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

In the sulfonylurea/insulin arm of the United King- and found an increased risk for MI, albeit less than
dom Prospective Diabetes Study (UKPDS), there before, and found no increased risk for CV mortality.
was no association between the use of insulin and Other meta-analysis have suggested that rosiglita-
CVD incidents, even after 10 years of follow-up. The zone is associated with a significantly increased risk
Outcome Reduction with Initial Glargine Intervention of MI and HF, without a significantly increased risk
(ORIGIN) trial with the long-acting insulin glargine in- of CV mortality. The bypass angioplasty revascular-
volved more than 12,000 patients with new-onset or ization investigation 2 diabetes (BARI 2D) trial in 2013
early T2DM, impaired glucose tolerance or impaired reported that among patients with T2DM and CAD,
fasting glucose, with a prior CV event or at high risk rosiglitazone is not associated with an increase in
for CVD, who were randomized either to glargine or major ischemic CV events. The PROspective piogli-
to standard care. The results demonstrated no as- tAzone clinical trial in macroVascular events (PRO-
sociation with macrovascular events in both groups. active) study has shown that in T2DM patients at
However, there was a positive link to both weight high risk for macrovascular events, pioglitazone sig-
gain and hypoglycemia. (11). The ORIGIN trial and the nificantly reduced a prespecified secondary endpoint
recently published legacy effects (ORIGINALE) study composed of death, non-fatal MI and stroke. In a sub-
followed up these patients for more 2.5 years and group analysis of the PROactive study, pioglitazone
confirmed that insulin glargine had neutral effects significantly decreased the risk of recurrent stroke
on CV health.(12). The hyperglycemia and its effect and of fatal and nonfatal MI and acute coronary syn-
after acute myocardial infarction on cardiovascular drome in high-risk patients with T2DM. Corroborating
outcomes in patients with type 2 diabetes mellitus this, a meta-analysis has revealed that pioglitazone
(HEART2D) trial No differences in respect of CV is associated with a significantly lower risk of death,
events between prandial versus basal strategies were MI or stroke in patients with T2DM. HF is increased
found.(13). Insulin degludec is a novel basal insulin by pioglitazone, although there is no increase in the
with a longer duration of action. The DEVOTE trial associated mortality.(15) However, a recent study re-
was designed to test its safety and efficiency in sub- ported that pioglitazone treatment did not produce
jects with T2DM at high risk of CV events. Published any significant reductions in the rate of primary CV
in the last ADA June 2017 Degludec vs glargine was events. (16) Both pioglitazone and rosiglitazone seem
associated with a statistically significant 40% reduc- to increase the risk of HF; nonetheless, the risk of
tion in severe hypoglycemia, as well as a statistically CV death is not increased. 17) Additionally, in a re-
significant 53% reduction in nocturnal severe hypo- cent Cochrane meta-analysis, PPAR-γ agonists were
glycemia and MACE shown to reduce recurrent stroke and total events
of CV death, as well as improving insulin sensitivity
Cardiovascular safety of TZD: Evidence from studies and carotid plaques stabilization.18) Despite these
TZD have the potential to modulate several CV risk impressive cardiovascular benefits with pioglitazone
factors, including lipids, BP, inflammatory bio mark- therapy, its use has also declined markedly, poten-
ers, endothelial function and fibrinolytic status. Both tially due to ‘guilt by association’ with rosiglitazone
pioglitazone and rosiglitazone can cause an increase and the description of new risks for fractures and
in HDL-c. LDL-c levels seem to remain unchanged bladder cancer.
with pioglitazone but to increase with rosiglitazone.
The Diabetes REduction Assessment with ramipril
and rosiglitazone Medication (DREAM) trial found Meglitinides
no increase in CV event rates with rosiglitazone, Meglitinides are insulin secretagogues that act on a
although the rosiglitazone group developed signifi- different receptor but have a similar mode of action
cantly more HF events. The Rosiglitazone Evaluated to sulfonylureas and exert similar but milder effects.
for CV Outcomes in Oral Agent Combination Therapy Repaglinide and nateglinide are the 2 agents in this
for T2DM (RECORD) trial showed that rosiglitazone class that are currently available. These agents low-
does not increase the risk of overall CV morbidity or er both glucose and hemoglobin A1c (HgA1c) levels
mortality; nevertheless, it confirmed an increased risk without a significant effect on lipids. The CV safety
of HF. In spite of this, issues related to trial design profile of meglitinides is largely unknown repaglinide
and data integrity led FDA to call for an independent controlled postprandial glucose excursion better than
reevaluation of the RECORD data, which reported glimepiride and was associated with a significant
similar results. A 2007 meta-analysis demonstrated decline in other surrogate CV markers, including
that rosiglitazone was associated with a significant markers of inflammation, platelet activation, and lip-
increase in the risk of MI and death from CV causes. id parameters, suggesting a beneficial role in lower-
In 2010, the same authors repeated the meta-analysis ing CVD risk. On the other hand, when compared to

GCDC 2017