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Diabetes and Cardiovascular Risk
Table 1: Comparison of Key Baseline Characteristics of [ACCORD] and VA Trial of Glycemic Control and Complications in
Patients in the ADVANCE, ACCORD and VADT Trials
Diabetes Mellitus Type 2 [VADT]) have reported no significant effects of
intensive versus standard glucose control on all combined major
ADVANCE ACCORD VADT
macrovascular events (ACCORD and VADT) or microvascular events
(n=11,140) (n=10,251) (n=1,791)
(VADT).
4,5
In fact, the ACCORD trial, targeting an HbA
Mean age (years) 66 62 60
1c
level of less than
6% and conducted in a different population in North America, was
Mean duration of diabetes (years) 8 10 11.5
Mean baseline HbA
terminated prematurely due to a 22% increase in the risk for all-cause
1c
(%) 7.5 8.3 9.4
Prior vascular disease (%) 32 35 40
mortality with intensive compared with standard glucose control, and
Insulin use at study entry (%) 1.4 35 52
questioned the safety of intensive glucose lowering in older patients
with diabetes of longer duration and existing cardiovascular
complications.
4
However, the ACCORD trial also demonstrated a 24%
Figure 4: Effects of Glucose Control Strategy on
Bodyweight in the ADVANCE Trial
decrease in the risk for non-fatal myocardial infarction with intensive
compared with standard glucose control and significant heterogeneity
in treatment effects across patient subgroups, with macrovascular
80
benefits suggested for those with HbA
1c
levels less than 8% or those
79
without prevalent cardiovascular disease.
4
Difference 0.75kg (95% CI 0.56–0.94); p<0.0001
78
ACCORD, like ADVANCE, was a large, well-designed, and rigorously
conducted factorial clinical trial of patients with established type 277
eight (kg)
W
diabetes, whereas VADT was a much smaller study of mainly male
76
patients with longer disease duration and inadequate glycemic control
Standard
Intensive
on maximum oral or insulin therapy.
75
0612 18 24 30 36 42 48 54 60
Follow-up (months)
Assuming the adverse mortality effects in ACCORD were not due to
chance, there are a number of explanations for the different findings in
and microvascular outcomes. As such, clinical guidelines universally the three trials. One is that ACCORD, VADT, and ADVANCE studied
recommend target HbA
1c
values of 7 or 6.5% for the prevention of both different types of patients (see Table 1), and another is that the different
microvascular and macrovascular disease complications. However, the approaches taken to intensive glucose control in the three trials led to
effects of strategies achieving target HbA
1c
levels below 6.5%, or indeed the differing results. However, post hoc analyzes of patient subgroups
below 7%, on macrovascular events in patients with type 2 diabetes, have defined by duration of diabetes and previous history of cardiovascular
not been examined, and the generalizability of the UKPDS results to a disease in ADVANCE did not reveal any significant heterogeneity in the
broader population of patients with type 2 diabetes, including patients treatment effects on-all cause mortality. Another explanation is that
with long-standing disease, remain untested. In this context, the ACCORD and VADT used an aggressive strategy with early
ADVANCE findings were important and timely. implementation of a regimen using multiple oral hypoglycemic agents,
as well as insulin, whereas ADVANCE used a more incremental
The results of the blood-glucose-lowering arm of the ADVANCE trial approach with progressive intensification over a much longer
indicated that HbA
1c
values at or below levels currently recommended time-frame. This is reflected in the high proportion of patients in the
by most guidelines could be safely achieved in patients with long- intensive glucose control arm of ACCORD who eventually took insulin
standing type 2 diabetes using the regimen employed in ADVANCE.
2
In (77%) and thiazolidinediones (92%), whereas ADVANCE had a slower
the short term, this approach did not reduce the risks of major rate of decline of HbA
1c
in the intensive arm, with more than 90% on a
cardiovascular events, but it did reduce the risk for new or worsening sulfonylurea (gliclazide-modified release) but only 40% on insulin and
nephropathy.
2
As worsening albuminuria and progressive renal 17% on thiazolidinediones by the end of follow-up. As a consequence,
dysfunction are strongly associated with increased risk for major most of the reduction in HbA
1c
achieved in the intensive group in
cardiovascular events, end-stage renal disease, and death in patients ACCORD and VADT was observed within six to eight months, whereas
with type 2 diabetes, the renal effects may yet prove beneficial for the decline in ADVANCE occurred over three years. Almost certainly as
long-term cardiovascular risk. As expected, an increased incidence of a consequence of the different strategies for intensive glucose control
hypoglycemia was observed among patients in the intensive glucose utilized, the rate of severe hypoglycemia (using comparable definitions)
control compared with standard control arms.
2
Overall, the incidence of in ACCORD and VADT was more than six times that observed in
severe hypoglycemia was much lower than that reported in other trials ADVANCE (approximately 16.1% over 3.5 years in ACCORD and 15.1%
of intensive glucose lowering. Using this approach, intensive glucose over 5.6 years in VADT compared with 2.7% over five years in
control was not associated with increased mortality, rather a small, non- ADVANCE).
2,4,5
There were also significant differences in the mean
significant reduction of 7% in all-cause death.
2
weight gain in these three studies. In the ACCORD and VADT trials, the
mean weight gain from baseline was 3.5 and 4kg in those on intensive
In contrast, two other recent large-scale clinical trials of intensive glucose lowering, respectively, whereas in the ADVANCE trial there was
glucose lowering (achieved HbA
1c
range 6.4–6.9%) in patients with type no weight gain among patients in the intensive glucose lowering arm
2 diabetes (the Action to Control Cardiovascular Risk in Diabetes (see Figure 4).
2,4,5
98 US ENDOCRINOLOGY
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