ELIXA: No Cardiac Risks, Benefits With Lixisenatide

BOSTON — The glucagon-like peptide-1 (GLP-1) receptor agonist lixisenatide appears to have a neutral effect on heart failure and other cardiovascular (CV) outcomes, according to data from the highly anticipated ELIXA study.

The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) study is the first clinical trial to examine CV safety in a GLP-1 receptor agonist. The findings, which were presented at the American Diabetes Association (ADA) 75th Scientific Sessions, are expected to remove a cloud of suspicion about GLP-1 receptor agonists and whether they may increase the risk for CV problems.

“In choosing pharmacologic agents to assist in the control of elevated glucose, physicians and patients should have firm data regarding possible benefits as well as risk of these agents. Glucagon-like peptide-1 receptor agonists are effective in assisting in the control of elevated glucose,” principal study investigator Marc Pfeffer, MD, PhD, professor of medicine at Harvard Medical School and senior physician in cardiology at Brigham and Women’s Hospital in Boston, said.

“Despite a favorable profile on several surrogate markers of cardiovascular risk, the influence of these agents on cardiovascular outcomes has not been robustly examined.”

ELIXA Results

ELIXA was a randomized, double-blind, placebo-controlled trial that included 6,068 patients from 49 countries with type 2 diabetes and a recent acute coronary syndrome (ACS) event who were assigned to lixisenatide (n=3,034) or matching placebo (n=3,034).

The initial dose was 10 mcg per day with down- or up-titration permitted to a maximum of 20 mcg per day.

Baseline characteristics were similar between groups. In the placebo and lixisenatide study arms, mean duration of diabetes was 9.4 and 9.2 years, mean fasting glucose was 148 mg/dL and 149 mg/dL, and mean HbA1c was 7.6% and 7.7%, respectively. About 11% in each group had retinopathy and about 17% had neuropathy. BMI was about 30 in both groups.

Average age was about 60 years, 76% were white, and the qualifying ACS event in most cases was MI.

In terms of CV history, about 22% had a history of MI before the index ACS event, 6% had a history of stroke prior to randomization and 22% had a history of heart failure. The majority underwent revascularization at some point, but not necessarily after their ACS event.

The primary endpoint was a composite of CV death, nonfatal MI, nonfatal stroke and hospitalization for unstable angina. Secondary endpoints included the primary endpoint in addition to hospitalization for heart failure; the primary endpoint, hospitalization for heart failure plus coronary revascularization; percent change in urinary albumin/creatinine ratio from baseline to 108 weeks; and all-cause death.

The researchers found no increased risk for the primary outcome with lixisenatide, as compared with placebo, with the primary outcome occurring in 13.4% of the lixisenatide group and 13.2% of the placebo group (HR=1.02; 95% CI, 0.89-1.17).

Similar results were observed for the primary outcome plus hospitalization for heart failure (HR=0.97; 95% CI, 0.85-1.10); hospitalization for heart failure (HR=0.96; 95% CI, 0.75-1.23); and all-cause death (HR=0.94; 95% CI, 0.78-1.13).

On average, HbA1c declined in both arms, favoring the lixisenatide arm, with a mean post-baseline difference of –0.27%. It is important to note, however, that ELIXA is not a glucose control comparison study, ELIXA researcher Matthew J. Riddle, MD, professor of medicine at Oregon Health and Science University, said during a press conference.

Other clinical findings showed that lixisenatide was associated with a 0.7-kg weight loss, as compared with placebo, as well as a 0.8-mm Hg decrease in systolic blood pressure and a lesser increase of albuminuria. Heart rate was unaffected, and there was also no increase in pancreatitis, pancreatic cancer or drug-related systemic allergy.

Data also showed that despite better blood glucose control, those who took lixisenatide were not more likely to have problems with hypoglycemia

As expected, nausea and vomiting were increased in the lixisenatide study arm, with about 4% discontinuing due to gastrointestinal-related adverse events.

“Other prespecified analyses for death from all causes, as well as hospitalizations for heart failure also showed no increase in the group randomized to lixisenatide. While nausea and vomiting more frequently led to study drug discontinuation, in the lixisenatide group there was no increase in their serious adverse reports and no imbalances or safety signals were observed for pancreatitis or pancreatic cancers,” Pfeffer said.

Clinical Implications

Because heart disease and stroke are the No. 1 causes of death and disability among people with type 2 diabetes, the U.S. Food and Drug Administration (FDA) has recently augmented CV surveillance for new drugs prescribed to treat elevated blood glucose in patients with type 2 diabetes, including GLP-1 receptor agonists.

“Modest favorable changes in body weight, systolic blood pressure and urine albuminuria were observed in the lixisenatide group,” Pfeffer told Endocrinology Advisor. “The take-home message is that glucose levels were lowered without numerically increasing severe hypoglycemic episodes with a cardiovascular safety profile that would be considered safe as defined by the FDA guidance document.” 

Eldrin Lewis, MD MPH, who is an associate professor of medicine at Harvard Medical School, said knowing this class of diabetes medications can be prescribed safely gives physicians another tool to further lower glucose without producing more hypoglycemia. He said these agents can provide a very important adjunct to therapy.