Efpeglenatide Demonstrates Cardioprotective Dose-Response Relationship

Efpeglenatide demonstrates a dose response protective effect against cardiovascular events when added to diabetic treatment regimens.

Efpeglenatide demonstrates a dose-response effect, in which higher dosing more efficaciously limits major adverse cardiovascular event (MACE) risk in individuals with type 2 diabetes, according to research published in Circulation.

Researchers randomly assigned participants with type 2 diabetes (n=4076; mean age, 64.5 years; 33% women) to weekly subcutaneous efpeglenatide injections (4 or 6mg) or placebo treatment, administered in conjunction with their current diabetes treatment regimens, in a 1:1:1 ratio and compared MACE (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or unknown causes) occurrence among the 3 cohorts during a 1.8 year study duration. The team also assessed secondary outcomes including coronary revascularization, hospitalization for unstable angina, and a kidney composite outcome comprising sustained new macroalbuminuria.

Efpeglenatide demonstrated the ability to reduce MACE risk, according to the report. A total of 125 (9.2%) individuals undergoing placebo treatment experienced a MACE compared with 105 (7.7%) treated with 4 mg efpeglenatide (hazard ratio [HR], 0.82; 95% CI, 0.63-1.06; P =0.14) and 84 (6.2%) who were assigned to 6 mg efpeglenatide treatment (HR, 0.65; 95% CI, 0.50-0.86; P =0.0027).

Efpeglenatide demonstrated an ability to reduce secondary outcomes as well, revealing  statistically significant reductions with 6 mg efpeglenatide treatment for kidney composite outcome (HR, 0.63; 95% CI, 0.52-0.77; P <0.0001), myocardial infarction (HR 0.64; 95% CI, 0.43-0.96), total mortality (HR, 0.66; 95% CI, 0.45-0.95), and incident macroalbuminuria (HR, 0.65; 95% CI, 0.53-0.79) compared with placebo treatment.

These findings, and the related evidence reviewed here, collectively and strongly support the use of highdose efpeglenatide to reduce cardiovascular outcomes in high-risk people.

Similarly, treatment with 4 mg efpeglenatide demonstrated an ability to reduce secondary outcome risk compared with placebo (HR, 0.73, 0.89, 0.93, and 0.72 for kidney composite outcome, myocardial infarction, total mortality, and incident macroalbuminuria, respectively). Treatment with the higher efpeglenatide dose significantly improved kidney function outcome and cardiovascular mortality compared with the lower-dose treatment (P =.012 and P =.027, respectively), the report shows.

Both 6 and 4 mg efpeglenatide doses reduced baseline hemoglobin A1c levels (-1.31% and -1.18%, respectively), weight (-2.73 and -2.46 kg, respectively) low density lipoprotein cholesterol (-0.09 and -0.06 mmol/L, respectively) and urine albumin:creatinine ratio compared with placebo.

“These findings, and the related evidence reviewed here, collectively and strongly support the use of highdose efpeglenatide to reduce cardiovascular outcomes in high-risk people,” according to the researchers. “They also strongly suggest that higher [glucagon-like peptide-1 receptor agonist] doses and more potent molecules are likely to confer even greater cardiovascular and renal benefits than those seen to date.”

Study limitations include a short duration and an overrepresentation of individuals of White ethnicity in the study sample.


Gerstein HC, Li Z, Ramasundarahettige C, et al. Exploring the relationship between efpeglenatide dose and cardiovascular outcomes in type 2 diabetes: insights from the AMPLITUDE-O trial. Circulation. 2023;147(13):1004-1013. doi:10.1161/CIRCULATIONAHA.122.063716.