomyolysis who
died, however, compared with those who recovered (mean age 62.6 6
versus 40 8 years old) [47]. Given the positive correlations between age,
osmolality, and increased mortality [4] it is particularly important to identify
and treat those patients in the geriatric population who present with
rhabdomyolysis as a component of their hyperglycemic emergency.
Thromboembolism
Although there are no data demonstrating the safety or efficacy of low-
dose or low-molecular-weight heparin in hyperglycemic crises, thrombopro-
phylaxis should be considered for all patients without a contraindication to
low-level anticoagulation. Diabetes itself is associated with various pro-
thrombotic abnormalities including vascular endothelial dysfunction, eleva-
tion of coagulation activation markers and clotting factors, increase in
plasminogen activator inhibitor type 1, decrease in the anticoagulant protein
C, and platelet hyperactivity (reviewed in [49]). In hyperglycemic crises, such
as HSS or DKA, the combination of severe dehydration, increased blood
viscosity, low cardiac output, and stimulation of prothrombotic mediators
by hyperglycemia can lead to a hypercoagulable state and thromboembo-
lism. A number of case reports and retrospective reviews from the 1970s
suggest an increased incidence of vascular occlusive disease including
cerebral infarct, myocardial infarction, pulmonary embolism, mesenteric
thrombosis, and disseminated intravascular coagulation in HHS and DKA
[50–52]. With the introduction of prophylactic anticoagulation (twice daily
low-dose subcutaneous heparin) and aggressive early hydration the incidence
1078 J.L. Gaglia et al / Med Clin N Am 88 (2004) 1063–1084
Cerebral edema
Asymptomatic cerebral edema is very common in hyperglycemic emer-
gencies and is usually present before treatment is begun [58]. Clinically
apparent cerebral edema is extremely rare in adults but occurs in
approximately 1% of children with DKA and is associated with a mortality
rate of approximately 20% [59]. It had been previously hypothesized that
cerebral edema is caused by the accumulation of idiogenic osmolytes in
brain cells exposed to hyperosmolar conditions and that the rapid decrease
in extracellular osmolality during treatment resulted in brain swelling. More
recent studies do not indicate an association between cerebral edema and the
change in serum glucose concentration during therapy or the rate of fluid or
sodium administration. Instead, cerebral edema may be related to brain
ischemia. Cerebral edema has been associated with lower partial pressures of
arterial carbon dioxide, higher BUN concentrations, slow rise in serum
sodium with treatment, and treatment with bicarbonate. Hypocapnia
(which causes cerebral vasoconstriction), dehydration (which decreases
brain perfusion), and bicarbonate therapy (which can cause central nervous
hypoxia) are all expected to increase brain ischemia and lead to worsening
vasogenic edema several hours after initiation of therapy and reperfusion.
This may also help explain why cerebral edema is more common in children
than adults, because children’s brains have higher oxygen requirements and
are more susceptible to ischemia [59]. A slow rise in serum sodium with
J.L. Gaglia et al / Med Clin N Am 88 (2004) 1063–1084 1079
Time
Vitals/Examination
Pulse
Blood Pressure
Respirations
Temperature
Mental Status
Laboratories
Na
K
Cl
HCO3
Cr
Ca
PO4
Mg
Anion Gap
Calculated Effective Osms
Fluids
Normal Saline
1/2 normal saline
Prevention
Unfortunately, one third of diabetes cases (usually type 2) are un-
diagnosed [63]. Members of ethnic minorities including African Americans,
Hispanic Americans, Native Americans, Asian Americans, and Pacific
Islanders are particularly at risk [64]. Twenty percent to 40% of patients
who present with hyperglycemic crises do not have a prior history of insulin
use [3] or diabetes [2,6] and the early signs and symptoms of hyperglycemia
J.L. Gaglia et al / Med Clin N Am 88 (2004) 1063–1084 1081
are often unnoticed. The strongest risk factor for undiagnosed diabetes is
increasing age with the odds increasing by 1.05 for each year increase in age
[7] and almost one third of those admitted to hospital with hyperosmolarity
come from nursing homes [2]. Wide implementation of the screening
guidelines proposed by the Expert Committee on the Diagnosis and
Classification of Diabetes Mellitus [64] would essentially eliminate these
undiagnosed cases of diabetes [7].
The geriatric population is at particular risk for developing hyperglyce-
mic crises with the development of diabetes. With increasing age, insulin
secretory reserve, insulin sensitivity, and thirst mechanisms decrease. The
elderly are particularly vulnerable to hyperglycemia and dehydration, the
key components of hyperglycemic emergencies. As mortality increases with
increasing age, it is particularly important to identify patients at risk within
the geriatric population. If recognized early, hyperglycemia can frequently
be treated in the outpatient setting even with moderate or large ketonuria,
provided patients can take fluids, monitor blood glucose frequently, and
follow standard ‘‘sick day rules’’ [65]. In the Memphis Chronic Disease
Program, hospital days for diabetes-related admissions were reduced by
over 60% after institution of an outpatient monitoring program [66,67].
With increased diabetes surveillance and aggressive early treatment of
hyperglycemia and its complications, morbidity and mortality from acute
diabetic crises in the geriatric population can be greatly reduced.
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Med Clin N Am 88 (2004) 1085–1105
Dr. Feinglos has received research support from Aventis Pharmaceuticals, Glaxo-Smith-
Kline, Pfizer Pharmaceuticals, Novartis, and Hoffman La-Roche.
* Corresponding author.
E-mail address: lien0002@mc.duke.edu (L.F. Lien).
0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2004.04.002
1086 L.F. Lien et al / Med Clin N Am 88 (2004) 1085–1105
Glycemic goals
Although the diagnosis of diabetes is clearly a predictor of poor outcome,
hyperglycemia has been shown to be an independent marker of in-hospital
1088 L.F. Lien et al / Med Clin N Am 88 (2004) 1085–1105
Management goals
The first goal of inpatient diabetes management is safety. In most cases,
the medical regimen used in the outpatient setting will need to be modified.
Oral hypoglycemic agents may need to be discontinued in favor of scheduled
insulin (see later discussion), and insulin requirements may be markedly
different. Multiple issues may contribute to the difficulty in attaining
L.F. Lien et al / Med Clin N Am 88 (2004) 1085–1105 1089
Monitoring
Bedside glucose monitoring should be performed at least four times
daily (ie, before meals and at bedtime for the patient who is eating). A
glucose check at 3 AM can also be useful in patients with fasting hyper-
glycemia because an elevated 3 AM glucose level could indicate insufficient
night time insulin dosing, whereas low 3 AM glucose may be indicative of
an early peak in PM insulin or insufficient caloric intake at bedtime.
Patients with persistent hypoglycemia may require an overall reduction in
insulin dose.
The patient who is assigned to no oral intake of food or liquid (NPO,
‘‘nothing by mouth’’) or to continuous tube feedings should have glucose
levels checked at least every 6 hours. In special circumstances, such as an
unusual bolus tube feeding schedule, the timing of the bedside glucose
checks should be carefully coordinated with the timing of the feedings.
1090 L.F. Lien et al / Med Clin N Am 88 (2004) 1085–1105
Subcutaneous insulin
Baseline data collection
One of the first steps in determining an appropriate insulin regimen for
an inpatient with type 2 diabetes consists of gathering important base-
line data on the diabetes history, if any. Crucial data items include outpa-
tient insulin or oral agent regimen, dietary habits, usual weight, duration
of diabetes, assessment of home glucose control (frequency of glucose
monitoring, glucose values, and compliance), frequency and severity of
hypoglycemia, and the presence and severity of diabetic complications.
Assessment of outpatient compliance may be particularly valuable; the
stated outpatient regimen may be excessive in patients who are not
regularly taking their medications. For example, a patient who reportedly
takes a total of 40 units of subcutaneous insulin twice daily at home but is,
in truth, noncompliant could suffer from hypoglycemia if this full regimen
is instituted on admission. A history of severe diabetes complications
should suggest the possibility of autonomic neuropathy, which can
complicate inpatient management of blood glucose and hemodynamic
monitoring.
Table 1
Types of insulin formulations
Insulin formulations Onset to peak Duration Appearance Comments
Ultra-short–acting
Lispro (Humalog) 15 min–1 h 3–4 h Clear Must be taken with food
Aspart (Novolog) 15 min–1 h 3–4 h Clear Must be taken with food
Short Acting
Regular 30 min–4 h 4–6 h Clear
Long Acting
Neutral protamine 1–8 h 12–20 h Cloudy Can be mixed, but draw the
Hagedorn (NPH) short acting insulin firsta
Ultralente 3–10 h 18–24 h Cloudy
Glargine (Lantus) ‘‘No peak’’ 24 h Clearb The only long-acting insulin
that is clearb
NPH dose should be cut by
approximately 20% when
converting to glargine
Cannot be mixed with
short-acting insulin
Combination insulins Long-acting component Short-acting component
70/30 (regular) 70% NPH 30% regular
NovoLog mix 70/30 70% aspart-protamine 30% aspart
suspension
75/25 75% lispro-protamine 25% lispro
suspension
a
The NPH insulin should not be drawn first because contamination of the regular insulin
bottle by a needle containing NPH can alter the kinetics of the regular insulin.
b
Clear.
Data from Refs. [28,32,66].
insulin sensitivity in patients with type 2 diabetes. Patients who are very
insulin resistant may require dosages as high as 0.6 to 1.0 units/kg/day [30],
whereas a patient who is previously insulin naıı̈ve may be more sensitive and
benefit from a lower starting dosage. After estimating total daily insulin
dose, the next step is to determine the frequency of standing dose insulin
administration. Several options are available.
Two injections daily. For patients who are eating, the estimated daily insulin
dose should be divided into two injections:
Sixty-seven percent (two thirds) of the total daily dosage is administered
in the morning, before breakfast.
Of this amount, 67% (two thirds) is given as neutral protamine
Hagedorn (NPH) insulin and 33% (one third) as regular insulin.
Thirty-three percent (one third) of the total daily dosage is administered
before the evening meal.
Of this evening amount, the dose is divided into 50% NPH and 50%
regular. Alternatively, in patients on this regimen with persistent
fasting hyperglycemia, the evening amount can be divided into 67%
(two thirds) NPH insulin and 33% (one third) regular insulin.
A premixed preparation of 70% NPH and 30% regular insulin is
available for the patient who has difficulty learning how to mix the insulins.
For the patient who can mix insulin, a ‘‘split-mix’’ regimen can provide
additional flexibility. In this regimen, the ratio of NPH to regular insulin can
be adjusted as needed [28]. For patients who are NPO, all doses of insulin
are typically reduced by 50%.
Four injections daily. There are two options for using a four-injection regimen
for the patient who is eating. The first option is to use regular insulin and NPH
insulin:
Twenty-five percent (one fourth) of the total daily dosage is admin-
istered as regular insulin before breakfast, and again before lunch, and
again before dinner.
Twenty-five percent (one fourth) of the total daily dosage is admin-
istered as NPH insulin before bedtime.
For optimal efficacy of the pre-meal regular and bedtime NPH intensive
regimens, it is important to consider proper timing of the regular insulin in
relation to meals. The most challenging aspect of this regimen in the
inpatient setting is to ensure the delivery of regular insulin 30 to 45 minutes
before a meal [4,17].
In the patient who is not eating, the total daily insulin dosage is reduced
by 50%. Twenty-five percent of the reduced total daily dosage is given as
regular insulin every 6 hours. NPH should not be used at bedtime in patients
who are NPO for an extended period of time. In the patient who is NPO
only overnight (ie, in preparation for a procedure), however, NPH can be
given at full dose to prevent fasting hyperglycemia.
The second option is to use ultra-short–acting insulin and long-acting,
peakless insulin:
Seventeen percent (one sixth) of the total daily dosage is administered as
ultra-short acting insulin (eg, lispro or aspart) before breakfast, and
again before lunch, and again before dinner.
Fifty percent (half) of the total daily dosage is administered before
bedtime as long-acting, peakless insulin (glargine).
An alternative method is to use 0.1 units/kg of ultra-short–acting insulin
at each meal and 0.3 to 0.7 units/kg of long-acting, peakless insulin at
bedtime [29]. Although glargine can be given consistently at any time of the
day, it is commonly given at bedtime, in part to prevent the mistake of
mixing it with a short-acting insulin [31]. Glargine is maintained at an acidic
pH level of 4 to maintain solubility, which is incompatible with other insulin
types [32].
Patients who are not eating should not receive ultra-short–acting insulin.
These patients can either be converted to regular insulin every 6 hours, as
above, or glargine can be used alone. Although there is little evidence to
support the use of glargine alone, when used at an appropriate dose, it
should not cause fasting hypoglycemia.
Supplemental insulin
Inappropriate use of sliding scale alone. A common misconception is that
a sliding scale insulin regimen alone is sufficient for diabetes management. A
sliding scale, when used alone, cannot achieve adequate management of
hyperglycemia. These regimens react to the presence of hyperglycemia
instead of acting to prevent the occurrence of hyperglycemia [17,25,29].
Therefore, by definition, patients using this regimen must reach an unaccept-
able level of hyperglycemia before receiving insulin. Sliding scale insulin
given at meal times alone also provides no coverage at night and, therefore,
may result in the development of fasting hyperglycemia. Therefore, a sliding
scale regimen should be used only as a supplemental regimen in conjunction
with a scheduled insulin dosage [17,25,28,29,34].
Table 2
Calculating supplemental insulin dose (The interval of the supplement should be 5% of the total
daily scheduled standing dose insulin. The number of dosage units shown in the table are provided
based on a patient receiving 100 units of insulin daily.)
Plasma glucose (mg/dL) Supplemental regular insulin
70–200 Give scheduled insulin
201–250 Add 5 units to scheduled insulin dose
251–300 Add 10 units to scheduled insulin dose
301–350 Add 15 units to scheduled insulin dose
351–400 Add 20 units and notify on-call physician
L.F. Lien et al / Med Clin N Am 88 (2004) 1085–1105 1095
Intravenous insulin
Intravenous insulin administration protocols
A number of protocols have been developed to assist with titration of IV
insulin infusion rates. One of the first published protocols was the Portland
protocol described by Furnary et al [20–22]. The need for an IV insulin
infusion protocol that addresses individual characteristics of the patient has
gradually received further attention by other authors as well [25]. Trence
et al [35] published an IV insulin infusion protocol consisting of four
algorithms that take into account the patient’s level of insulin sensitivity.
Similarly, Lien et al [36] developed an IV insulin nomogram that dictates the
rate of change of the insulin infusion according to the rate of change of
glucose levels through the novel method of using a multiplication factor
obtained from an easily accessed format. This allows an even more
individualized approach to patients with varying insulin sensitivity. Imple-
mentation of the new nomogram was found to significantly reduce errors in
the delivery of IV insulin, which also reduced persistent hyperglycemia in
critical care patients [36].
Biguanides
Metformin is currently the only biguanide available for use in the United
States. This agent acts primarily by reducing hepatic glucose output and
increasing peripheral glucose uptake [38]. Metformin is presently considered
a first-line agent for treatment of obese patients with type 2 diabetes because
it does not promote weight gain and may facilitate weight loss. It has the
additional advantage of not causing hypoglycemia.
The most feared complication of metformin is the development of lactic
acidosis. Lactic acidosis can be classified into two types. Type A is typically
caused by marked tissue hypoperfusion with resulting anaerobic production
of lactic acid. In contrast, the mechanism of type B lactic acidosis is less well
understood. Patients with type B lactic acidosis do not exhibit signs of
hypoperfusion. Postulated mechanisms include toxin-induced impairment of
cellular metabolism or regional areas of ischemia [39]. Lactic acidosis
associated with metformin therapy is of the type B and has been attributed
to accumulation of the drug [40].
The actual incidence of lactic acidosis attributable to metformin is
unclear. The use of another biguanide, phenformin, was clearly associated
with the development of lactic acidosis, and this medication was withdrawn
from the market in the late 1970s. Phenformin was estimated to cause an
incidence of lactic acidosis of 40 to 64 cases per 100,000 patient-years. In
contrast, recent examinations of lactic acidosis attributable to metformin
estimate the incidence to be 9 cases per 100,000 patient-years [41].
The incidence of lactic acidosis is presumed to be higher in patients who
have conditions predisposing to hypoxia, including renal insufficiency,
congestive heart failure requiring medical therapy, cardiovascular collapse,
acute myocardial infarction, and septicemia. According to the product
labeling, metformin is contraindicated in these patients; and caution should
be used in patients older than 80, those with hepatic disease, and in those
with chronic obstructive pulmonary disease associated with hypoxemia [42].
However, there are abundant data that demonstrates that metformin is
frequently prescribed for patients who have one or more contraindications
to its use [43–45]. The impact of this prescribing pattern is difficult to
evaluate. In a recent systematic review of 176 prospective and cohort studies
[46] (including 17,156 patients taking metformin and 8943 not taking
metformin), no cases of lactic acidosis were identified. Within the 164
prospective studies included in the systematic review, 156 cases allowed the
inclusion of patients with at least one contraindication, and no adverse
effects were observed; however, there was insufficient information to
estimate the number of participants having a contraindication. These and
other studies have speculated that the association of metformin and lactic
1098 L.F. Lien et al / Med Clin N Am 88 (2004) 1085–1105
acidosis may be coincidental rather than causal, but until the drug is studied
in this population, the safety of metformin in this setting remains unproven.
Concern regarding lactic acidosis and the use of metformin also arises in
conjunction with the use of contrast media. Metformin is excreted unchanged
in the urine, and, in patients with normal renal function, over 90% of
the drug is eliminated within 24 hours. When renal function is impaired,
however, metformin accumulates, theoretically increasing the risk of lactic
acidosis. The administration of contrast media carries the risk of contrast-
induced nephropathy with a peak incidence occurring after approximately 24
to 48 hours. The risk of contrast-induced nephropathy is increased in patients
who are volume-depleted and in those with diabetic nephropathy. Although
the development of lactic acidosis in this setting is a rare complication, it has
been estimated that the incidence of lactic acidosis in diabetic patients
receiving metformin and contrast media is 2 cases per million patients per
year [47]. Current recommendations are that metformin be stopped before
and for 48 hours after contrast administration. Serum creatinine should be
followed closely to detect the development of renal insufficiency. Pretreat-
ment with adequate hydration and N-acetylcysteine has also been shown to
reduce the risk of contrast-induced nephropathy [48–50].
Sulfonylureas
Sulfonylureas act by binding to and closing an ATP-dependent potas-
sium channel (KATP). In the pancreatic b-cell, this binding-closing
mechanism results in sustained membrane depolarization, activation of
voltage-dependent calcium channels, calcium influx, and migration of
insulin-containing vesicles to the cell surface, culminating in insulin release.
The most commonly used sulfonylureas in the United States are glyburide,
glipizide, and glimepiride. In the inpatient setting, the use of sulfonylurea
therapy is limited by the propensity for hypoglycemia. Sulfonylureas should
be discontinued in any patient who is NPO. The kinetics of sulfonylureas
may be changed with hepatic or renal dysfunction; thus, they should be
avoided in patients with significant impairment.
Although the morbidity and mortality benefits of intensive glycemic
control in the acute setting have been demonstrated, particularly among
patients after acute myocardial infarction, the role of sulfonylureas in
achieving glucose control is uncertain. In fact, the debate over the safety of
sulfonylurea therapy is ongoing in patients with concomitant heart disease.
The findings of the University Group Diabetes Program [51] demonstrated
excess cardiovascular mortality in a group treated with tolbutamide,
compared with groups treated with placebo or insulin. However, subsequent
criticism of the University Group Diabetes Program study design and lack
of demonstrable risk in other large studies, such as the United Kingdom
Prospective Diabetes Study [52] revitalized the use of these agents for
diabetes control.
L.F. Lien et al / Med Clin N Am 88 (2004) 1085–1105 1099
Thiazolidinediones
Thiazolidinediones bind to peroxisome proliferator-activator receptors
and enhance peripheral insulin sensitivity through a series of mechanisms
resulting in transcription of insulin-responsive genes [57]. Both pioglitazone
and rosiglitazone are currently available for use in the United States.
Troglitazone, the first thiazolidinedione was removed from the market
because of reports of liver failure. Thiazolidinediones should not be used in
patients with active liver disease or those with transaminases increased more
than 2.5 times normal. If thiazolidinediones are discontinued in the inpatient
setting, effects on insulin sensitivity may persist. Therefore, as the drug effect
wanes, insulin requirements may increase.
The use of thiazolidinediones has been implicated in the exacerbation of
fluid retention, a particular concern in patients with congestive heart failure.
Although both animal and human studies have demonstrated a beneficial
effect of thiazolidinediones on markers of congestive heart failure (ie,
increased cardiac output and stroke volume, decreased peripheral vascular
resistance, decreased left ventricular cavity dilatation), the contribution of
excess edema to worsening heart failure has been more difficult to assess
1100 L.F. Lien et al / Med Clin N Am 88 (2004) 1085–1105
reproducible from day to day. However, all three meals should not have
identical carbohydrate content [63]. The consistent carbohydrate approach
also emphasizes the importance of a mixed meal. Meals consisting solely of
carbohydrates, although palatable, may not be tolerated by inactive
inpatients. Carbohydrate should be consumed in a balanced meal with
protein, fat, and fiber.
The patient diagnosed with type 2 diabetes who has been managed by
dietary control requires careful attention in the inpatient setting. The stress
of acute illness may prompt an intensification of treatment that can be
accomplished with either insulin or oral agents, as outlined above.
In patients receiving continuous tube feeding, 25% of the total daily
insulin dose should be administered as regular insulin every 6 hours. In
patients receiving bolus tube feeding, the most important aspect of insulin
administration is coordination of the timing of the insulin with the timing of
the feeding. Collaboration with the inpatient nutritionist is essential. For
example, if a patient is being initiated to bolus feeds, suggest a feeding
schedule of every 3 hours to help correspond better with the insulin
administered on an every 6-hour schedule.
Summary
Hospital management of the patient with type 2 diabetes poses many
challenges but also a unique opportunity to improve glycemic control and
patient care. A basic understanding of the goals of inpatient management
and glycemic targets is essential. Proper administration of subcutaneous and
IV insulin, as well as appropriate use or discontinuation of oral hypogly-
cemic agents, can reduce the complexity of a patient’s hospital course and
potentially reduce overall morbidity and mortality.
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Med Clin N Am 88 (2004) 1107–1116
This work was supported in part by NIH grants R37 DK27085, MO1 RR00036, P60
DK20579, and T32 DK07120, and grants from the American Diabetes Association.
* Corresponding author.
E-mail address: pcryer@wustl.edu (P.E. Cryer).
0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2004.04.003
1108 S. Banarer, P.E. Cryer / Med Clin N Am 88 (2004) 1107–1116
Frequency of hypoglycemia
During aggressive glycemic therapy, the person with T1DM typically suf-
fers plasma glucose concentrations less that 50 to 60 mg/dL (2.8–3.3 mmol/L)
approximately 10% of the time, symptomatic hypoglycemia approximately
twice per week, and severe, and at least temporarily disabling, hypoglycemia
approximately once per year [4,5]. Based on controlled studies designed to
include treatment to near euglycemia, valid estimates of the frequencies of
these hypoglycemias during aggressive glycemic therapy of T2DM are limited.
Overall, however, the rates are lower in T2DM [4,5].
Representative event rates for severe iatrogenic hypoglycemia (ie, those
episodes that require the assistance of another person) during aggressive
glycemic therapy of T1DM range from 62 [1] through 110 [8] to 170 [9]
episodes per 100 patient-years. Event rates for severe iatrogenic hypogly-
cemia during aggressive glycemic therapy of T2DM with insulin range from
3 [10] through 10 [11] to 73 [9] episodes per 100 patient-years. Based on these
data, it appears that the rates of severe hypoglycemia in T2DM are roughly
10% of those in T1DM, even during aggressive therapy with insulin; rates of
severe hypoglycemia are undoubtedly much lower during treatment with
oral agents.
Unfortunately, hypoglycemia event rates in persons with T2DM have not
been reported in the UKPDS. The cumulative incidence of major hypogly-
cemia (defined as requiring medical assistance or hospital admission) over
6 years was 3.3% in patients taking a sulfonylurea and 11.2% in those taking
insulin [12]. For comparison, severe hypoglycemia (requiring the assistance
of another person) occurred in 65% of persons with T1DM over 6.5 years in
the DCCT [1]. Notably, the UKPDS did report an incidence of major
hypoglycemia in patients using metformin [12]. In theory, biguanides,
thiazolidinediones, and a-glucosidase inhibitors should not cause hypogly-
cemia [5]. Based on data from 5063 patients with T2DM using monotherapy
S. Banarer, P.E. Cryer / Med Clin N Am 88 (2004) 1107–1116 1109
Imperfect Insulin
Replacement
HYPOGLYCEMIA
Hypoglycemia Defective Glucose
Unawareness Counterregulation
Reduced Autonomic (Including
Adrenomedullary) Responses
Symptom Epinephrine
levels (ie, those patients approaching the insulin-deficient end of the spectrum
of T2DM) as it is in T1DM. Furthermore, in these patients and another group
with more insulin-sufficient T2DM, glycemic thresholds for sympathoadrenal
and symptomatic responses to hypoglycemia were shifted to lower plasma
glucose concentrations following hypoglycemia, as they are in T1DM. Thus,
people with advanced T2DM, like those with T1DM, are at risk for developing
hypoglycemia-associated autonomic failure, that is, defective glucose counter-
regulation and hypoglycemia unawareness. This may explain why iatrogenic
hypoglycemia becomes progressively more limiting to glycemic control as
patients approach the insulin-deficient end of the spectrum of T2DM [14–16].
Ultimately, these patients become indistinguishable from those with T1DM,
from a pathophysiologic and therapeutic perspective; this perspective is
illustrated in Fig. 2.
Nondiabetic
T1DM No No Attenuated
T2DM - No - No - Attenuated
Fig. 2. Iatrogenic hypoglycemia, the limiting factor in the glycemic management of diabetes, is
the result of the interplay of absolute or relative therapeutic insulin excess and compromised
physiologic and behavioral defenses against falling plasma glucose concentrations in T1DM
and advanced T2DM.
category that are well established in T1DM [4,5,21,22] and are relevant to
T2DM, include: (1) insulin deficiency; (2) a history of severe hypoglyce-
mia, hypoglycemia unawareness, or both; and (3) aggressive glycemic
therapy per se, as evinced by lower HbA1C levels or lower glycemic goals.
These are clinical surrogates of the key features of HAAF in diabetes
[4,5,17,18]. Insulin deficiency indicates that insulin levels will not decrease
and predicts accurately that glucagon levels will not increase as plasma
glucose concentrations fall. A history of hypoglycemia, or of hypoglyce-
mia unawareness or aggressive glycemic therapy per se, which imply
recent antecedent hypoglycemia, are proximate causes of HAAF.
Summary
Iatrogenic hypoglycemia is the limiting factor in the glycemic manage-
ment of diabetes and a barrier to true glycemic control and its established
microvascular and potential macrovascular long-term benefits. Compared
with T1DM, severe hypoglycemia occurs less frequently in T2DM, even
during aggressive glycemic therapy, presumably because of intact glucose
counter-regulatory systems early in the course of T2DM. Iatrogenic
hypoglycemia, however, becomes a progressively more frequent problem,
ultimately approximating that in T1DM, in advanced T2DM because of
compromised physiologic and behavioral defenses against falling plasma
glucose concentrations. These syndromes of defective glucose counter-
regulation and hypoglycemia unawareness and the concept of hypoglyce-
mia-associated autonomic failure are analogous to those that develop early
in the course of T1DM. Caregivers should strive to reduce mean glycemia as
much as can be accomplished safely by practicing hypoglycemia risk
S. Banarer, P.E. Cryer / Med Clin N Am 88 (2004) 1107–1116 1115
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