CagriSema (cagrilintide + semaglutide) – REDEFINE 1 and REDEFINE 2 Trials: 6 deaths, all in active arms; BBIU warns of the need for intensive post-marketing surveillance
Publication date: August 14, 2025 (online June 22) – NEJM
Context: Presented simultaneously at ADA 2025.
1. Truthfulness of Information
Both articles present results from phase 3a trials, randomized, double-blind, placebo-controlled, with detailed methodological descriptions and prespecified primary and secondary outcome measures.
The figures for weight loss, HbA1c reduction, and adverse event rates are presented with point estimates, confidence intervals, and p values.
Verdict: High integrity – Consistent and measurable data, with no claims beyond the scope of the results.
2. Source Referencing
Primary source: The New England Journal of Medicine, verified DOI.
Additional data from ADA 2025 presentations and Novo Nordisk press releases.
Information cross-checked with ACC.org, Applied Clinical Trials, PubMed, and PRNewswire.
Verdict: High integrity – Primary and secondary references are concordant.
3. Reliability & Accuracy
Key metrics (mean weight loss, proportions of patients reaching given targets, HbA1c changes, adverse event rates) are reproducible and aligned with data reported in prior scientific presentations.
No indications of statistical manipulation nor omission of relevant data in the main results.
Verdict: High integrity – Precision and consistency maintained.
4. Contextual Judgment
REDEFINE 1: Patients without diabetes → mean weight loss –20.4%.
REDEFINE 2: Patients with type 2 diabetes → mean weight loss –13.7% plus substantial glycemic improvement.
Within the BBIU framework, this represents a clinically significant leap in efficacy compared to current therapies, but with a tolerability profile dominated by GI events (~70–80%).
Strategic implications: potential disruption of the anti-obesity market, competitive pressure on existing GLP-1s, and possible therapeutic repositioning for combined management of obesity and diabetes.
Verdict: High contextual integrity – Analysis connected to sector trends and competitive pipeline.
5. Inference Traceability
Inferences regarding clinical impact and commercial potential are supported by hard trial data, with no speculative extrapolations beyond the studied populations.
Risks (GI tolerability, long-term adherence) are implicitly acknowledged in discontinuation rates and the nature of reported adverse events.
Verdict: High integrity – Inferences anchored in traceable data.
BBIU Opinion
REDEFINE 2 — NCT05394519
Title: A Research Study to See How Well CagriSema Helps People With Type 2 Diabetes and Excess Body Weight Lose Weight
Status: Completed
Conditions: Overweight, Obesity, Type 2 Diabetes Mellitus
Interventions:
Cagrilintide
Semaglutide
Placebo cagrilintide
Placebo semaglutide
Study design:
Allocation: Randomized
Model: Parallel
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Primary endpoints:
Relative (%) change in body weight from baseline (week 0) to end of treatment (week 68).
Proportion of participants achieving ≥5% weight reduction from baseline to week 68.
Safety (NEJM – key metrics):
“Any AE”: 90.2% (CagriSema) vs 85.4% (placebo).
GI AEs: 72.5% vs 34.4% (mostly mild–moderate).
Discontinuation due to AE: 8.4% vs 3.0% (GI → 4.8% vs 0.7%).
SAE: 10.4% (CagriSema) vs 12.9% (placebo).
Deaths: 4 in CagriSema (various causes; adjudicated as not related).
REDEFINE 1 — NCT05567796
Title: A Research Study to See How Well CagriSema Helps People With Excess Body Weight Lose Weight
Status: Active, not recruiting
Conditions: Obesity
Interventions:
Cagrilintide
Semaglutide
Placebo cagrilintide
Placebo semaglutide
Study design:
Allocation: Randomized
Model: Parallel
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Primary endpoints:
Relative (%) change in body weight from baseline (week 0) to end of treatment (week 68).
Proportion of participants achieving ≥5% weight reduction from baseline to week 68.
Safety (NEJM – key metrics):
“Any AE”: 92.3% (CagriSema) vs 82.3% (placebo).
GI AEs: 79.6% vs 39.9%.
Discontinuation due to AE: 5.9% vs 3.5% (GI → 3.6% vs 0.6%).
SAE: 9.8% (CagriSema) vs 6.1% (placebo).
Deaths: 2 in CagriSema (suicide and cancer; adjudicated by independent committee).
Note on sample sizes
REDEFINE 1 (NCT05567796):
ITT population (NEJM abstract): 3,417 randomized subjects.
Safety population (AE tables): 3,415 subjects (two randomized did not receive treatment, excluded from safety analysis).
REDEFINE 2 (NCT05394519):
ITT population: 2,916 subjects (matches safety population).
Combined total:
ITT: 6,333
Safety: 6,331
Risk of blindness and population scaling
In the two REDEFINE trials, no cases of blindness or NAION were reported.
Using incidence observed in cohorts (0.04% in GLP-1 users), in a sample of 6,331 we would expect ~2.5 theoretical cases.
The absence of signal in Phase 3 is compatible with a rare event incidence <0.05%.
When scaled to mass market:
10 million users × 0.04% = ~4,000 potential NAION cases/year.
Even very low risks in phase 3 become clinically relevant in post-marketing pharmacovigilance.
⚠️ BBIU Warning:
Although the six deaths reported in the REDEFINE trials were adjudicated as not related to treatment, the fact that all occurred in active arms justifies intensive post-marketing surveillance to rule out emerging risk patterns in real-world practice.
Mortality references in the REDEFINE trials
REDEFINE 1 – Adults with overweight or obesity without diabetes
Reference: Garvey T, Blüher M, Contreras C, et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2025; DOI: 10.1056/NEJMoa2502081
Mortality report: 2 deaths in the CagriSema arm, adjudicated as not related to the drug (suicide and cancer of unknown primary). Determination made by independent committee.
REDEFINE 2 – Adults with overweight or obesity and type 2 diabetes
Reference: Davies M, Bajaj H, Broholm C, et al. Cagrilintide–Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes. N Engl J Med. 2025; DOI: 10.1056/NEJMoa2502082
Mortality report: 4 deaths in the CagriSema arm, adjudicated as not related to treatment, attributable to underlying causes.
