PDF: AMPLITUDE-O
(2021)Objective
Efpeglenatide - To evaluate whether weekly subcutaneous efpeglenatide reduces cardiovascular and renal outcomes in patients with type 2 diabetes and high cardiovascular or renal risk.
Study Summary
• Risk of stroke was reduced by 26%, though not statistically significant.
Intervention
International, randomized, placebo-controlled trial across 344 sites in 28 countries. 4076 patients with type 2 diabetes and established cardiovascular disease or kidney disease plus ≥1 risk factor were randomized to weekly efpeglenatide (4 or 6 mg) or placebo for median 1.8 years.
Inclusion Criteria
Adults ≥18 with T2DM and either: (1) cardiovascular disease (CAD, stroke, PAD), or (2) kidney disease (eGFR 25–59.9) with ≥1 CV risk factor. Excluded if recent GLP-1RA or DPP-4 use.
Study Design
Arms: Efpeglenatide 4 mg or 6 mg weekly vs. Placebo
Patients per Arm: Efpeglenatide: 2717; Placebo: 1359
Outcome
• MACE: HR 0.73 (95% CI: 0.58–0.92), p=0.007 [oai_citation:1‡Efpeglenatide Amplitude O.pdf](file-service://file-Ms3kCzA8wyunPeSpybG8vg)
• Composite renal outcome: HR 0.68 (95% CI: 0.57–0.79), p<0.001
• Expanded MACE: HR 0.79 (95% CI: 0.65–0.96), p=0.02
• MACE or non-CV death: HR 0.73 (95% CI: 0.59–0.91)
• GI side effects (nausea, vomiting, diarrhea) were more common in the efpeglenatide group.
Bottom Line
Efpeglenatide significantly reduced major cardiovascular events and kidney outcomes in patients with type 2 diabetes and high cardiovascular or renal risk, with a tolerable safety profile mainly limited to gastrointestinal side effects.
Major Points
- Efpeglenatide (4 or 6 mg weekly) reduced MACE by 27% vs. placebo (HR 0.73, p=0.007).
- Renal composite outcome was reduced by 32% (HR 0.68, p<0.001).
- Trial included 4076 participants across 28 countries, followed for median 1.81 years.
- Subgroup analysis showed consistent benefit across age, sex, eGFR, and SGLT2 use.
- Adverse effects included higher GI side effects (nausea, constipation, diarrhea).
- Suggests efficacy of long-acting exendin-4–based GLP-1 RA, even with SGLT2 inhibitors.
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 4076
- Follow-up
- Median 1.81 years
- Centers
- 344
- Countries
- United States, Canada, Europe, Mexico, South America, Asia
Primary Outcome
Definition: MACE: nonfatal MI, nonfatal stroke, or CV/undetermined death
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 9.2% | 7.0% | 0.73 (0.58–0.92) | 0.007 |
Limitations & Criticisms
- Short median follow-up (1.81 years)
- Did not reach original target event count (314 vs. 330)
- Limited generalizability to lower-risk populations
- Increased GI adverse events
Citation
N Engl J Med 2021;385:896–907