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Cardiovascular Risk in Type 2 Diabetes – Reflecting on the ADVANCE Study
shown to produce significant reductions in the risk of microvascular Table 1: Comparison of Key Baseline Characteristics of
events but only a non-significant trend towards a reduction in
Patients in the ADVANCE, ACCORD and VADT Trials
myocardial infarction.
3,18
In combination, the observational data and
the randomised evidence provided by the UKPDS provided support
ADVANCE ACCORD VADT
for the notion that strategies that lowered glucose levels to below
(n=11,140) (n=10,251) (n=1,791)
Mean age (years) 66 62 60
those achieved in the UKPDS should further reduce the risks of
Mean duration of diabetes (years) 8 10 11.5
macrovascular and microvascular outcomes. As such, clinical
Mean baseline HbA
1c
(%) 7.5 8.3 9.4
guidelines universally recommend target HbA
1c
values of 7 or 6.5%
Prior vascular disease (%) 32 35 40
for the prevention of both microvascular and macrovascular disease
Insulin use at study entry (%) 1.4 35 52
complications. However, the effects of strategies achieving target
HbA
1c
levels below 6.5%, or indeed below 7%, on macrovascular
Figure 4: Effects of Glucose Control Strategy on
events in patients with type 2 diabetes, have not been examined,
Bodyweight in the ADVANCE Trial
and the generalisability of the UKPDS results to a broader population
of patients with type 2 diabetes, including patients with long-
80
standing disease, remain untested. In this context, the ADVANCE
findings were important and timely.
79
Difference 0.75kg (95% CI 0.56–0.94); p<0.0001
78
The results of the blood-glucose-lowering arm of the ADVANCE trial
indicated that HbA
1c
values at or below levels currently
77
eight (kg)
recommended by most guidelines could be safely achieved in
W
patients with long-standing type 2 diabetes using the regimen
76
Standard
Intensive
75
0612 18 24 30 36 42 48 54 60
Follow-up (months)
Using this approach, intensive glucose
control was not associated with increased
longer duration and existing cardiovascular complications.
4
However, the ACCORD trial also demonstrated a 24% decrease in
mortality, rather a small, non-significant the risk of non-fatal myocardial infarction with intensive compared
reduction of 7% in all-cause death.
with standard glucose control and significant heterogeneity in
treatment effects across patient subgroups, with macrovascular
benefits suggested for those with HbA
1c
levels less than 8% or
those without prevalent cardiovascular disease.
4
employed in ADVANCE.
2
In the short term, this approach did not
reduce the risks of major cardiovascular events, but it did reduce ACCORD, like ADVANCE, was a large, well-designed and rigorously
the risk of new or worsening nephropathy.
2
As worsening conducted factorial clinical trial of patients with established type 2
albuminuria and progressive renal dysfunction are strongly diabetes, whereas VADT was a much smaller study of mainly male
associated with increased risk of major cardiovascular events, end- patients with longer disease duration and inadequate glycaemic
stage renal disease and death in patients with type 2 diabetes, the control on maximum oral or insulin therapy.
renal effects may yet prove beneficial for long-term cardiovascular
risk. As expected, an increased incidence of hypoglycaemia was Assuming the adverse mortality effects in ACCORD were not due to
observed among patients in the intensive glucose control chance, there are a number of explanations for the different findings
compared with standard control arms.
2
Overall, the incidence of in the three trials. One is that ACCORD, VADT and ADVANCE studied
severe hypoglycaemia was much lower than that reported in other different types of patients (see Table 1), and another is that the
trials of intensive glucose lowering. Using this approach, intensive different approaches taken to intensive glucose control in the three
glucose control was not associated with increased mortality, rather trials led to the differing results. However, post hoc analyses of
a small, non-significant reduction of 7% in all-cause death.
2
patient subgroups defined by duration of diabetes and previous
history of cardiovascular disease in ADVANCE did not reveal any
In contrast, two other recent large-scale clinical trials of intensive significant heterogeneity in the treatment effects on-all cause
glucose lowering (achieved HbA
1c
range 6.4–6.9%) in patients with mortality. Another explanation is that ACCORD and VADT used an
type 2 diabetes (the Action to Control Cardiovascular Risk in aggressive strategy with early implementation of a regimen using
Diabetes [ACCORD] and VA Trial of Glycemic Control and multiple oral hypoglycaemic agents, as well as insulin, whereas
Complications in Diabetes Mellitus Type 2 [VADT]) have reported no ADVANCE used a more incremental approach with progressive
significant effects of intensive versus standard glucose control on intensification over a much longer time-frame. This is reflected in
all combined major macrovascular events (ACCORD and VADT) or the high proportion of patients in the intensive glucose control arm
microvascular events (VADT).
4,5
In fact, the ACCORD trial, targeting of ACCORD who eventually took insulin (77%) and thiazolidinediones
an HbA
1c
level of less than 6% and conducted in a different (92%), whereas ADVANCE had a slower rate of decline of HbA
1c
in
population in North America, was terminated prematurely due to a the intensive arm, with more than 90% on a sulphonylurea
22% increase in the risk of all-cause mortality with intensive (gliclazide-modified release) but only 40% on insulin and 17% on
compared with standard glucose control, and questioned the safety thiazolidinediones by the end of follow-up. As a consequence, most
of intensive glucose lowering in older patients with diabetes of of the reduction in HbA
1c
achieved in the intensive group in ACCORD
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