John Buse, MD, PhD; Mark Harmel, MPH


June 17, 2016

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The LEADER trial randomly assigned diabetic patients at high risk for cardiovascular disease to receive liraglutide or placebo.[1] The top-line result was a 13% reduction in heart attack, stroke, and cardiovascular death with liraglutide. In addition, the study found consistent reductions across a broad spectrum of cardiovascular outcomes and reductions in microvascular events, specifically in new persistent macroalbuminuria.

This encouraging result makes us think about the other trials that have been reported recently. One of these is the ELIXA trial with lixisenatide, another drug from the same class. Does the lack of cardiovascular benefit in ELIXA indicate that there is no class effect? I am not sure. In particular, that trial involved patients with post-acute coronary syndrome, and it had a different primary endpoint. Thus, it is difficult to compare the trials. Another trial from this class suggests a benefit for cardiovascular endpoints, but we only have press releases from that study.[2]

The other trial that everyone will ponder is the EMPA-REG trial with empagliflozin. In the EMPA-REG trial, the separation between the curves [demonstrating benefit with the study drug compared with placebo] came very early,[3] whereas in the LEADER trial, the separation of the curves starts very slowly and diverges over time. The cardiovascular benefits in EMPA-REG were spottier depending on the endpoint. Specifically, the EMPA-REG trial showed no benefit in stroke with empagliflozin, whereas there was more consistency with liraglutide in the LEADER trial.

My guess is these drugs are affecting cardiovascular disease through very different mechanisms, with liraglutide perhaps having an effect on the basic biology of atherosclerosis, whereas empagliflozin may have more of a hemodynamic effect or perhaps an effect on ketone bodies and their utility in the setting of heart failure.

The exciting question is, can you take these two drugs, empagliflozin and liraglutide, with very different patterns of benefits in cardiovascular disease, and combine them? Unfortunately, up to today we did not even have the regular trials looking at glycemic control and the safety of these combinations, so we still have a lot of work to do.


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