AMPLITUDE-O
Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes
Year of Publication: 2021
Authors: Gerstein HC, Sattar N, Rosenstock J, ..., for the AMPLITUDE-O Trial Investigators
Journal: New England Journal of Medicine
Citation: N Engl J Med 2021;385:896–907
PDF: Clinical Question
Does weekly efpeglenatide reduce the risk of cardiovascular and renal events in patients with type 2 diabetes and cardiovascular or kidney disease?
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.
Design
Study Type: Randomized, double-blind, placebo-controlled trial
Randomization: 1
Blinding: Double-blind
Enrollment Period: May 2018 – April 2019
Follow-up Duration: Median 1.81 years
Centers: 344
Countries: United States, Canada, Europe, Mexico, South America, Asia
Sample Size: 4076
Analysis: Cox proportional hazards model, intention-to-treat, Kaplan–Meier, mixed-effects model
Inclusion Criteria
- Adults with type 2 diabetes
- HbA1c > 7%
- Established CVD (CAD, PAD, stroke)
- OR kidney disease (eGFR 25–59.9) + one CV risk factor
Exclusion Criteria
- Use of GLP-1 RA or DPP-4 inhibitors within 3 months
- Gastroparesis, severe retinopathy, pancreatitis
- Prolonged vomiting, uncontrolled GERD
Baseline Characteristics
| Characteristic | Comorbidities | Qualifying Event |
|---|---|---|
| Hypertension | 91.3 | |
| Diabetes | 1 | |
| Smoker | 15.5 |
Arms
| Field | Efpeglenatide 4/6 mg | Control |
|---|---|---|
| Intervention | Weekly subcutaneous injection, 2 mg titrated to 4 mg or 6 mg | Matching placebo injection |
| Duration | Median 1.81 years | Median 1.81 years |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| MACE: nonfatal MI, nonfatal stroke, or CV/undetermined death | Primary | 9.2% | 7.0% | 0.73 | 0.007 |
| Expanded MACE (MACE + revascularization or unstable angina) | 95% CI: 0.65–0.96 | Secondary | 11.6% | 9.5% | 0.79 | 0.02 |
| Renal composite (macroalbuminuria, 40% eGFR↓, dialysis) | 95% CI: 0.57–0.79 | Secondary | 18.4% | 13.0% | 0.68 | <0.001 |
| MACE or death from non-CV causes | 95% CI: 0.59–0.91 | Secondary | 10.5% | 7.9% | 0.73 | 0.004 |
| Severe GI symptoms | Adverse | 3.3% vs. 1.8% | |||
| Nausea, vomiting, bloating | Adverse | 1.2% vs. 0.4% | |||
| Discontinuation due to AEs | Adverse | 5.4% vs. 3.6% | |||
| Pancreatitis | Adverse | 0.4% vs. 0.5% | |||
| Hypoglycemia | Adverse | 0.9% vs. 1.0% | |||
| Retinopathy | Adverse | 1.7% vs. 2.0% |
Subgroup Analysis
No heterogeneity of MACE effect by age, sex, eGFR, SGLT2i use, metformin, or geography
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
Funding
Sanofi
Based on: AMPLITUDE-O (New England Journal of Medicine, 2021)
Authors: Gerstein HC, Sattar N, Rosenstock J, ..., for the AMPLITUDE-O Trial Investigators
Citation: N Engl J Med 2021;385:896–907
Content summarized and formatted by NeuroTrials.ai.