The SA Journal Diabetes & Vascular Disease Vol 13 No 1 (July 2016)

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SA JOURNAL OF DIABETES & VASCULAR DISEASE REVIEW
VOLUME 13 NUMBER 1 • JULY 2016 43
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How 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.
None of the three studies met their
primaryobjectiveofreducingcardiovascular
events, despite achieving significantly
lower HbA1c levels. In the ACCORD
study, the data-monitoring committee
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
management may reduce coronary artery
events. This observationwas first noted over
a decade ago in the UKPDS study, in which
Effects of intensive glycaemic control on ischaemic heart disease
more intense glycaemic control reduced
the rate of myocardial infarction (MI).
The ACCORD investigators now report a
consistent reduction of about 15 to 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 HbA1c level,
the benefit was attenuated, which implies
that better glycaemic control may be causal
in reducing ischaemic events.
It is important to remember that this
was a post hoc analysis and still could not
reconcile the higher rates of death in the
intensive-strategy arm. But it raises the
possibility that there may be strategies that
can both safely lower glucose and reduce
cardiovascular events. How you improve
glycaemic control may be as important as
the actual HbA 1c target level. The score of
ongoing cardiovascular outcome trials of
novel antihyperglycaemic agents will likely
provide further insight into this clinical
dilemma.
The researchers assessed 10 251 adults
aged 40 to 79 years with established type
2 diabetes, mean HbA1c concentration of
67 mmol/ml (8.3%) and risk factors for
ischaemic heart disease, enrolled in the
ACCORD trial. Participants were assigned
to intensive or standard therapy [target
HbA1c level < 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 further mean of 1.2 years.
Raised glucose concentration was a
modifiable risk factor for ischaemic heart
disease in middle-aged people with type
2 diabetes and other cardiovascular
risk factors. MI was less frequent in the
intensive- than in the standard-therapy
group during active treatment (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 revascularisation and unstable
angina (active treatment HR 0.89, 95% CI:
0.79–0.99, overall HR 0.87; 95% CI: 0.79–
0.96), and for coronary revascularisation
alone (HR 0.84, 95% CI: 0.75–0.94) and
unstable angina alone (HR 0.81, 95% CI:
0.67–0.97) during full follow up. With
lowest achieved HbA1c concentrations
included as a time-dependent covariate,
all hazards became non-significant.
1. The Lancet, early online publication, 1 August
2014, doi:10.1016/S0140-6736(14)60611-5.
2.
/16753-effects-of-intensive-glycemic-control-on-
ischemic-heart-disease.