(Updated 3/7/16 with commentary) New top-line trial data released today show that liraglutide (Victoza, Novo Nordisk) significantly reduces the risk of major adverse cardiovascular events.
The results come from the multicenter, international Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER) trial. The study began in 2010 and followed 9340 high-risk adults with type 2 diabetes for 5 years, comparing those randomly assigned to liraglutide or placebo, along with standard treatment.
The primary end point was defined as the composite outcome of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The trial met criteria for both noninferiority and superiority for all three of the end-point components, Mads Krogsgaard Thomsen, PhD, Novo Nordisk executive vice president and chief science officer, announced during an investor call.
"Mechanistically and based on previous findings, the CV risk reduction in the liraglutide-treated patients may be expected to be disease-modifying and relate in part to improved glucose control and in part to improvements in other parameters related to CV risk," he noted.
"People with type 2 diabetes generally have a higher risk of experiencing major adverse cardiovascular events. That's why we are very excited about the results from LEADER," added Dr Thomsen.
The safety profile was consistent with previous liraglutide trials.
The full data set from LEADER will be presented in June at the American Diabetes Association's Annual Scientific Sessions and likely published around the same time in a peer-reviewed medical journal. Top-line data are normally released early once the outcome of a trial is known, in order to satisfy US financial regulations.
Third Agent to Show CV Benefit
Liraglutide is now the third glucose-lowering agent to show cardiovascular benefit and the first of the glucagonlike peptide-1 (GLP-1) class. Another GLP-1 agonist, lixisenatide (Lyxumia, Sanofi), did not show CV benefit in the ELIXA trial reported at the ADA meeting last year.
In February, one analyst predicted that the outcome of LEADER would "shape the fortune" of the GLP-1 class, which currently only reaches 2% of patient share in the overall diabetes market. Liraglutide is the most prescribed GLP-1 agonist, accounting for approximately 55% of the GLP-1 market and now stands to gain more from these positive LEADER data.
Diabetologists reacted enthusiastically to news of the first glucose lowering drug to show a cardiovascular benefit, in September 2015, when the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG) trial of the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) was reported at the EASD meeting in Stockholm.
However, Dr Thomsen pointed out in response to a question that in contrast to liraglutide, the empagliflozin benefit was seen only for one component of the primary composite end point, cardiovascular death. The overall composite result for empagliflozin was significant, but the results for nonfatal myocardial infarction and nonfatal stroke were not.
"We seem to have a different profile in comparison with empagliflozin," he said, adding that the company will be looking further into the mechanism and that it's possible the two drugs might turn out to be even more beneficial when used in combination.
Pioglitazone (Actos, Takeda Pharmaceuticals) demonstrated cardiovascular benefit over a decade ago in the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) and more recently in in the IRIS study in patients with insulin resistance but not diabetes. However, it is also associated with higher rates of edema, weight gain, and heart failure.
On hearing of the news from LEADER, senior author of the EMPA-REG trial, Silvio Inzucchi, MD, of Yale Diabetes Center, New Haven, Connecticut, told Medscape Medical News: "It's exciting to have, in the span of just 6 months, now a total of three diabetes drugs with proven CV benefits—empagliflozin, pioglitazone (in the IRIS trial…admittedly in a nondiabetic population), and now liraglutide," although he cautioned that it would be necessary to see the full results of LEADER to really appreciate the implications.
Nevertheless, "What a change from just 1 year ago when we diabetologists were all bordering on clinical depression because every time a study came out testing this question, the results were neutral!"
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Cite this: Top-Line Data Show CV Benefit for Liraglutide in Type 2 Diabetes - Medscape - Mar 04, 2016.