Tullis-Tulane Alumni Chair in Diabetes
Professor of Medicine
Chief, Section of Endocrinology
Tulane University School of Medicine
New Orleans, Louisiana
Vivian A. Fonseca, MD, FRCP, has disclosed that he has received consulting fees from Amgen, AstraZeneca, Eli Lilly, Janssen, Novo Nordisk, sanofi-aventis, and Takeda and funds for research support from Asahi Kasei Pharma, Bayer, EndoBarrier, and Gilead Sciences.
The phase III LEADER trial is a cardiovascular outcomes trial comparing the GLP-1 RA liraglutide vs placebo in 9340 patients with type 2 diabetes who have a relatively high risk of cardiovascular disease. The goal of this randomized, placebo-controlled trial was to demonstrate the cardiovascular safety of liraglutide with a prespecified assessment of benefit. The trial was remarkable for particularly outstanding participant retention with up to 5 years of follow-up and a larger than expected number of events, all of which make the results very robust.
The results of the LEADER trial were very reassuring about safety but also demonstrated a cardiovascular benefit over and above the expected improvement in glycemic control and reduction in body weight. Liraglutide was well tolerated despite uptitration to a near maximal dose and caused no major harm. The efficacy results were consistent across all endpoints, with a particularly significant 22% reduction in the risk of cardiovascular death (HR: 0.78; 95% CI: 0.66-0.93; P = .007). Individually, the frequencies of nonfatal myocardial infarction and stroke were not reduced significantly. However, when major adverse cardiovascular events were pooled together (eg, 3-point major adverse cardiac event), this composite primary outcome occurred in fewer patients on liraglutide, 13% compared with 14.9% in the placebo group (HR: 0.87; 95% CI: 0.66-0.93; P < .001 for noninferiority; P = .01 for superiority).
Anecdotal reports have suggested that treatment of type 2 diabetes with GLP-1 RAs or DPP-4 inhibitors may be associated with pancreatitis, resulting in a recommendation that patients be monitored carefully, particularly those who have abdominal pain, to rule out pancreatitis and stop the therapy should it occur. Fortunately, there was no increase in pancreatitis in the LEADER trial, a trial of more than 9000 patients during the course of approximately 5 years, which is very reassuring. There was a slight increase in the mean level of serum lipase, which is probably not clinically relevant. Even so, in patients with a history of prior pancreatitis, one might consider using other antidiabetic therapies such as SGLT2 inhibitors or thiazolidinediones. GLP-1 RAs have also been linked to pancreatic cancer. Although the risk of this cancer in the LEADER trial was numerically higher with liraglutide compared with placebo, the incidence was low.
Let’s now consider the LEADER results in the context of cardiovascular outcome trials for other diabetic therapies. The results of trials with DPP-4 inhibitors showed no cardiovascular benefit and a small increase in risk of hospitalization for heart failure. The randomized ELIXA trial of another GLP-1 RA, lixisenatide, also failed to show a cardiovascular benefit. However, it was conducted in a much higher risk population and over a shorter duration—the median follow-up was 25 months. Of importance, the SGLT2 inhibitor empagliflozin showed a very significant reduction in cardiovascular events during a 3-year period in the EMPA-REG outcomes trial. Specifically, treatment was associated with a highly significant reduction in mortality due to cardiovascular events and hospitalization for heart failure. Similar trials are ongoing with 2 additional SGLT2 inhibitors, canagliflozin and dapagliflozin.
There are now 2 diabetes drugs, liraglutide and empagliflozin, that have been shown in cardiovascular outcomes trials to have cardiovascular benefit. These results will have to be considered in revising guidelines. It may also open diabetes therapy to a more personalized approach by allowing us to target these therapies to high-risk patients with established cardiovascular disease and a risk of heart failure and/or death when treating their diabetes.
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