Efpeglenatide reduces MACE, kidney events in high-risk patients with T2D

Roshini Claire Anthony
23 Jul 2021

In patients with type 2 diabetes (T2D) with cardiovascular (CV) risk factors or impaired kidney function, weekly doses of the exendin-based GLP-1* receptor agonist (RA) efpeglenatide may reduce their risk of major adverse cardiovascular events (MACE) or kidney outcomes, according to findings from the AMPLITUDE-O trial presented at ADA 2021.

“The AMPLITUDE-O trial establishes efpeglenatide … as an effective cardioprotective drug for T2D patients with CV and/or kidney disease,” said first author Professor Hertzel Gerstein from McMaster University and Hamilton Health Sciences, and the Population Health Research Institute in Ontario, Canada.

This international trial included 4,076 adults (mean age 64.5 years, 33 percent female, 86.7 percent White) with T2D (HbA1c >7.0 percent) and a history of CV disease (CVD; 89.6 percent) or current kidney disease (eGFR 25.0–59.9 mL/min/1.73 m2; 31.6 percent) plus 1 CV risk factor (21.8 percent had both CVD history and current kidney disease). They were randomized 1:1:1 to receive subcutaneous efpeglenatide (4 or 6 mg) or placebo weekly.

About 15 percent of patients were on SGLT-2* inhibitors at baseline, 73.2 percent were on metformin, and 62.8 percent on insulin. Eighty-one percent were on statins, 80 percent on ACE inhibitors, ARBs, or ARN inhibitors*, and 65.5 percent on beta-blockers. Mean diabetes duration was 15.4 years.

Over a median 1.81 years, a significant reduction in the incidence of MACE (nonfatal myocardial infarction, nonfatal stroke, or death from CV or undetermined causes) was noted with efpeglenatide vs placebo (7.0 percent vs 9.2 percent; hazard ratio [HR], 0.73, 95 percent confidence interval [CI], 0.58–0.92; pnoninferiority<0.001; psuperiority=0.007). [ADA 2021, session 3-CT-SY28; N Engl J Med 2021;doi:10.1056/NEJMoa2108269]

This translated to an incidence rate of 3.9 vs 5.3 per 100 person-years with efpeglenatide vs placebo, with an estimated 46 patients needing to be treated with efpeglenatide for 1.8 years to avoid one MACE incident.

The effect of efpeglenatide appeared consistent regardless of sex, age, race, diabetes duration, HbA1c, BMI, eGFR, CVD history, or SGLT-2 inhibitor or metformin use.

The incidence of renal outcomes** was also reduced with efpeglenatide vs placebo (13.0 percent vs 18.4 percent; HR, 0.68, 95 percent CI, 0.57–0.79; psuperiority<0.001).

Patients on efpeglenatide also had a reduced incidence of a composite of MACE, coronary revascularization, or hospitalization for unstable angina compared with placebo (9.5 percent vs 11.6 percent; HR, 0.79; psuperiority=0.02), as well as MACE or non-CV death (7.9 percent vs 10.5 percent; HR, 0.73; psuperiority=0.004).

Efpeglenatide also reduced several other CV and renal risk factors vs placebo (reflected with least-squares mean differences) including HbA1c (-1.24 percent), BMI (-0.9), body weight (-2.6 kg), systolic and diastolic blood pressure (-1.5 and -0.6 mm Hg, respectively), pulse pressure (-2.1 mm Hg), LDL-cholesterol (-2.7 mg/dL), and UACR (-21 percent), and increased heart rate (+3.9 beats/min) and eGFR (+0.9 mL/min/1.73 m2).

Severe gastrointestinal adverse events (AEs) occurred more frequently in the efpeglenatide than placebo group (3.3 percent vs 1.8 percent; p=0.009), as did constipation, diarrhoea, nausea, vomiting, or bloating (1.2 percent vs 0.4 percent; p=0.03). Rates of other AEs were comparable between groups. “[T]here was no evidence of retinal, pancreatic, or thyroid-related events,” the authors highlighted.

More patients on efpeglenatide than placebo discontinued the trial regimen due to AEs (5.4 percent vs 3.6 percent; p=0.02).

“We are encouraged that this once-a-week injection, safely and effectively reduced CV and progression of kidney disease in patients with long-standing diabetes who had a high prevalence of CV and kidney disease,” said Gerstein. However, the authors noted that the findings apply to T2D patients with a profile similar to those in the study and not necessarily those with lower risk.

“[T]he fact that these findings accrued with a long-acting exendin-4–based GLP-1 RA suggests that the CV benefits of this class of agents are not restricted to GLP-1 RAs that are structurally similar to human GLP-1,” they added.


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