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most likely by blocking glucose entry into the cell, ergy with the metabolic substrate shift achieve the
and indirectly reduce insulin secretion, improve in- degree of cardioprotection revealed in the EMPA-REG
sulin sensitivity and increase the peripheral glucose OUTCOME and CANVAS trial
uptake. This drug acts independently of the severity
of insulin resistance and β-cell failure; Conclusion
The recently published EMPA-REG OUTCOME (25) Due to a high prevalence of cardiovascular morbid-
study presented exciting CV results with empagli- ity and mortality in T2DM, the optimal approach to
flozin. In fact, empagliflozin was shown to signifi- the reduction of cardiovascular risk should focus
cantly reduce deaths among patients with T2DM on aggressive management of the standard cardio-
and established CVD when compared with placebo. vascular risk factors rather than purely on intensive
These patients exhibited a 14% reduction in the three- glycemic control. As can be seen from the various
point MACE primary endpoint. This effect was mainly trials reviewed here, favorable glycemic efficacy does
due to the benefits related to CV death, since em- not necessarily translate to favorable cardiovascular
pagliflozin did not reduce the rate of nonfatal MI or outcomes. Clinicians must therefore make careful in-
nonfatal strokes. Overall, this drug displayed a 38% formed decisions based on the cardiovascular effects
reduction in CV death and a 32% reduction in all- of the various anti-diabetic drugs when prescribing.
cause mortality. A significant reduction in the key Based on current evidence, metformin should re-
secondary endpoint, which was the primary compos- main the first-line drug of choice in T2DM, being the
ite endpoint plus hospitalization for unstable angina, most extensively studied and demonstrating excel-
was also apparent, as well as a 35% reduction in HF lent cardiovascular safety even with long term use.
hospitalization (26). The CANVAS trial (29,30) looked Although evidence for the cardiovascular safety of
at canagliflozin versus placebo in patients at high sulfonylureas are inconsistent, the first-generation
risk for cardiovascular (CV) disease and in patients agents are probably associated with net harm and
with established CV disease. The primary endpoint should be avoided. Newer generation sulfonylureas
of three-point major adverse CV events (MACE)— have a comparatively more favorable cardiovascular
nonfatal myocardial infarction, nonfatal stroke, and profile, but weight gain remains a concern. The meg-
CV death—was statistically significantly lowered with litinides and AGIs lack cardiovascular safety data in
canagliflozin compared with placebo, demonstrating T2DM and should therefore be reserved in favor of
about a 14% reduction in risk Specifically, there was other second-line agents. Among the TZDs, rosigli-
no statistically significant reduction in CV death, but tazone may be associated with an increased risk of
there was a very significant reduction in congestive MI, while pioglitazone may have beneficial cardio-
heart failure, a secondary endpoint, with a 39% reduc- vascular effects. Both are however contraindicated in
tion in hospitalization for heart failure. The Multicenter heart failure. The incretin-based drugs have been at
Trial to Evaluate the Effect of Dapagliflozin on the In- the forefront of this era of cardiovascular safety trials
cidence of Cardiovascular Events (DECLARE-TIMI58), and have been extensively studied. Current evidence
(27,28) expected to be finished in 2019, was de- suggests that the gliptins have neutral overall cardio-
signed to evaluate the effect of dapagliflozin on the vascular effect, but may increase risk of heart failure,
incidence of CV events Inhibitor of sodium–glucose particularly saxagliptin. Among the GLP-1 agonists,
cotransporter 2 (SGLT2) in patients with type 2 diabe- liraglutide may have beneficial effects on cardiovas-
tes and high CV risk the reduction in MACE is due cular outcomes, but this requires further validation.
to multiple mechanisms like modest improvement in Similarly, the SGLT-2 inhibitors have shown promising
glycemic control, small decrease in body weight, and results with both empagliflozin and Canaglifozin may
persistent reductions in blood pressure and uric acid potentially confer cardiovascular benefits, the results
level, enhanced diuresis and reduced blood pressure) of ongoing clinical trials will provide further evidence
may be at play. Under conditions of mild, persistent about the cardiovascular safety and perhaps efficacy
hyperketonemia, such as those that prevail during of diabetes drugs. These trials will certainly help to
treatment with SGLT2 inhibitors, b-hydroxybutyrate is further refine therapeutic guidelines in the future.
freely taken up by the heart (among other organs)
and oxidized in preference to fatty acids. This fuel References
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sumption into work efficiency at the mitochondrial betes Mellitus-Evaluating cardiovascular risk in new antidiabetic therapies
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