Efpeglenatide Lowers CV and Renal Events in Type 2 Diabetes-associated CKD

Individuals with diabetes are at increased risk of adverse cardiovascular events compared with those without diabetes. People with diabetes are also at increased risk of adverse rental events. The risk of adverse cardiovascular events in patients with type 2 diabetes have been shown to be reduced with use of glucagon-like peptide-1 (GLP-1) receptor agonists that are structurally similar to human GLP-1.

Efpeglenatide, an exendin-based GLP-1 receptor agonist, administered weekly via subcutaneous injection, lowers glucose levels without causing hypoglycemia. There are few data available on the effect of efpeglenatide on cardiovascular and renal outcomes in patients with type 2 diabetes who are at high risk for adverse cardiovascular events.

Hertzel C. Gerstein, MD, and colleagues, conducted an international, randomized, controlled trial (the AMPLITUDE-O trial) at 344 sites in 28 countries to evaluate efpeglenatide in participants with type 2 diabetes and either a history of cardiovascular disease or current kidney disease (defined as estimated glomerular filtration rate [eGFR] of 25.0 to 59.9 mL/min/1.73 m2) plus at least one other cardiovascular risk factor. The trial was designed by the sponsor (Sanofi) in conjunction with an independent international steering committee. Sanofi also managed the trial sites and collected the data. Study results were reported online in the New England Journal of Medicine [doi:10.1056/NEJMoa2108269].

Participants were randomized in a 1:1:1 ratio to (1) receive efpeglenatide at a weekly dose of 2 mg for 4 weeks and then 4 mg per week until the end of the trial; (2) efpeglenatide at a dose of 2 mg per weeks, then 4 mg per week for 4 weeks, and then 6 mg per week until the end of the trial; or (3) placebo. The treatment period was defined as the time of randomization until the end of the trial, death, or discontinuation of the assigned regimen.

The primary outcome of interest was the first occurrence of a major adverse cardiovascular event (MACE; a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or undetermined causes). Secondary outcomes of interest included an expanded MACE composite outcome (MACE, coronary revascularization, or hospitalization for unstable angina) and a composite renal outcome (incident macroalbuminuria [defined as a urinary albumin-to-creatinine ratio of >300, as measured in milligrams of albumin to grams of creatinine, or >33.9, as measured in milligrams of albumin to millimoles of creatinine], plus an increase in the urinary albumin-to-creatinine ratio of ≥30% from baseline, a sustained decrease in eGFR of ≥40% for ≥30 days, renal replacement therapy for ≥90 days, or a sustained eGFR of <15 mL/min/1.73 m2 for ≥30 days).

Between May 11, 2018, and April 25, 2019, 5732 patients underwent screening. Of those, 4076 met eligibility requirements and subsequently underwent randomization: 1359 to receive the 4-mg dose of efpeglenatide, 1358 to receive the 6-mg dose of efpeglenatide, and 1359 to receive placebo. After a median follow-up period of 1.81 years, follow-up ended on December 10, 2020 (total follow-up: 7395.4 person years). As of the end of follow-up, primary outcome status was known for 96.7% (n=3941) of the 4076 participants, and the vital status was known for 99.9% (n=4073) of the participants.

At baseline, mean age of study participants was 64.5 years; 47.9% (n=1954) were <65 years of age; and 33.0% (n=1344) were female. A total of 3650 participants (89.6%) had a  history of cardiovascular disease, 1287  (31.6%) had eGFR <60 mL/min/1.73 m2, 888 (21.8%) had both cardiovascular disease and low eGFR, and 618 (15.2%) were using a sodium-glucose cotransporter 2 (SGLT2) inhibitor. Usage of various glucose-lowering or cardioprotective drugs was similar among the three groups at baseline. At the last trial visit, a greater percentage of participants in the placebo group than in the two efpeglenatide groups (pooled data) were taking a dipeptidyl peptidase 4 inhibitor (1.9% vs 0.9%, P=.005) or an SGLT2 inhibitor (21.2% vs 17.5%, P=.004).

During follow-up, at least one MACE occurred among 7.0% (189/2717) of participants in the efpeglenatide groups and 9.2% (n=125/1359) of those in the placebo group (3.9 vs 5.3 events per 100 person-years; hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.58-0.92; P<.001 for noninferiority at both the 1.8 and 1.3 margins and P=.007 for superiority).

Participants in the efpeglenatide groups also reported a significantly lower incidence of at least one expanded MACE composite event (HR, 0.79; 95% CI, 0.65-0.96; P=.02), a renal composite outcome event (HR, 0.68; 95% CI, 0.57-0.79; P<.001), and a MACE or death from noncardiovascular causes (HR, 0.73; 95% CI, 0.59-0.91; P=.004).

In predefined, clinically relevant subgroups of participants, analysis of the evident effect of efpeglenatide on the primary outcome did not vary with sex, age, race, duration of diabetes, glycated hemoglobin level, body mass index, eGFR, history of cardiovascular disease, use of SGLT2 inhibitors, or use of metformin.

A higher percentage of participants in the efpeglenatide groups reported severe gastrointestinal adverse effects compared with the placebo group (P=.009). The percentage of participants reporting constipation, diarrhea, nausea, vomiting, or bloating was also higher among those in the efpeglenatide groups than in the group receiving placebo. Other prespecified safety outcomes and other adverse effects were similar among the three groups.

Limitations to the study cited by the authors included the short follow-up period, the occurrence of the primary outcome in fewer participants than anticipated, and selection for previous cardiovascular disease and kidney disease, limiting the power of the trial and its generalizability to individuals at lower-risk with type 2 diabetes.

In conclusion, the researchers said, “The results of our trial show that efpeglenatide reduces the risk of serious adverse cardiovascular and renal events among persons with type 2 diabetes and either a history of cardiovascular disease or current kidney disease.”

Takeaway Points

  1. The AMPLITUDE-O trial was designed to assess the effects of efpeglenatide, an exendin-based glucagon-like peptide-1 receptor agonist, in patients with chronic kidney disease associated with type 2 diabetes.
  2. A composite renal outcome (a decrease in kidney function or macroalbuminuria) occurred in 13.0% of participants randomized to receive efpeglenatide compared with 18.4% of participants in the placebo group (hazard ratio, 0.68; 95% confidence interval 0.57-0.79; P<.001).
  3. The risk of cardiovascular events was lower among those in the efpeglenatide groups than in the placebo group (hazard ratio, 0.73; 95% confidence interval, 0.58-092; P<.001).