Novel Diabetes Drug Shows No Sign of Increasing Events in ACS Patients

LONDON, England—A novel glucose-lowering agent is safe in ACS patients with type 2 diabetes and a history of heart failure, suggests extended results from the ELIXA trial presented August 31, 2015, at the European Society of Cardiology Congress. 

Previous results from the trial provided reassurance that the injectable glucagon-like peptide receptor agonist lixisenatide does not raise the risk of cardiovascular events. In a press conference prior to his presentation here, Eldrin F. Lewis, MD, of Brigham and Women’s Hospital (Boston, MA), said the new data extend the findings by looking at the primary endpoint (a composite of cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for unstable angina) plus heart failure outcomes. 

In the trial, the researchers evaluated 6,068 patients (mean age 60.3 years; 69.3% men) with type 2 diabetes and a history of ACS within the past 180 days. Patients from 49 countries were randomized to lixisenatide or placebo between July 2010 and August 2013. 

During a run-in period of 7 days prior to randomization, patients were trained to self-administer the daily injections of medication (lixisenatide or volume-matched placebo equivalent to 10 μg/d lixisenatide). Once patients were randomized, the dose could be down- or up-titrated to a maximum of 20 μg/d in the absence of symptoms, such as hypoglycemia or GI distress. 

Consistent Neutrality

At a mean follow-up of approximately 800 days, there were no differences in heart failure events or mortality between the lixisenatide and placebo groups (table 1).

According to Dr. Lewis, about 22% of ELIXA patients had preexisting chronic heart failure. A separate analysis of those patients found that while their overall rate of hospitalization for heart failure was higher than in those without a history of heart failure, randomization to lixisenatide did not contribute excess risk compared with placebo (HR 0.93; 95% CI 0.66-1.30).  

Lixisinatide did, however, reduce HbA1c, systolic BP, and body weight. There also was less of an increase in albuminuria and a slight increase in heart rate with lixisinatide (P < .05 for all).

Dr. Lewis said although heart failure hospitalization was not part of the primary outcome in ELIXA, events were adjudicated based on the importance of the outcome in this population. Patients who were hospitalized for heart failure had a substantially higher risk of death compared with those who were not (HR 9.3; 95% CI 7.2-11.9); 18% of all deaths in ELIXA occurred in patients hospitalized for heart failure.

This suggests, he said, “that heart failure hospitalization is a very meaningful endpoint” in the ACS population with type 2 diabetes.

A Waste of Resources

Following the presentation, discussant Philippe Gabriel Steg, MD, of Hôpital Bichat (Paris, France), said while the trial was “well conducted and carefully reported,” he questions the necessity of this type of trial for new diabetes agents. Although the FDA requires cardiovascular safety studies of novel antidiabetic agents, Dr. Steg said numerous similar completed or ongoing trials enrolling over 150,000 total patients have shown no safety issues or even signals of a possible problem.  

“One has to wonder whether this is not a waste of resources given the number of patients that participate in these trials, the money required, and the fact that this is diverting resources from more important tasks,” he asserted.

Additionally, Dr. Steg said “an unfortunate side effect in this whole story” is that noninferiority trials are “being often mistakenly interpreted as lack of efficacy trials among nonspecialists to generate skepticism regarding treatment of diabetes or the need to control glycemia.”

Source: 
Lewis EF. Evaluation of lixisenatide in acute coronary syndrome (ELIXA). Presented at: European Society of Cardiology Congress; August 31, 2015; London, England. 

Disclosures:

• Dr. Lewis reports no relevant conflicts of interest. 
• Dr. Steg reports receiving research grants from Sanofi and Servier; serving as a consultant or speaker for multiple pharmaceutical companies; and being a stockholder in Aterovax. 

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