Efpeglenatide, an investigational nonhuman exendin-based GLP-1 receptor agonist, may reduce the risk for cardiovascular and renal outcomes in patients with high-risk type 2 diabetes compared with placebo, according to new study findings published in the New England Journal of Medicine.

In the AMPLITUDE-O trial (NCT03496298), investigators randomly assigned 4076 patients with type 2 diabetes to receive weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg or placebo. The patients had a mean age 64.5 years and 86.7% were White. Most (89.6%) had a history of cardiovascular disease, 31.6% had an estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2, and 21.8% had both cardiovascular disease and a low eGFR.

The primary outcome was the first major adverse cardiovascular event (MACE), including nonfatal myocardial infarction or stroke, or death from cardiovascular or undetermined causes. During a median follow-up of 1.81 years, the composite MACE occurred in 7.0% of patients assigned to receive efpeglenatide (3.9 events per 100 person-years) and 9.2% of patients assigned to receive placebo (5.3 events per 100 person-years). Efpeglenatide treatment proved superior to placebo, significantly reducing the risk for composite MACE by 27%, Hertzel C. Gerstein, MD, from Hamilton Health Sciences in Canada, and colleagues reported.

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The secondary composite renal outcome of a decrease in kidney function or development of macroalbuminuria occurred in 13.0% of patients assigned to receive efpeglenatide and 18.4% assigned to receive placebo. Efpeglenatide treatment significantly reduced the risk for this composite renal endpoint by 32% compared with placebo, Dr Gerstein and his colleagues reported.

Investigators defined kidney function decline as a 40% or greater drop in eGFR, a sustained eGFR of less than 15 mL/min/1.73 m2,or need for renal-replacement therapy and defined macroalbuminuria as an increase in urinary albumin-to-creatinine ratio (UACR) of 30% or more from baseline to levels exceeding 300 mg/g.

Efpeglenatide was taken in addition to current therapy. Approximately 15% of the cohort was also taking a sodium glucose transporter 2 (SGLT2) inhibitor. According to the investigators, the cardiovascular and renal benefits associated with efpeglenatide treatment appeared to be independent of SGLT2 inhibitor use, metformin use, and baseline kidney function.

“A variety of possibilities may account for the protective effects of efpeglenatide on the heart and the kidneys,” Dr Gerstein’s team wrote. “The drug significantly reduced several risk factors for both cardiovascular and kidney disease, including glycated hemoglobin level, blood pressure, body-mass index, low-density lipoprotein cholesterol level, eGFR, and the albumin-to-creatinine ratio.”

The investigators pointed out that the GLP-1 receptor agonist was from an animal source, suggesting that the cardiovascular benefits of this class of agents are not restricted to GLP-1 receptor agonists that are similar to human GLP-1.

Diarrhea, constipation, nausea, vomiting, or bloating occurred in a significantly higher proportion of the efpeglenatide than placebo group (1.2% vs 0.4%). A significantly higher proportion of the efpeglenatide group discontinued treatment (5.4% vs 3.6%).

Disclosure: This research was supported by Sanofi. Please see the original reference for a full list of disclosures.


Gerstein HC, Sattar N, Rosenstock J, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med. Published online June 28, 2021. doi:10.1056/NEJMoa2108269