VOLUME 11 NUMBER 3 • SEPTEMBER 2014
107
SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
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H
ow can three landmark trials of intensive versus standard
glucose-lowering strategies – ADVANCE, ACCORD and
VADT – raise more questions than they answer? This was the
conundrum a recent
post hoc
analysis of the studies looked to
address.
All three studies did not meet their primary objective of reduc-
ing cardiovascular events, despite achieving significantly lower
HbA
1c
levels; in the ACCORD study, the data-monitoring com-
mittee prematurely stopped the intensive-strategy arm due to an
excess rate of cardiovascular death. These results flew squarely
in the face of conventional wisdom that lowering HbA
1c
to
‘normal’ levels would improve cardiovascular outcomes, similar
to the clearly proven benefit of reducing microvascular complica-
tions. Each trial has subsequently published numerous analyses
that have tried, mostly unsuccessfully, to explain why mortality,
in particular, did not decrease, or in the case of ACCORD even
increased, with a more intensive glycaemic strategy.
What is interesting is that across these studies, there does
appear to be a consistent signal that improved glycaemic man-
agement may reduce coronary artery events. This observation
was first noted over a decade ago in the UKPDS study, in which
more intense glycaemic control reduced the rate of myocardial
infarction (MI).
The ACCORD investigators now report a consistent reduction
of about 15–20% in non-fatal MI, unstable angina and coronary
revascularisation in the intensive-therapy arm. The benefit became
more apparent during the longer follow-up period, suggesting a
legacy effect. Interestingly, when controlling for achieved HbA
1c
level, the benefit was attenuated, which implies that better gly-
caemic control may be causal in reducing ischaemic events.
It is important to remember that this is a
post hoc
analysis
and still cannot reconcile the higher rates of death in the inten-
sive-strategy arm. But it raises the possibility that there may be
Effects of intensive glycaemic control on ischaemic heart disease
strategies that can both safely lower glucose and reduce cardio-
vascular events. How you improve glycaemic control may be as
important as the actual HbA
1c
target. The score of ongoing car-
diovascular outcome trials of novel antihyperglycaemic agents
will likely provide further insight into this clinical dilemma.
The researchers assessed 10 251 adults aged 40–79 years
with established type 2 diabetes, mean HbA
1c
concentration of
67 mmol/ml (8.3%) and risk factors for ischaemic heart dis-
ease enrolled in the ACCORD trial. Participants were assigned
to intensive or standard therapy [target HbA
1c
< 42 or 53–63
mmol/ml (< 6.0 or 7.0–7.9%), respectively]. They assessed fatal
or non-fatal MI, coronary revascularisation, unstable angina and
new angina during active treatment (mean 3.7 years) plus a fur-
ther mean of 1.2 years.
Raised glucose concentration is a modifiable risk factor for
ischaemic heart disease in middle-aged people with type 2 dia-
betes and other cardiovascular risk factors. MI was less frequent
in the intensive- than in the standard-therapy group during
active treatment [hazard ratio (HR) 0.80, 95% CI: 0.67–0.96;
p
= 0.015] and overall (HR 0.84, 95% CI: 0.72–0.97;
p
= 0.02).
Findings were similar for combined MI, coronary revasculari-
sation and unstable angina (active treatment HR 0.89, 95% CI:
0.79–0.99, overall HR 0.87; 95% C: 0.79–0.96) and for coronary
revascularisation alone (HR 0.84, 95% CI: 0.75–0.94) and unsta-
ble angina alone (HR 0.81, 95% CI: 0.67–0.97) during full follow
up. With lowest achieved HbA
1c
concentrations included as a
time-dependent covariate, all hazards became non-significant.
Source
Lancet
, early online publication, 1 August 2014, doi:10.1016/S0140-6736(14)
60611-5.
glycemic-control-on-ischemic-heart-disease.
