Commentary by Eldrin F. Lewis, MD, MPH and George Grunberger, MD
“Prior studies have established that patients with type 2 diabetes are at higher risk for incident cardiovascular disease than people who do not have type 2 diabetes, and some glucose-lowering drugs have been associated with increased risk of cardiovascular disease,” study coauthor Eldrin F. Lewis, MD, MPH, a physician in the Cardiovascular Medicine Division at Brigham and Women’s Hospital and Associate Professor at Harvard Medical School, in Boston, Mass, said in a statement to the press.
As a result, cardiovascular safety studies were mandated by the July 2008 United States Food and Drug Administration (FDA) guidance to pharmaceutical companies trying to market anti-diabetic drugs, explained George Grunberger, MD, President, American Association of Clinical Endocrinologists.
“ELIXA is the first GLP-1 receptor agonist trial to report findings, and it showed cardiovascular safety in patients with longstanding uncontrolled type 2 diabetes with recent acute coronary event,” commented Dr. Grunberger. “That result is reassuring even though there was no obvious risk of cardiovascular harm with this class of medications during their development to begin with. As such, one expects there will be minimal clinical implication of these results.”
“Physicians have to realize that these FDA-mandated studies are designed and powered for noninferiority,” said Dr. Grunberger, who also is Chairman of the Grunberger Diabetes Institute and Clinical Professor of Internal Medicine and Molecular Medicine and Genetics at Wayne State University School of Medicine in Detroit, MI. “Thus, when noninferiority is demonstrated the trial can be judged to be successful. Sometimes prescribers do not understand that these exercises are not designed to show that the drug in question provides cardiovascular benefit and then are disappointed when the results are neutral.”
Study Included More than 6,000 Patients
The multicenter, double-blind, placebo-controlled study included 6,068 patients (mean age, 60.3 years) with type 2 diabetes and a history of myocardial infarction (83%) or hospitalization for unstable angina (17%) within the past 180 days.
The patients were randomized to receive daily injections of 10 to 20 μg lixisenatide or placebo and were followed for a minimum of 10 months to measure the primary outcome: a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina. Adjustment of concomitant glucose-lowering agents or the addition of other antidiabetic medications (except other incretin therapies) was allowed in this study.
This outcome occurred in 13.4% of the lixisenatide group compared to 13.2% of the placebo group, with an adjusted hazard ratio of 1.02 and a 95% confidence interval (0.89-1.17) that was “well below the standard set by the FDA,” Dr. Lewis noted. This finding showed noninferiority of lixisenatide to placebo (P<0.001), but did not show superiority (P=0.81).
Lixisenatide also was safe in patients with a history of heart failure. Hospitalization for heart failure during follow-up occurred in 10% of patients with a history of heart failure compared with 2.4% of patients without a history of heart failure.
In addition, lixisenatide was not associated with an increased rate of the following serious adverse events compared with placebo: severe hypoglycemia, pancreatitis, pancreatic neoplasms, or allergic reactions.
Study Strengths and Limitations
One of the strengths of the study “is the number of randomized patients and completeness of follow up as well as the ability to collect additional safety data (eg, regarding hypoglycemia, pancreatitis, pancreatic cancer and allergic reactions),” Dr. Grunberger said.
“A weakness of the study, necessitated by the FDA mandate (focus on cardiovascular events) is the selection of patients with type 2 diabetes who did not represent the majority of patients who are candidates for the drugs in this class,” Dr. Grunberger said. “Further, the 2-year follow-up period is too short to derive meaningful long-term relevance of the findings. These patients had longstanding, advanced uncontrolled disease, and thus the results limit the ability to extrapolate to the general population of patients with type 2 diabetes.”
“In spite of the design requiring similar glycemic control in both study arms, there was an immediate and statistically significant A1c reduction in the lixisenatide group greater than in the placebo group, which persisted during the entire study. Additionally, patients assigned to lixisenatide had more weight loss and reduction in systolic blood pressure during the trial,” Dr. Grunberger told EndocrineWeb.
December 17, 2015
Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247-2257.
European Society of Cardiology. Press release: ELIXA Trial Shows CV Safety of Lixisenatide. http://www.escardio.org/The-ESC/Press-Office/Press-releases/Last-5-years/elixa-trial-shows-cv-safety-of-lixisenatide. Accessed December 15, 2015.