Cardiovascular and Renal Outcomes With Efpeglenatide in Type 2 Diabetes - AMPLITUDE-O

Contribution To Literature:

Highlighted text has been updated as of March 27, 2023.

The AMPLITUDE-O trial showed that weekly subcutaneous injection of efpeglenatide was beneficial at reducing the risk of cardiovascular events.


The goal of the trial was to evaluate the exendin-based glucagon-like peptide 1 (GLP-1) receptor agonist efpeglenatide compared with placebo among patients with diabetes and cardiovascular or kidney disease.

Study Design

  • Randomized
  • Parallel
  • Placebo
  • Stratified

Patients with diabetes and either a history of cardiovascular disease or kidney disease, plus one other cardiovascular risk factor, were randomized to a weekly subcutaneous injection of efpeglenatide 4 or 6 mg (n = 2,717) versus placebo (n = 1,359).

  • Total number of enrollees: 4,076
  • Duration of follow-up: 1.8 years
  • Mean patient age: 65 years
  • Percentage female: 33%
  • Percentage with diabetes: 100%

Inclusion criteria:

  • Participants with type 2 diabetes ≥18 years of age
  • Glycated hemoglobin >7%
  • History of cardiovascular disease (coronary artery disease, stroke, or peripheral artery disease) or men >50 years or women >55 years and history of kidney disease (estimated glomerular filtration rate 25.0-59.9 ml/min/1.73 m2) plus one additional cardiovascular risk factor

Exclusion criteria:

  • Uncontrolled gastroparesis, reflux, prolonged nausea or vomiting, severe retinal disease, pancreatitis, or use of a GLP-1 receptor agonist or a dipeptidyl peptidase 4 (DPP-4) inhibitor within the previous 3 months

Other salient features/characteristics:

  • Duration of diabetes: mean 15 years

Principal Findings:

The primary outcome of death, myocardial infarction, or stroke occurred in 7.0% of the efpeglenatide group compared with 9.2% of the placebo group (p = 0.007). Results were similar regardless of sodium–glucose cotransporter 2 (SGLT2) inhibitor use at baseline (p for interaction = 0.68).

Secondary outcome:

  • Decrease in kidney function or macroalbuminuria: 13.0% of the efpeglenatide group compared with 18.4% of the placebo (p < 0.001)

Outcomes according to dose:

  • Major adverse cardiovascular events: efpeglenatide 6 mg vs. placebo (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.50-0.86), efpeglenatide 4 mg vs. placebo (HR 0.82, 95% CI 0.63-1.06)
  • Cardiovascular mortality: efpeglenatide 6 mg vs. placebo (HR 0.55, 95% CI 0.35-0.88), efpeglenatide 4 mg vs. placebo (HR 0.93, 95% CI 0.62-1.38)
  • Kidney function outcome: efpeglenatide 6 mg vs. placebo (HR 0.61, 95% CI 0.42-0.87), efpeglenatide 4 mg vs. placebo (HR 0.97, 95% CI 0.70-1.33)


Among patients with type 2 diabetes and cardiovascular disease or kidney disease and an additional cardiovascular risk factor, efpeglenatide was beneficial. Efpeglenatide compared with placebo was associated with a reduction in major adverse cardiovascular events (death, myocardial infarction, or stroke) and a reduction in composite renal events (decrease in kidney function or macroalbuminuria). Efpeglenatide improved outcomes in a dose-response relationship. Four GLP-1 receptor agonists and now an exendin-based GLP-1 receptor agonist have been shown to improve cardiovascular outcomes in patients with diabetes. The beneficial effect of efpeglenatide appeared to be independent of SGLT2 inhibitor use.


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;147:1004-13.

Lam CS, Ramasundarahettige C, Branch K, et al. Efpeglenatide and Clinical Outcomes with and without Concomitant Sodium-Glucose Co-Transporter-2 Inhibition Use in Type 2 Diabetes: Exploratory Analysis of the AMPLITUDE-O Trial. Circulation 2022;145:565-74.

Presented by Dr. Carolyn S.P. Lam at the American Heart Association Virtual Annual Scientific Sessions (AHA 2021), November 14, 2021.

Gerstein HC, Sattar N, Rosenstock J, et al., on behalf of the AMPLITUDE-O Trial Investigators. Cardiovascular and Renal Outcomes With Efpeglenatide in Type 2 Diabetes. N Engl J Med 2021;385:896-907.

Presented by Dr. Hertzel C. Gerstein at the Virtual 81st Scientific Sessions of the American Diabetes Association (June 25-29, 2021).

Clinical Topics: Diabetes and Cardiometabolic Disease, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD)

Keywords: AHA Annual Scientific Sessions, AHA21, Cardiovascular Diseases, Coronary Artery Disease, Diabetes Mellitus, Type 2, Glomerular Filtration Rate, Injections, Subcutaneous, Kidney Diseases, Renal Insufficiency, Chronic, Metabolic Syndrome, Myocardial Infarction, Peripheral Arterial Disease, Primary Prevention, Risk Factors, Stroke, Vascular Diseases

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