Efpeglenatide Reduces Cardiovascular Events in Some Patients With Type 2 Diabetes

woman doing injection with insulin pen
Investigators assessed the effect of efpeglenatide, an exendin-based glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes at increased risk for cardiovascular events.

Weekly subcutaneous injections of efpeglenatide 4 mg or 6 mg were found to be associated with a decreased risk of cardiovascular events in patients with type 2 diabetes and a history of either cardiovascular disease (CVD) or current kidney disease with at least 1 CV risk factor, according to research results published in The New England Journal of Medicine.

Data show that weekly subcutaneous injections of the glucagon-like peptide-1 (GLP-1) receptor agonist efpeglenatide lowers glucose levels without causing hypoglycemia through a mechanism of action similar to GLP-1 receptor agonists that are similar to human GLP-1. This similarity, in combination with an acceptable safety profile, suggests that efpeglenatide may also have both CV and renal benefits in patients with diabetes and concomitant CVD, kidney disease, or both.

To investigate this hypothesis, researchers conducted the AMPLITUDE-O trial (ClinicalTrials.gov Identifier: NCT03496298), an international randomized controlled trial conducted at 344 sites in 28 countries. Participants included adults with type 2 diabetes and glycated hemoglobin (HbA1c) greater than 7% with a history of CVD or those who were at least 50 (for men) or 55 (for women) years of age and had kidney disease with at least 1 CV risk factor.

The primary study outcome was the first occurrence of a major adverse CV event (MACE). Key secondary outcomes included an expanded MACE composite outcome of MACE, coronary revascularization, or hospitalization for unstable angina and a composite renal outcome of incident macroalbuminuria plus an increase in the urinary albumin-to-creatinine ratio of ≥30%.

The total cohort included 4076 participants who were randomly assigned 1:1:1 to receive either efpeglenatide 2 mg for 4 weeks, then 4 mg per week through the trial conclusion (n=1359); efpeglenatide 2 mg for 4 weeks, then 4 mg for 4 weeks, then 6 mg through the trial conclusion (n=1358); or placebo (n=1359).

At baseline, mean participant age was 64.5±8.2 years, and 33% were women. A total of 89.6% of participants had a history of CVD, 31.6% had an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2, and 21.8% had both CVD and low eGFR. A total of 15.2% were being treated with a sodium-glucose cotransporter-2 (SGLT2) inhibitor at baseline, and similar percentages of participants in the efpeglenatide and placebo groups were being treated with glucose-lowering or cardioprotective drugs at baseline.

Over the follow-up period, 7% and 9.2% of patients receiving efpeglenatide or placebo, respectively, had at least 1 MACE (3.9 vs 5.3 events per 100 person-years; hazard ratio [HR], 0.73), allowing researchers to conclude that “an estimated 46 similar patients would need to be treated with efpeglenatide for 1.8 years to prevent 1 MACE.”

Results of exploratory analyses suggested a possible dose-response effect, reflected by a hazard ratio (HR) of 0.82 for the comparison between the efpeglenatide 4 mg and placebo groups and a HR of 0.65 for the comparison between efpeglenatide 6 mg and placebo groups.

Those in the efpeglenatide groups reported a significantly lower incidence of at least 1 expanded MACE composite event (HR, 0.79), a renal composite outcome event (HR, 0.68), and a MACE or death from noncardiovascular causes (HR, 0.73). Median time to death from noncardiovascular causes was 1.81 years (interquartile range, 1.69-1.98).

No effects of efpeglenatide on the primary outcome were noted in terms of variability of sex, age, race, diabetes duration, HbA1c, body mass index, eGFR, history of CVD, or treatment with either an SGLT2 inhibitor or metformin.

During the follow-up period, the effect of efpeglenatide on least-squares mean differences in continuous variables included a 1.24% decrease in HbA1c, a 0.9-kg/m2 decrease in body mass index, a 2.6-kg decrease in body weight, and a 1.5-mm Hg and a 0.6-mm Hg decrease in systolic and diastolic blood pressures, respectively. Pulse pressure, low-density lipoprotein cholesterol, and urinary albumin-to-creatinine ratio were also lower in those treated with efpeglenatide, while heat rate and eGFR were higher.

More patients in the efpeglenatide groups vs the placebo group experienced severe gastrointestinal adverse including constipation, diarrhea, nausea, vomiting, or bloating. Other prespecified safety outcomes and adverse effects were similar among participant groups.

Study limitations include the short follow-up period; the occurrence of a primary outcome event in fewer participants than planned; and limited selection for previous CV or kidney disease, which limits generalizability of the study findings.

“The results of our trial show that efpeglenatide reduces the risk of serious adverse [CV] and renal events among persons with type 2 diabetes and either a history of [CVD] or current kidney disease,” the researchers concluded.

Disclosure: This clinical trial was supported by Sanofi. Please see the original reference for a full list of authors’ disclosures.


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