Highlight
- Cagrilintide and semaglutide coadministration (CagriSema) led to a mean 13.7% reduction in body weight over 68 weeks.
- Significantly more patients achieved clinically meaningful weight loss thresholds (5%, 10%, 15%, and 20%) with CagriSema than placebo.
- Glycemic control improved substantially, with 73.5% of treated subjects achieving HbA1c ≤6.5%.
- The combination was well tolerated; gastrointestinal adverse effects were common but mostly mild/moderate and transient.
Study Background and Disease Burden
Obesity and type 2 diabetes mellitus (T2DM) are intertwined global health epidemics with significant morbidity and mortality. Weight reduction is a cornerstone in managing T2DM to improve glycemic control and reduce cardiovascular risk. However, achieving sustained weight loss remains challenging. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) such as semaglutide have demonstrated substantial benefits in both weight loss and glycemic control. Cagrilintide, an amylin analogue, also promotes weight loss through appetite regulation but has not been widely studied in combination therapy. Prior monotherapy evidence supports their individual efficacy. This study sought to evaluate the long-term efficacy and safety of combined once-weekly cagrilintide and semaglutide (CagriSema) in adults with overweight or obesity and T2DM, an area of unmet clinical need, especially considering the added complexity of glucose control in this population.
Study Design
This was a multicenter, phase 3a, double-blind, randomized, placebo-controlled trial conducted across 12 countries involving 1,206 adults. Eligible participants had a body-mass index (BMI) ≥27, HbA1c between 7.0% and 10.0%, and established type 2 diabetes. Participants were randomized in a 3:1 ratio to receive either once-weekly injections of cagrilintide-semaglutide combination (2.4 mg of each drug) or placebo, alongside standardized lifestyle intervention, for 68 weeks. Primary endpoints were percentage change in body weight from baseline and proportion of patients achieving at least 5% weight loss. Secondary endpoints included proportions achieving ≥10%, ≥15%, and ≥20% weight loss, changes in glycemic parameters (notably HbA1c), and safety outcomes. Effect estimates were analyzed using the treatment-policy estimand, consistent with intention-to-treat analysis.
Key Findings
Among the 1,206 randomized participants, 904 received CagriSema and 302 received placebo. The combination therapy induced a mean body weight reduction of 13.7% (95% CI not specified here) from baseline to week 68, compared to 3.4% with placebo. The between-group difference was a highly significant 10.4 percentage points (95% CI, -11.2 to -9.5; P<0.001).
The proportion of patients achieving clinically meaningful weight loss was substantially higher in the treatment group:
- 5% or greater: significantly more in CagriSema vs. placebo (P<0.001)
- 10%, 15%, and 20% or greater: also significantly higher with the combination (P<0.001 for 20% weight loss)
This gradient underscores a robust dose-dependent effect on weight reduction.
In terms of glycemic control, the proportion of patients reaching an HbA1c ≤6.5% was 73.5% in the CagriSema group compared to 15.9% in the placebo cohort, indicating pronounced diabetes control benefits from the combination therapy.
Safety data revealed that gastrointestinal adverse events were the most common, reported in 72.5% of participants in the active group versus 34.4% with placebo. However, these events were primarily mild or moderate in severity and transient, consistent with known profiles of GLP-1RAs and amylin analogues. No new safety signals emerged over the 68-week treatment period.
A subgroup of participants underwent continuous glucose monitoring (CGM), supporting the glycemic efficacy findings, although detailed CGM outcomes were not explicitly reported here.
Expert Commentary
The REDEFINE 2 trial adds important knowledge about combined incretin-based and amylin analogue therapy for managing obesity and T2DM, confirming additive or synergistic effects on weight loss and glycemic improvement beyond monotherapy. The magnitude of weight reduction (mean 13.7%) surpasses typical results seen with either agent alone, suggesting enhanced efficacy from dual receptor targeting.
Notably, the combination also enables significant improvement in HbA1c levels, with nearly three-quarters of patients achieving recommended targets, which can potentially reduce the need for additional glucose-lowering medications and associated risks.
The safety and tolerability findings align with previous experience of these drug classes, emphasizing the importance of patient education and gradual dose escalation to mitigate gastrointestinal symptoms.
Limitations include the 3:1 randomization ratio offering fewer placebo comparators and the lack of detailed subgroup analyses for CGM and other metabolic parameters, which might elucidate mechanisms further. Also, real-world adherence and long-term maintenance beyond 68 weeks require further study.
From a mechanistic perspective, semaglutide, a GLP-1RA, enhances insulin secretion, reduces glucagon, and slows gastric emptying, while cagrilintide mimics amylin’s effects by promoting satiety and delaying gastric emptying. Their combined action likely amplifies appetite suppression and glycemic regulation, contributing to sustained weight loss and metabolic benefits.
Conclusion
Once-weekly combined cagrilintide and semaglutide therapy (2.4 mg each) significantly reduces body weight and improves glycemic control in adults with overweight or obesity and type 2 diabetes over 68 weeks compared to placebo, with a tolerable safety profile.
This trial supports the therapeutic potential of combination incretin-amylin analogue treatment as an effective strategy for managing the dual challenges of obesity and diabetes, addressing a critical unmet need in clinical practice. Further research is warranted to confirm long-term outcomes, cardiovascular benefits, and applicability across broader patient populations.
References
Davies MJ, Bajaj HS, Broholm C, Eliasen A, Garvey WT, le Roux CW, Lingvay I, Lyndgaard CB, Rosenstock J, Pedersen SD; REDEFINE 2 Study Group. Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes. N Engl J Med. 2025 Aug 14;393(7):648-659. doi: 10.1056/NEJMoa2502082. Epub 2025 Jun 22. PMID: 40544432.
Additional relevant literature:
1. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989–1002.
2. Khera R, Murad MH, Chandar AK, et al. Association of Pharmacological Treatments for Obesity With Weight Loss and Adverse Events: A Systematic Review and Meta-analysis. JAMA. 2016;315(22):2424–2434.
3. American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2024. Diabetes Care. 2024;47(Suppl 1):S125–S138.