AMPLITUDE-O: Efpeglenatide Shows Promise for Reducing CV, Kidney Events in Patients with Diabetes

Hertzel Gerstein, MD

Data from the AMPLITUDE-O trial suggest use of efpeglenatide was associated with 27% reduction in cardiovascular events and a 32% lower risk of kidney disease progression in patients with type 2 diabetes with cardiovascular or chronic kidney disease.

Presented at the American Diabetes Association’s 81st Scientific Sessions (ADA 2021), results of the trial provide the most substantial evidence demonstrating the exendin-4-based GLP-1 receptor agonist (GLP-1 RA) could reduce the risk of cardiovascular and renal-related adverse events in patients with type 2 diabetes.

“The AMPLITUDE O trial establishes efpeglenatide, an exendin-4 based GLP-1 RA, as an effective cardioprotective drug for type 2 diabetes patients with cardiovascular and/or kidney disease,” said Hertzel C. Gerstein, MD, MSc, Professor, McMaster University and Hamilton Health Sciences, and Deputy Director Population Health Research Institute in Ontario, Canada, in a statement. “We are encouraged that this once-a-week injection, safely and effectively reduced cardiovascular and progression of kidney disease in patients with long-standing diabetes who had a high prevalence of cardiovascular and kidney disease.”

With an interest in examining whether the exendin-4-based GLP-1 RA could attenuate the risk of cardiovascular and renal outcomes in patients with type 2 diabetes, the randomized, placebo-controlled AMPLITUDE-O trial enrolled 4076 patients from 344 sites across 28 countries. For inclusion in the study, patients needed to have type 2 diabetes and either a history of cardiovascular disease or current kidney disease plus at least 1 other cardiovascular risk factor.

Patients deemed eligible for inclusion were randomized in a 1:1:1 ratio to weekly subcutaneous injections of efpeglenatide 4 mg, efpeglenatide 6 mg, or placebo. Investigators noted randomization was stratified according to SGLT2 inhibitor use. The primary outcome was first incident of a major adverse cardiovascular event, which investigators defined as a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or undetermined causes.

In total, 5732 patients underwent screening and 4076 underwent randomization. Of these, 1359 were assigned to efpeglenatide 4 mg, 1358 were assigned to efpeglenatide 6 mg, and 1359 were assigned to placebo. The overall study population had a mean age of 64.5±8.2 years, 33% were female, 89.6% had a history of cardiovascular disease, 31.8% had current kidney disease, and 62.8% were using insulin.

During a follow-up period lasting a median of 1.81 years, the primary outcome occurred among 189 (7.0%) participants randomized to efpeglentaide and 125 (9.2%) randomized to placebo (HR, 0.73; 95% CI, 0.58-0.92; P <.001; P for non-inferiority <.001; P for superiority=.007). When assessing for a composite renal outcome, which was defined as a decrease in kidney function or macroalbuminuria, results indicated such an event occurred in 353 (13.0%) patients randomized to efpeglenatide and in 250 (18.4%) patients randomized to placebo (HR 0.68; 95% CI, 0.57-0.79; P <.001).

In safety analyses, results suggested diarrhea, constipation, nausea, vomiting, or bloating occurred more frequently with efpeglenatide. Investigators also highlighted further analysis demonstrated the effects of efpeglenatide were consistent regardless of the presence or absence of an SGLT2 inhibitor.

This study, “Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes,” was published in the New England Journal of Medicine and presented at ADA 2021.