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Cardiovascular safety

Completed studies

Numerous observational studies have shown a clear relationship be-
tween hyperglycaemia and cardiovascular (CV) disease. Because of
the known increase in the risk of CV disease in T2DM and the emphasis
on CV safety in the development of T2DM medications by regulatory
authorities there is considerable interest in the degree to which T2DM
treatments influence CV health. However, very little is known about
37
the CV effects of newer T2DM treatments.

Several large, long-term studies have investigated the CV safety of T2DM
treatments, i.e. UKPDS, ACCORD, ADVANCE and VADT, all of which
failed to show that intensive glucose control significantly reduces CV
events. 33, 38-40 Indeed, ACCORD was terminated early due to higher
(non-significant) mortality in the intensive treatment group, which has
led to the conclusion in some quarters that intensive glucose control
not only has no effect on the risk of CV events, but can even be harm-
ful in patients at high CV risk. It is possible to argue that in the UKPDS
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metformin was associated with an improvement in CV mortality (this is
supported by recent meta-analyses – see the end of this chapter). This
41
follow-up study of the tight glucose intervention in the UKPDS showed
that intensive glucose control was associated with a significant reduc-
tion in the risk for myocardial infarction, diabetes-related deaths and
all-cause mortality. This suggests that early, strict glucose control gen-
41
erates a legacy that is eventually translated into CV protection. Cur-
rently, this is nothing more than a hypothesis that requires testing. 41
The PROACTIVE study showed that pioglitazone can reduce the risk
of secondary macrovascular events in a high-risk patient population
with T2DM and established macrovascular disease; however, the study
failed on the primary composite endpoint and only demonstrated CV
benefit on a secondary endpoint. 42-45

The RECORD trial demonstrated that while the addition of rosiglitazone
to glucose-lowering therapy did not increase the risk of overall mortal-
ity and morbidity, it did increase the risk of heart failure. In the STOP-
46
NIDDM trial, acarbose was associated with a CV benefit, however, this
was a trial in IGT, not T2DM, and the number of observed CV events was
very low. Whether early insulin treatment results in a beneficial effect
47
on the CV system remains an open question, but one that the ORIGIN
47
trial will attempt to answer, the first results of which are expected in
2012. The Steno-2 study demonstrated CV risk improvement, but this is
a small study and the multi-factorial interventions make it impossible to
attribute the observed effect to a single compound. 48

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