CagriSema Cardiovascular Outcomes Trial Enrolls 7,076 High-Risk Adults
REDEFINE 3 tests whether CagriSema — combining amylin and GLP-1 agonism — reduces heart attacks, strokes, and death in overweight patients with established CVD.
Summary
REDEFINE 3 is a large, double-blind, randomized cardiovascular outcomes trial evaluating CagriSema — a once-weekly subcutaneous combination of cagrilintide (amylin receptor agonist) and semaglutide (GLP-1 receptor agonist) — in adults with established cardiovascular disease and excess body weight. Between January 2023 and December 2024, 7,076 participants across 575 sites in 24 countries were enrolled. The average age was 66 years, 76% had a BMI of 30 or above, and 61% had type 2 diabetes averaging 12 years' duration. The primary safety objective is to confirm cardiovascular non-inferiority versus placebo on three-point MACE; the efficacy objective is to confirm superiority on four-point MACE including revascularization. Results from REDEFINE 3 will determine whether CagriSema's potent weight-loss and glycemic benefits translate into reduced cardiovascular events in a broad, high-risk population.
Detailed Summary
Heart disease remains the leading cause of premature death in adults with obesity and type 2 diabetes, and the field urgently needs therapies that go beyond glucose control to directly reduce cardiovascular risk. CagriSema — a fixed-dose, once-weekly subcutaneous injection pairing the amylin receptor agonist cagrilintide with the GLP-1 receptor agonist semaglutide — has already demonstrated superior weight reduction and improved glycemic control compared with either agent alone in earlier trials. REDEFINE 3 was designed to determine whether those metabolic gains translate into reduced rates of fatal and non-fatal cardiovascular events.
The trial is a double-blind, randomized, placebo-controlled study enrolling adults with established cardiovascular disease (CVD) and a BMI of 25 kg/m² or above, with or without type 2 diabetes. Participants receive CagriSema 2.4 mg/2.4 mg or matched placebo added to standard-of-care therapy. The safety objective requires demonstrating non-inferiority on three-point MACE (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke); the efficacy objective requires demonstrating superiority on four-point MACE, which adds revascularization to the primary composite.
Between January 2023 and December 2024, 7,076 adults were enrolled at 575 sites across 24 countries. The mean age was 66 years. Three-quarters of participants had a BMI of 30 or above, and 61% had type 2 diabetes with a mean duration of 12 years and mean HbA1c of 7.7%. The most common qualifying CVD event was prior myocardial infarction, present in 62% of participants; prior stroke was recorded in 19% and peripheral arterial disease in 11%.
REDEFINE 3 is the first cardiovascular outcomes trial of a dual amylin–GLP-1 combination therapy and could reshape cardiometabolic treatment guidelines if superiority is demonstrated. Success would position CagriSema alongside semaglutide monotherapy (SELECT trial) as a cardioprotective obesity treatment, potentially offering even greater benefit through deeper weight loss.
Key caveats include substantial Novo Nordisk involvement in trial design and authorship, and the current report is limited to baseline characteristics — outcome data are pending. The summary here is based on the published abstract only.
Key Findings
- 7,076 adults with established CVD and excess weight randomized to CagriSema or placebo across 575 sites in 24 countries.
- 61% of enrollees have type 2 diabetes with a mean 12-year duration and mean HbA1c of 7.7%.
- 76% of participants have a BMI ≥30 kg/m², and 62% have a prior myocardial infarction — a high-risk cohort.
- Trial tests both cardiovascular non-inferiority (3-point MACE) and superiority (4-point MACE including revascularization).
- First outcomes trial of a combined amylin + GLP-1 receptor agonist — could extend cardiometabolic protection beyond semaglutide alone.
Methodology
REDEFINE 3 is a double-blind, randomized, placebo-controlled cardiovascular outcomes trial with dual objectives: non-inferiority on 3-point MACE (safety) and superiority on 4-point MACE (efficacy). Enrollment ran from January 2023 to December 2024 across 575 international sites. This publication reports only trial design and baseline characteristics; primary outcome data have not yet been released.
Study Limitations
This publication covers only trial design and baseline characteristics — no efficacy or safety outcome data are yet available, limiting clinical conclusions. Several authors are Novo Nordisk employees or equity holders, representing a significant industry conflict of interest. The summary is based on the abstract only, as the full text is not open access.
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