Efpeglenatide Reduces CV Risk, Progression of Renal Disease in High-risk T2D Population

Results from the international AMPLITUDE-O trial demonstrate significant reduction in the first occurrence of heart attack, stroke, or death, and a reduction in progression of kidney disease in patients with type 2 diabetes (T2D) with weekly use of efpeglenatide, an exendin-4-based glucagon-like peptide 1 receptor agonist (GLP-1 RA).

The data, presented at the American Diabetes Association 81st Scientific Sessions and published simultaneously in the New England Journal of Medicine showed a 27% lower risk of a heart attack, stroke, or cardiovascular death, a 32% lower risk of kidney disease progression; and a 27% lower risk of a heart attack, stroke, or death from any cause.

“The AMPLITUDE O trial establishes efpeglenatide...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.”

The well of evidence is deep for the cardioprotective benefits of 4 GLP-1 receptor agonists structurally similar to human GLP-1 in patients with T2D but less is known about the impact on kidney function. This, in part, led Gerstein and coinvestigators to examine the potential for the exendin-4-based peptide to reduce the risk for both cardiovascular and renal outcomes.

AMPLITUDE-O enrolled 4076 patients from 344 study sites across 28 countries. Eligible participants had T2D and either a history of cardiovascular disease or current kidney disease plus at least 1 other cardiovascular risk factor.

Patients were randomized in a 1:1:1 fashion to receive weekly subcutaneous injections of efpeglenatide 4 mg (n=1359), 6 mg (n=1358) or placebo (n=1359). Investigators stratified randomization according to sodium-glucose contranspoerter-2 (SGLT-2) inhibitor use (15% of participants). Overall, the 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.

The primary outcome was the first major adverse cardiovascular event, or MACE, (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or undetermined causes).

Follow up lasted a medial of 1.8 years during which the primary outcome occurred in 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_{non-inferiority} <.001; P_superiority=.007). A composite renal outcome (decrease in kidney function or macroalbuminuria) 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).

Adverse events included diarrhea, constipation, nausea, vomiting, or bloating which occurred more frequently with efpeglenatide. Further analysis found efpeglenatide effects were consistent regardless of the presence or absence of an SGLT2 inhibitor.