Efpeglenatide Has Cardiovascular and Renal Benefit Outcomes in Type 2 Diabetes

Efpeglenatide has proven to significantly reduce several risk factors for cardiovascular and renal disease. 

The incidence of cardiovascular and renal adverse events among patients with diabetes is much more significant than in those without diabetes. This significant rise increases with kidney dysfunction, history of cardiovascular disease, duration of diabetes, and higher urinary albumin-to-creatinine ratio. Many patients with type 2 diabetes also have at least one chronic condition, including hypertension, kidney disease, or cardiovascular disease. To promote patient adherence as patients are often taking multiple medications to treat comorbid conditions, it is crucial to study new diabetes medications that treat multiple conditions at once. Efpeglenatide, a long-acting exendin-4 GLP-1 receptor agonist, has been shown to lower blood glucose levels while offering cardiovascular and renal benefits. This medication works similarly to human GLP-1 receptor agonists, which also have reduced cardiovascular risks. Efpeglenatide has successfully passed its phase 2 clinical trial, revealing significant benefits regarding HbA1c and weight reduction in patients with type 2 diabetes1. Cardiovascular and renal outcomes in those taking GLP-1 receptor agonists have been previously reported; however, their effects on such outcomes taken with SGLT2 inhibitors are unknown2. 

An international, randomized, controlled trial3 (the AMPLITUDE-O trial) assessed the use of efpeglenatide among 4,076 patients in 28 countries. The objective was to evaluate efpeglenatide in patients with type 2 diabetes and either a history of kidney or cardiovascular disease and at least one cardiovascular risk factor. Patients were randomly assigned in a 1:1:1 ratio to receive a subcutaneous injection of efpeglenatide once weekly at a dose of either 4 or 6 mg or placebo. Additionally, randomization was stratified according to the current or future use of SGLT2 inhibitors. The primary outcome was the first occurrence of a major adverse cardiovascular event such as nonfatal myocardial infarction, nonfatal stroke, or death. The secondary outcomes included an expanded MACE outcome (hospitalization for unstable angina) and composite renal outcome (macroalbuminuria, renal replacement for more than 90 days, and an increase in the urinary albumin-to-creatinine ratio of more than 30% from baseline). Analysis was performed following the intention-to-treat principle, and Kaplan-Meier curves displayed cumulative risks.  

Patients taking efpeglenatide had a 27% reduction in cardiovascular adverse events including heart attack or stroke (95% CI, 0.58-0.92; P = .0069) and a 32% reduction in renal events (95% CI, 0.57-0.79; P < .001). However, those who had gastrointestinal adverse events such as diarrhea or vomiting were higher in the efpeglenatide than the placebo group. MACE occurred in 7% of patients who received efpeglenatide and in 9.2% of patients who received placebo. A composite renal outcome occurred in 13% of those receiving efpeglenatide and 18.4% in the placebo group. 

This study showed that the use of efpeglenatide, particularly at a higher dosage, lowered the risk of cardiovascular and renal adverse events among those with type 2 diabetes and a history of cardiovascular or renal disease. These results also showed cardiovascular and renal benefits in more than 15% of participants using concomitant SGLT2 inhibitors, suggesting that the cardiovascular and renal benefits in efpeglenatide occurred independently of the SGLT2 inhibitor usage. SGLT2 inhibitors work in a different way to reduce blood glucose, which did not show better outcomes than efpeglenatide in this trial. This finding is significant as many experts recommend high-risk patients taking a medication in each class; however, their benefits seem complementary. Limitations of this trial included a primary outcome event in fewer individuals than anticipated and a short follow-up period. Future studies should be conducted to analyze efpeglenatide in lower-risk patients with type 2 diabetes instead of only selecting those at high risk or with previous cardiovascular or kidney disease. 

Practice Pearls: 

• GLP-1 receptor agonists have previously been shown to reduce the risk of cardiovascular events among patients with type 2 diabetes.
• A randomized, controlled trial found a 27% reduction in cardiovascular adverse events and a 32% reduction in renal events in those takingefpeglenatidefor the treatment of type 2 diabetes 
• The analysis ofefpeglenatideregarding cardiovascular events was not affected by sex, age, duration of diabetes, eGFR, or use of SGLT2 inhibitors. 

1. Del Prato, Stefano et al. “Efficacy and safety of once-monthly efpeglenatide in patients with type 2 diabetes: Results of a phase 2 placebo-controlled, 16-week randomized dose-finding study.” Diabetes, obesity & metabolism  
2. Kristensen, Soren L et al. “Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.” The lancet. Diabetes & endocrinology  
3. Gerstein, Hertzel C et al. “Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes.” The New England journal of medicine 

Dalia Elabed, PharmD Candidate 2022, University of South Florida Taneja College of Pharmacy