Journal of Diabetes 1 (2009) 7375
EDITORIAL
What is the evidence base for the randomized controlled
trial?
Michael Rawlins, in his Harveian Oration on the con-
cept of evidence in clinical decision making, discusses a
number of issues relevant to the development of opti-
mal glycemic treatment approaches for people with
diabetes.1
The ability to generalize from randomized controlled
trials (RCT) of glycemic treatment may be limited.
Treatments may be more effective in patients younger
or older, or with longer or shorter duration of disease,
or with greater or lesser severity of already existing
complications, or with more or fewer comorbidities
or risk factors, or with different ethnicity, or with sex
differences, or socioeconomic differences, or cultural
differences. Longer duration, high baseline A1c, and
existing cardiovascular complications appear to be
particularly associated with treatment harm in the
Action to Control Cardiovascular Risk in Diabetes
(ACCORD)2 and Veterans Affairs Diabetes Trial
(VADT)3 trials, but other patient-specic factors may
be equally important. Treatments may be given at too
high or too low a dose or, perhaps relevant to the ques-
tion of glycemic treatment, the metric used in assessing
dose may not be sufciently exible to accommodate
all patients. We refer here to the perhaps mistaken use
of A1c as the sine qua non in determining glycemia,
inasmuch as there is good evidence of heterogeneity in
the degree to which different individuals glycate hemo-
globin, so that a high glycator may be excessively trea-
ted at a given level of A1c, leading to predictable side-
effects of excessive glucose-lowering medication.4
The various treatment regimens used to attain con-
trol of glycemia surely cannot be assumed to be identi-
cal in effect, so that the notion of glycemic strategy,
in which various classes of medications can be used at
the discretion of the treating physician and then com-
pared, must be seen as one that may obscure impor-
tant differences between agents. Furthermore, with
long periods of treatment, the duration of therapeutic
effectiveness of various agents becomes an important
issue, so that recommendations for use of sulfonylu-
reas,5 which show good short-term but poor long-term
efcacy,6 may be inappropriate. In addition, the com-
mon nding that side-effects of a given agent tend to
2009 Ruijin Hospital and Blackwell Publishing Asia Pty Ltd
be seen early in their use but improvements in outcome
emerge only after many years of treatment is likely to
lead to incorrect interpretation of riskbenet ratios of
agents intended for long-term use. Other issues include
factors related to patient adherence compliance, the
potential of a given agent to show adverse interactions
with comedication, and the setting in which the studied
treatment is ultimately to be used. Prescription and
monitoring by less expert healthcare providers may
markedly change the quality of care and the potential
benet of a given approach.
An important corollary of these concepts is Rawlins
assertion that we have incorrectly elevated the RCT to
a position at the peak of the hierarchy of sources of
clinical knowledge.1 In addition to the issue of general-
izability, he points out that devising stopping rules to
end a trial early, the performance of subgroup analy-
ses, the assessment of multiple endpoints, and the
related assessment of adverse outcomes all require
multiple calculations of statistical signicance, leading
to overestimation of likelihood. An example of this is
the increase in mortality leading to termination of the
ACCORD trial (Fig. 1). One presumes that multiple
potential adverse outcomes were examined, at multiple
time points, and the trend to subsequent benet of the
primary endpoints of cardiovascular (CV) mortality,
non-fatal myocardial infarction, and non-fatal stroke,
particularly with evidence that the mortality benet of
the Steno 2 intervention in diabetic patients was not
seen until after more than a decade of treatment with,
in fact, a trend to increased mortality at 4 years
(Fig. 2),7 suggests further limitation of the RCT as the
sole approach to determining appropriate glycemic
treatment interventions for people with diabetes.
Rawlins nally discusses the resource implications of
reliance on the RCT to determine approaches to medi-
cal intervention.1 The typical 6-month trial has a cost
well over US$10 000 per patient. Let us consider the
potential requirements for an intensive glycemic treat-
ment trial of early diabetes, a target many have sug-
gested as appropriate given the suggestion of harm to
people with more advanced disease in ACCORD and
VADT. It appears that CV event rates in people with
73
Editorial
(a) 25
20
Patients with events (%)
Standard therapy
15
10
Intensive therapy
5
0 2.5%
0 1 2 3 4 5
Years
(b) 25
Patients with events (%)
20
15
10 Intensive therapy
5 Standard therapy
0 bases with high levels of excellence in ascertainment
0 1 2 3 4 5
Years
Figure 1 The Action to Control Cardiovascular Risk in Diabetes
Study. (a) Composite of cardiovascular mortality, non-fatal myocar-
dial infarction, and non-fatal stroke. (b) Total mortality. The trial was
discontinued at a mean follow up of 3.5 years. The suggestion of
benefit emerging at 5 years was seen in <10% of the original
cohort and was not of statistical significance. Reprinted with per-
mission from Action to Control Cardiovascular Risk in Diabetes
Study Group.1
Type 2 diabetes who are receiving appropriate lipid,
blood pressure, and antiplatelet therapies are lower
than previously thought, with the relatively advanced
disease patients in ACCORD only having a 5-year inci-
dence of the primary endpoint of approximately 10%.2
Asymptomatic patients with earlier diabetes appear to
have CV rates less than half as great.8 A conservative
estimate may then be event rates of 68% at 10 years
in diabetic patients receiving optimal risk factor treat-
ment. In this setting, the efcacy of glycemic treatment
in reducing CV events may be no more than 1015%.
The early diabetes trial would then require a sam-
ple size of 15 00050 000 people, assuming a statisti-
cal power of 80%. The true cost would be no less
than US$10 000 per patient per year, for a total of
US$1.55 billion, dwarng the cost of all prior diabetes
74
70 50%
60
50
Conventional therapy
40
P = 0.02
30
20 30%
6.3%
10 Intensive therapy
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Years of follow-up
6
Figure 2 Steno study,7 mortality. Note that at 3.5 years (the time
of termination of ACCORD for increased mortality), mortality in the
intensive therapy group was more than twice that in the conven-
tional therapy group (6.3% vs 2.5%, respectively), although over
the subsequent decade the mortality in the conventional therapy
groups was approximately 60% as great as that in the intensive
therapy group. Reprinted with permission from Gaede et al.7
studies. Issues of generalizability, multiple subanalyses,
and appropriate statistical hypothesis testing remain.
What are the alternatives? Establishing large data-
6 of treatments, CV and glycemic risk factors, and med-
ical and health economic outcomes will allow prospec-
tive acquisition of data to address basic questions
required in planning appropriate treatment for the
coming diabetes epidemic. Does treating early diabetes
matter more than treating it later? Does glycemic
treatment of early diabetes actually lead to improved
outcome? Is A1c a good test for mean glucose in indi-
vidual patients and should A1c be used as the goal,
or should the goal be given in terms of self-monitored
(or continuously monitored) glucose levels? Is hypo-
glycemia important in Type 2 diabetes? Do drugs with
a longer duration of glycemic control lead to more
favorable outcomes? Should sulfonylureas continue to
be widely used or should agents less likely to cause
hypoglycemia be considered despite their greater
cost? The potential for human suffering is great, the
costs associated with diabetes are immense, and the
potential for future benet suggests this endeavor to
be of enormous importance. Of course, we should not
abandon the RCT. Particularly when investigating
outcomes affecting a large subset (or all) of the par-
ticipants, the RCT is a sturdy approach to under-
standing the effect of an intervention. However, we
must incorporate a more exible concept of appropri-
ate clinical evidence in the development of treatments
for hundreds of millions of people who have, and will
have, diabetes.
2009 Ruijin Hospital and Blackwell Publishing Asia Pty Ltd

Zachary Bloomgarden
Editor-in-Chief
Mount Sinai School of Medicine, 4.
Clinical Center for Endocrine and Metabolic Diseases,
Email: zbloom@gmail.com
5.
Guang Ning
Editor-in-Chief
Ruijin Hospital afliated to Jiao Tong
University School of Medicine,
Email: guangning@medmail.com.cn
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