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436 Cardiovascular Outcomes With Antihyperglycemic Therapy:
Past , Present , and Future Impact on Practice

guidance, in majority of the studies major adverse debate whether the response would have been dif-
CV events (MACE) has been selected as a primary ferent in a newly diagnosed diabetes population but
end point which include CV mortality, MI and stroke it reliably proved the principle that glycemic control
and also includes hospitalization for acute coronary alone is not a reliable surrogate marker for reduction
syndrome, urgent revascularization procedures and of CV events. However, a meta-analysis by Turnbull
heart failure (HF) (2) et al of these three trials together with first 5 years
of follow up data from UKPDS showed a significant
Cardiovascular outcome trials from the past reduction of MACE and particularly a risk reduction
on intense glycemic control in MI with intensive glucose lowering (3). There were
other trials which looked into CV events and mortality
In the past large scale landmark trials like United endpoints and did not solely concentrate on glucose
Kingdom Prospective Diabetes Study (UKPDS) have lowering strategies like the Record trial and Proactive
tried to address the effects of HbA1c lowering on CV trial which will be discussed later.
outcomes. In this trial, the effect of intensive glucose
lowering on micro vascular effects were undisputed
(25% relative risk reduction, p=0.0099) after a follow Metformin
up of 10 years compared to the conventional therapy Metformin acts by reducing insulin resistance, par-
but the relative risk reduction for MI reached border- ticularly in the liver and skeletal muscle, suppressing
line significance only (16%, p=0.052) and there was hepatic gluconeogenesis and increasing insulin sen-
no significant reduction in all cause death, stroke or sitivity and peripheral glucose utilization. This drug
composite of any diabetes related end point It was has beneficial effects on lipid decrease in the pro-
only with a further 10 years of post interventional trial portion of small dense LDL particles, associated with
follow up, significant risk reductions were noted for weight loss , have a moderate blood pressure (BP)
MI (15%, p=0.01) and all cause mortality (13%, p=0.007) lowering effect, protect against diabetes-induced
in the former intensive group with greater results in vascular disease, decrease inflammation preserve
the metformin subgroup . Further large scale stud- the endothelium, exhibits anti-thrombotic effects
ies have tried to evaluate the efficacy of intensive The UK Prospective Diabetes Study (UKPDS) was
versus standard glucose lowering strategies on CV a landmark study of the CV benefits of metformin,
outcomes. The Action to Control Cardiovascular Risk which demonstrated that, compared to the conven-
in Diabetes (ACCORD) trial with a median follow up tional-treatment group, metformin was able to reduce
of 3.7 years showed a significant decrease rate of any diabetes-related endpoint, diabetes-related death
non-fatal MI but was stopped prematurely because and all-cause mortality. When compared to chlorpro-
of an unexpected 22% increased relative risk of all pamide, glibenclamide or insulin, metformin showed
cause mortality from CV deaths in the intensive a more pronounced effect for any diabetes related
treatment group . The Action in Diabetes and Vas- endpoint, all-cause mortality and stroke. Moreover,
cular disease: Preterax and Dimicron MR Controlled the metformin treated group displayed a sustained
Evaluation (ADVANCE) trial had a median follow up risk reduction, lower all-cause mortality reduce the
of 5 years and reported a statistically significant 10% risk of macrovascular disease. Systematic reviews
reduction in the primary endpoint of major macro have revealed that treatment with metformin is as-
vascular and micro vascular events in the inten- sociated with a decreased risk of CV mortality and
sive glycemic group (HR: 0.90, 95% CI: 0.82-0.98) with a significant reduction of CV events, especially
but when analyzed separately the effect on macro in younger patients. However, in the A Diabetes Out-
vascular outcomes were not significant (HR: 0.94, come Progression Trial (ADOPT) metformin did not
95% CI: 0.84-1.06) . The Veterans Affairs Diabetes demonstrate any advantage in terms of risk of death
trial (VADT) included a similar standard treatment or CV events over glibenclamide or rosiglitazone.
and an intensive therapy arm with a median follow Moreover, the CV safety of metformin has been ques-
up of 5.6 years There was no significant difference tioned since there is evidence of greater CV mortality
between the two groups in any component of the when it is added to sulfonylurea. More specifically, a
primary outcome or in the rate from death from any study found that patients treated with SU in combina-
cause (HR: 1.07; 95% CI, 0.81-1.42; p=0.62). The con- tion with metformin were at higher risk of adverse CV
clusion from this trial was very similar to other trials outcomes than those treated with metformin alone.
like ADVANCE, ACCORD which didn’t show any as- A number of studies have pointed to beneficial ef-
sociation between intensive glycemic control and risk fects of metformin in heart failure (HF), namely lower
reduction of CV events . These trials enrolled patients rates of mortality, mainly CV mortality, and a lower
with long standing diabetes and it remains a topic of

GCDC 2017