FDA Panel Backs Liraglutide to Reduce CV Risk Factors in Diabetes

Troy Brown, RN

June 21, 2017

( updated ) The US Food and Drug Administration's (FDA's) Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) voted overwhelmingly to recommend liraglutide (Victoza, Novo Nordisk) injection for the additional indication as "an adjunct to standard treatment of cardiovascular risk factors to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in adults with type 2 diabetes mellitus and high cardiovascular risk."

The panel voted 17 "yes" and 2 "no" that the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial provides the substantial evidence needed to establish that liraglutide 1.8 mg reduces cardiovascular risk in patients with type 2 diabetes and established cardiovascular disease. Liraglutide was associated with a 13% reduction in risk for cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, which was the primary end point of the trial, compared with those who received placebo.

The advisory committee also voted unanimously that the results of the LEADER trial establish that use of liraglutide in patients with type 2 diabetes is not associated with excess cardiovascular risk.

Liraglutide is a glucagonlike peptide 1 (GLP-1) analog that is injected subcutaneously and has prolonged GLP-1 receptor agonist activity. The FDA approved liraglutide on January 25, 2010, for the treatment of adults with type 2 diabetes. It is used adjunctively with diet and exercise to improve glycemic control. It is also approved under a different brand name, Saxenda, for the treatment of obesity.

The panel's discussion included the potentially increased risk for neoplasms, including medullary thyroid cancer and pancreatic cancer, and pancreatitis.

"I thought the primary outcome was very compellingly demonstrated — I think it was demonstrated in the population with established heart disease. I think it may well be useful in other people, but I don't think that this study proved that," temporary voting committee member Judith Fradkin, MD, director, division of diabetes, endocrinology, and metabolic diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, said.

Not the Only Game in Town

The ability to reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes is welcome news, and a number of pharmaceutical companies are exploring opportunities to expand the indications for their antidiabetic medications to include MACE prevention.

The FDA approved empagliflozin (Jardiance, Boehringer Ingelheim Pharmaceuticals) — a sodium glucose cotransporter-2 (SGLT2) inhibitor — for the additional indication of reducing the risk for cardiovascular death in adults with type 2 diabetes and cardiovascular disease, based on the results of EMPA-REG OUTCOME.

EMPA-REG OUTCOME included more than 7000 patients with type 2 diabetes and cardiovascular disease who were already taking statins, ACE inhibitors, and aspirin. Results showed that empagliflozin was associated with a 38% relative risk reduction in cardiovascular death and a 32% risk reduction in all-cause mortality compared with placebo.

The EMDAC's vote to recommend empagliflozin for the indication of reducing cardiovascular mortality was much closer (12 yes, 11 no) than that for liraglutide, likely because they were voting to recommend whether it should be approved to reduce CV death, rather than CV events, and also in part because empagliflozin was the first medication in a fairly new class of agents under consideration for reduction of CV risk.

Now the CANVAS program results for another SGLT2 inhibitor — canagliflozin (Invokana, Janssen Pharmaceuticals) — presented earlier this month at the American Diabetes Association (ADA) 2017 Scientific Sessions — seem to suggest the reduction in CV outcomes may be a class effect, with this second SGLT2 inhibitor associated with a 14% reduction in the primary composite outcome of cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke.

"Slippery Slope": Do We Need More Than One Trial?

Although the panel voted by a large margin in favor of the added indication for liraglutide, at least two panel members expressed ambivalence on the basis of factors including: the issue that the application was based on only a single study (LEADER); the lack of a significant benefit in US patients compared with those in other countries in that study; and the potential for adverse events. Several members questioned whether the overall trial results are generalizable to patients in the United States.

All but two speakers at the open public-hearing portion of the meeting spoke in favor of the revised label.

"I do worry about a slippery slope of using single trial data for new indications when there are questions and when you do have a significant interaction term for the US vs the rest of the world," voting committee member Daniel Budnitz, MD, US Public Health Service and director, medication safety program, division of healthcare quality promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, said.

Dr Budnitz said he would like to see another international trial where the US subgroup is not different from the rest of the world or a US trial.

"LEADER is a reasonable postmarketing study; total MACE was statistically significantly different between the two groups, favoring liraglutide, as was cardiovascular deaths; however, nonfatal [myocardial infarctions] and nonfatal strokes were not statistically different….Angina, coronary revascularization, and [congestive heart failure] admissions were also not individually statistically significantly different," said voting committee member Kenneth D Burman, MD, chief, endocrine section, Medstar Washington Hospital Center and professor, department of medicine, Georgetown University, in Washington, DC.

"The FDA usually requires two or more adequate trials with important end points; Here, we are considering a single trial that probably meets the FDA criteria to be reliable, statistically significant, and have important clinical results, thus in my view allowing determination of a label on a single trial."

CV Benefits Outweigh Concerns About Thyroid and Pancreatic Cancer and Pancreatitis

Meanwhile, Dr Burman said evidence regarding the potential side effects of liraglutide including pancreatic cancer, pancreatitis, hypoglycemia, skin cancer, and possible immunogenicity is probably inconclusive.

Other disagreed, with some panel members saying that the warning for liraglutide for medullary thyroid cancer (MTC) should be removed.

Overall, however, there was a general feeling that none of these side effects warrants real concern and that any risk from these is far outweighed by the cardiovascular benefits of liraglutide.

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