No Benefit in Cardiovascular Outcomes for Patients with Type 2 Diabetes Treated with Lixisenatide

“You can never, ever really have too much safety data,” said Marc A. Pfeffer, MD, PhD, lead author of the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) study.

With nearly 400 million people diagnosed with type 2 diabetes worldwide (a number that is projected to rise to 600 million within the next 20 years), identifying safe and effective treatments is crucial. Pfeffer, of Brigham and Women’s Hospital, and colleagues evaluated the use of lixisenatide in patients with type 2 diabetes and acute coronary syndrome (ACS). The study was designed to determine if the drug could safely lower glucose levels in this group of patients. The findings were revealed during a presentation at the American Diabetes Association 75^th Scientific Sessions in Boston, MA.

Each of the 6,068 patients enrolled in the study had type 2 diabetes and an ACS event within the 180 days leading up to randomization — including STEMI, non-STEMI, and unstable angina. Additional inclusion criteria included being at least 30 years old with HbA1c from 5.5 to 11.0%. The participant pool, consisting of patients from 49 countries, was randomized so half would receive injections of lixisenatide while the other half received placebo. Since this was a double-blind study, the health providers were told to manage their patients’ glucose levels to the best of their abilities using the standard guidelines.

“It is important to remember that glucose lowering has a wide variety of beneficial effects,” one of the authors Hertzel C. Gerstein, MD, MSc, FRCPC, said during the meeting.

The initial dose of lixisenatide or matching placebo was 10 µg/day, increasing to 20 µg/day. However, that dosage decreased if needed on an individual basis. One of the authors, Eldrin F. Lewis, MD, MPH, noted that 5 participants were released from treatment because they either had an adverse event within the first 3 days or were found to have pancreatitis, pancreatic cancer, or allergic reaction. This is the first time a GOB-1 receptor antagonist was used in a trial.

The average amount of time a patient in the lixisenatide group remained on the medication was 1.9 years and (1.8 for the placebo group). During that time the researchers collected data on glucose level benefits, cardiovascular risks, and adverse effects.

HbA1c levels proved to be higher in the placebo group across the board, with lixisenatide patients having a modestly lower average level (0.27%). Patients who received lixisenatide also experienced a mean post-baseline difference in body weight of a 0.7 kg when compared to placebo.

The lixisenatide group had an average lower fasting plasma glucose by 0.27 and systolic blood pressure by 0.8. The baseline difference in heart rate was actually slightly higher in the lixisenatide group by 0.4; however, the occurrences were mainly in the beginning of the trial and do not hold statistical significance, according to study author Matthew C. Riddle, MD.

Additional data from the study included:

• Frequency of hypoglycemia: lixisenatide 504 (16.6%) placebo 462 (15.2%)
• Malignancies (including lung, colorectal, thyroid, prostate breast, and other): lixisenatide 89 (2.9%) placebo 78 (2.6%)
• Adverse effects (including nausea, vomiting, and diarrhea): lixisenatide 2,447 (81%) placebo 2,321 (77%)
• Nausea (most common adverse effect): lixisenatide 659 placebo 181
• Discontinued treatment due to the adverse effects: lixisenatide 347 (11.4%) placebo 217 (7.2%)

In addition, 434 patients died during the course of this study from a variety of causes.

While there are slight variations between the groups, a theme in the presentation was confirming that the numbers did not hold statistical significance. Although the results showed that lixisenatide lowered HbA1c levels without affecting cardiovascular health, the researchers stressed that this does not mean that the drug improves cardiovascular outcomes in any way either.

“We can’t stand up here and say that we are reducing cardiovascular events in this population,” Pfeffer declared at the conference.

The takeaway message is that the team has “great confidence” that lixisenatide can safely lower glucose levels in patients with type 2 diabetes who are susceptible to cardiovascular events.