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AMPLITUDE-O

Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes

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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

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2108269

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2108269

Clinical Question

Does weekly efpeglenatide reduce the risk of cardiovascular and renal events in patients with type 2 diabetes and cardiovascular or kidney disease?

Study Overview

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

Efpeglenatide significantly reduced major cardiovascular events and renal complications.
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 (HbA1c >7%) 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.

Patients per Arm

Efpeglenatide: 2717; Placebo: 1359

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 344 sites in 28 countries, followed for median 1.81 years.
Subgroup analysis showed consistent MACE benefit across sex, age, eGFR, and SGLT2i use, but point estimates across the four geographic regions showed wide variation with overlapping CIs suggesting possible heterogeneity by geography.
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: 344 sites across 28 countries; regions per Table 1: Canada and United States, Mexico and Central and South America, Europe, Other

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%
Age ≥18 with established CVD (CAD, PAD, stroke)
OR age ≥50 (male) or ≥55 (female) with kidney disease (eGFR 25.0–59.9 mL/min/1.73 m²) plus ≥1 additional CV risk factor

Exclusion Criteria

Use of GLP-1 RA or DPP-4 inhibitors within the previous 3 months
Gastroparesis, severe retinal disease, pancreatitis
Uncontrolled reflux, prolonged nausea or vomiting

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 composite (MACE, coronary revascularization, or hospitalization for unstable angina)	Secondary	11.6%	9.5%	0.79	0.02
Composite renal outcome (incident macroalbuminuria [UACR >300 mg/g or >33.9 mg/mmol] plus UACR increase ≥30% from baseline, sustained eGFR decrease ≥40% for ≥30 days, renal-replacement therapy ≥90 days, or sustained eGFR <15 mL/min/1.73 m² for ≥30 days)	Secondary	18.4%	13.0%	0.68	<0.001
MACE or death from noncardiovascular causes	Secondary	10.5%	7.9%	0.73	0.004
Kidney-function outcome (sustained eGFR decrease ≥40% for ≥30 days, ESKD [dialysis ≥90 days, kidney transplant, or sustained eGFR <15 for ≥30 days], or death from any cause)	Secondary	5.6% (76/1359)	4.5% (121/2717)	0.77	0.07
MACE, death from noncardiovascular causes, hospitalization for heart failure, or kidney-function outcome event	Secondary	12.1% (164/1359)	8.9% (243/2717)	0.71	NR (hierarchical testing stopped at prior outcome)
Discontinuation due to AEs	Adverse	49 (3.6%)	147 (5.4%)		0.02
Severe GI event	Adverse	25 (1.8%)	90 (3.3%)		0.009
Constipation, diarrhea, nausea, vomiting, or bloating	Adverse	6 (0.4%)	32 (1.2%)		0.03
Confirmed pancreatic event	Adverse	15 (1.1%)	32 (1.2%)		0.87
Severe hypoglycemia	Adverse	13 (1.0%)	24 (0.9%)		0.67
Diabetic retinopathy and related complications	Adverse	27 (2.0%)	47 (1.7%)		0.50
Acute kidney failure	Adverse	39 (2.9%)	88 (3.2%)		0.62
Any cancer	Adverse	37 (2.7%)	72 (2.6%)		0.81

Subgroup Analysis

Consistent MACE effect across sex, age, race, duration of diabetes, HbA1c, BMI, eGFR, prior CVD, SGLT2 inhibitor use, and metformin use. Point estimates of effect across the four geographic regions (Canada/US; Mexico and Central/South America; Europe; Other) showed wide variation with overlapping confidence intervals, which may indicate heterogeneity of effect by 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
Possible heterogeneity of MACE effect by geographic region

Funding

Sanofi

Based on: AMPLITUDE-O (New England Journal of Medicine, 2021)