Results are the first from a cardiovascular safety trial in the GLP-1 agonist class. A commentator at the 75th Scientific Sessions of the American Diabetes Association asked whether the FDA-mandated studies are giving physicians the right information.
The first cardiovascular (CV) outcomes trial for a drug in the GLP-1 agonist class found no risks or benefits for patients with type 2 diabetes mellitus (T2DM) who took lixisenatide, according to results presented in Monday at the 75th Scientific Sessions of the American Diabetes Association.1
Lixisenatide is available in Europe, Japan, and a few other countries, but its maker, Sanofi, withdrew its application before FDA while awaiting the results from ELIXA, which stands for the Evaluation of Lixisenatide in Acute Coronary Syndrome.2 The study involved 6068 patients who were followed for approximately 2 years.
While the results may be enough for Sanofi to seek FDA approval, a commenter who spoke at the end of the presentation in Boston asked whether the “cottage industry” of cardiovascular safety trials demanded by regulators are asking the right questions.
Mark Pfeffer, MD, PhD, Dzau Professor of Medicine at Harvard Medical School and a cardiologist at Brigham and Women’s Hospital, presented the primary results of the study in the conference hall, in which a series of curves representing the study drug and the placebo were in alignment across a host of measures: for the CV composite, for CV death, all-cause mortality, and also for hospitalization for heart failure—a key measure that has caused headaches for other new diabetes drugs in other classes.
“There has been a cloud of suspicion over all new diabetes drugs, including GLP-1 agonists, over whether they may increase the risk for cardiovascular problems,” Dr Pfeffer said. “There has also been some hope that some of these drugs may improve cardiovascular health. GLP-1 receptor agonists were being used around the world while CVD safety had yet to be established.”3
Thus, ELIXA’s significance is its role as the first trial to report on CV safety for the GLP-1 agonists, which Dr Pfeffer said should reassure physicians and patients.
“You can never, never really have enough safety data,” Dr Pfeffer told attendees at the session.
While the study had the potential to demonstrate a CV benefit, the fact that it did not does not alarm researchers, who met the FDA’s bar for safety in the wake of the rosiglitazone episode in the last decade. Results from the TECOS trial, being presented right after ELIXA, were also a result of new regulatory approaches that emerged after 2007, when the New England Journal of Medicine published a meta-analysis that found rosiglitazone, then a blockbuster, presented increased heart attack risk.
Results presented Monday also showed a modest benefit from lixisenatide for weight control, and no increase in the risk for hypoglycemia or pancreatic injury. Risks of pancreatic injury or cancer have been of keen interest to FDA in recent years.
Silvio E. Inzucchi, MD, of the Yale Diabetes Center, was the discussant after results were presented. He reminded the audience of the history with rosiglitazone and the genesis for the current wave of cardiovascular outcomes trials. He said that given the requirement to give those on placebo other drugs to keep blood glucose levels in check, the neutral result in ELIXA “is not unexpected.”
While praising the quality of the ELIXA trial, Dr Inzucchi asked of the CV trials: are they asking the right questions? Are we recruiting the right patients? “We as clinicians want to know a little more than just safety,” he said.
Given the medical profile of the patients involved, Dr Inzucchi said it might be “naïve” for physicians primarily focused on diabetes care to believe that they can also affect CV outcomes. But if a therapy were developed that achieved that, “Only then would we have achieved the holy grail.”
1. Pfeffer MA, et al. The evaluation of lixisenatide in acute coronary syndrome—the results of the ELIXA trial. Symposium at the 75th Scientific Sessions of the American Diabetes Association; Boston, MA; June 8, 2015.
2. Nainggolan L. No CV benefit with lixisenatide in ELIXA, but results reassure. Medscape. Published and accessed June 8, 2015. http://www.medscape.com/viewarticle/846074#vp_2.
3. First CVD outcome trial of a GLP-1 agonist finds no cardiac risk or benefit [press release]. Boston, MA: American Diabetes Association; June 8, 2015.