CagriSema
Cagrilintide/semaglutide fixed-dose combination
Investigational once-weekly fixed-dose combination of cagrilintide (amylin analog) and semaglutide (GLP-1 agonist) by Novo Nordisk that achieved -20.4% body weight reduction vs -3.0% placebo over 68 weeks in the Phase 3 REDEFINE 1 trial (PMID 40544433, NCT05567796).
Last updated: 2026-03-10
Safety Summary
In REDEFINE 1, gastrointestinal adverse events affected 79.6% of the CagriSema group vs 39.9% of placebo, including nausea, vomiting, diarrhea, constipation, and abdominal pain. Most were transient and mild-to-moderate in severity (PMID 40544433). In REDEFINE 2, GI AEs affected 72.5% of the CagriSema group vs 34.4% of placebo (PMID 40544432). In the Phase 2 trial, AEs were reported by 68% of CagriSema participants, 71% semaglutide, and 80% cagrilintide; no level 2 or 3 hypoglycemia or fatal AEs were reported (PMID 37364590). A meta-analysis of 4 RCTs (N=4419) found GI AEs were more frequent with CagriSema vs controls (RR 1.32) (PMID 41759565). Vomiting was significantly higher with CagriSema vs semaglutide monotherapy in a separate meta-analysis of 3 RCTs (N=430) (PMID 39676787). The cagrilintide component showed no clinically relevant QTcF prolongation at supratherapeutic doses (4.5 mg) in a dedicated cardiac safety study in healthy participants (PMID 39279639).
Known Side Effects
common
common
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uncommon
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rare
Who Should NOT Use This
Expected contraindication based on semaglutide component labeling. GLP-1 receptor agonists caused thyroid C-cell tumors in rodents. No approved CagriSema label exists; this is inferred from semaglutide class labeling.
Expected contraindication based on semaglutide component and GLP-1 RA class labeling. No approved CagriSema label exists.
Excluded from all clinical trials. Expected contraindication consistent with semaglutide labeling.
CagriSema already contains both a GLP-1 RA (semaglutide) and an amylin analog (cagrilintide). Adding additional agents from either class would duplicate mechanisms and increase adverse event risk.
GLP-1 receptor agonist class-associated risk. Inferred from semaglutide component labeling. No CagriSema-specific pancreatitis data in available sources.
Both components slow gastric emptying through distinct mechanisms (PMID 41747885, PMID 39426704). Combined effect on gastric motility could be clinically significant.
Excluded from REIMAGINE 5 trial eligibility criteria (NCT06534411, ctgov-active source). Limited data in this population.
Talk to Your Doctor
Before considering CagriSema, discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-12]
Evidence Assessment
Tier 2: Positive Phase 3 RCT data, not yet FDA-approved. Two pivotal Phase 3 trials published in NEJM (REDEFINE 1, PMID 40544433, N=3417; REDEFINE 2, PMID 40544432, N=1206) demonstrated significant weight loss vs placebo. A Phase 2 active-controlled trial also showed efficacy (PMID 37364590, N=92). A 2026 meta-analysis of 4 RCTs (N=4419) confirmed findings (PMID 41759565). NDA submitted to FDA December 2025; FDA drug and label searches returned no matches as of the source collection date. Head-to-head REDEFINE 4 vs tirzepatide did not meet non-inferiority endpoint.
1Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity.NCT05567796PMID 40544433
Garvey WT et al. - New England Journal of Medicine (2025) - RCT (Phase 3a) -- REDEFINE 1 - N=3417 (CagriSema 2108, semaglutide 302, cagrilintide 302, placebo 705)
Mean percent weight change at 68 weeks: CagriSema -20.4% vs placebo -3.0% (estimated difference -17.3 pp, 95% CI -18.1 to -16.6, P<0.001). CagriSema superior on all weight loss thresholds (>=5%, >=20%, >=25%, >=30%, P<0.001 for all). GI AEs 79.6% vs 39.9% placebo, mainly transient and mild-to-moderate.
Limitations: Industry-funded (Novo Nordisk). 68-week duration; longer-term data pending. Semaglutide and cagrilintide arms were smaller (n=302 each). Open-label for semaglutide/cagrilintide arms.
2Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes.NCT05394519PMID 40544432
Davies MJ et al. - New England Journal of Medicine (2025) - RCT (Phase 3a) -- REDEFINE 2 - N=1206 (CagriSema 904, placebo 302)
Mean weight change at 68 weeks: CagriSema -13.7% vs placebo -3.4% (estimated difference -10.4 pp, 95% CI -11.2 to -9.5, P<0.001). HbA1c <=6.5%: 73.5% CagriSema vs 15.9% placebo. GI AEs: 72.5% vs 34.4%. Weight reduction >=10%, >=15%, >=20% all significantly more likely with CagriSema (P<0.001).
Limitations: Industry-funded (Novo Nordisk). No active comparator arm. 68-week duration. Conducted in 12 countries.
3Efficacy and safety of co-administered once-weekly cagrilintide 2.4 mg with once-weekly semaglutide 2.4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial.NCT04982575PMID 37364590
Frias JP et al. - Lancet (2023) - RCT (Phase 2) - N=92 (CagriSema 31, semaglutide 31, cagrilintide 30)
HbA1c change at 32 weeks: CagriSema -2.2 pp vs semaglutide -1.8 pp vs cagrilintide -0.9 pp. CagriSema vs cagrilintide P<0.0001; vs semaglutide P=0.075 (not significant). Weight loss: CagriSema -15.6% vs semaglutide -5.1% vs cagrilintide -8.1% (P<0.0001 for both comparisons). FPG: CagriSema -3.3 mmol/L. CGM time-in-range: 88.9% at week 32 (baseline 45.9%). No level 2/3 hypoglycemia.
Limitations: Small sample size (N=92). Short duration (32 weeks). Single country (US). Industry-funded (Novo Nordisk).
4CagriSema Reduces Blood Pressure in Adults With Overweight or Obesity: REDEFINE 1.NCT05567796PMID 41328546
Verma S et al. - Hypertension (2026) - Secondary/post-hoc analysis of Phase 3a RCT - N=3417 (from REDEFINE 1); resistant hypertension subgroup n=167
SBP change: CagriSema -10.9 mmHg vs placebo -2.8 mmHg. DBP: -5.4 vs -1.7 mmHg. BP targets reached: 63.0% CagriSema vs 32.0% placebo. Resistant hypertension subgroup: 42.0% vs 29.3% reached BP targets (OR 1.7, 95% CI 0.7-4.4). 39.6% of CagriSema patients on antihypertensives decreased/stopped treatment vs 18.8% placebo.
Limitations: Secondary/post-hoc analysis, not powered for BP outcomes. Short duration (68 weeks). Authors include Novo Nordisk employees. Multiple subgroup analyses.
5CagriSema drives weight loss in rats by reducing energy intake and preserving energy expenditure.PMID 40629149
Jacobsen JM et al. - Nature Metabolism (2025) - Animal study (preclinical) - Rat study (diet-induced obesity model)
CagriSema achieved 12% weight loss with 39% food intake reduction. Pair-feeding caused less weight loss, while weight-matching required 51% food intake reduction. Approximately one-third of CagriSema weight loss efficacy arises from blunting metabolic adaptation (preserving energy expenditure).
Limitations: Animal (rat) study; direct translation to humans uncertain. All authors are Novo Nordisk employees or collaborators.
6CagriSema Versus Semaglutide Monotherapy or Placebo for Obesity: A Systematic Review and Meta-Analysis of Randomized Controlled Trials with GRADE Assessment.PMID 41759565
Gadelmawla AF et al. - American Journal of Cardiology (2026) - Systematic review and meta-analysis - 4 RCTs, N=4419 (CagriSema 3055, control 1364)
CagriSema significantly reduced percent weight loss (Cohen's d -1.38, 95% CI -1.84 to -0.91, I2=94.8%). Greater absolute weight loss (MD -11 kg), waist circumference (MD -9.41 cm), SBP (MD -7.06 mmHg). GI AEs more frequent (RR 1.32).
Limitations: High heterogeneity (I2=94.8%). Limited to 4 RCTs. Includes both obesity and T2D populations. Underlying studies largely manufacturer-sponsored.
7Efficacy and Safety of Cagrilintide Alone and in Combination with Semaglutide (Cagrisema) as Anti-Obesity Medications: A Systematic Review and Meta-Analysis.PMID 39676787
Dutta D et al. - Indian Journal of Endocrinology and Metabolism (2024) - Systematic review and meta-analysis - 3 RCTs, N=430
At 20-32 weeks, CagriSema achieved significantly greater weight loss vs semaglutide 2.4 mg: percentage weight (MD -9.07%, 95% CI -11.91 to -6.23, P<0.00001) and absolute weight (MD -9.11 kg, P<0.00001). GI AEs and vomiting higher with CagriSema vs semaglutide. Cagrilintide alone had comparable weight loss to semaglutide/liraglutide with lower vomiting rates.
Limitations: Based on early-phase data (pre-REDEFINE 1/2). Small total sample (N=430). High heterogeneity (I2=96-98%).
8Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis.PMID 38286487
Yao H et al. - BMJ (2024) - Systematic review and network meta-analysis - 76 RCTs, N=39246 (across 15 GLP-1RAs)
CagriSema resulted in the highest weight loss of all 15 GLP-1RAs in T2D (MD -14.03 kg, 95% CI -17.05 to -11.00 vs placebo; high confidence). Tirzepatide was most effective for HbA1c (MD -2.10%) and FPG (MD -3.12 mmol/L).
Limitations: CagriSema data from single Phase 2 trial at time of analysis. Network meta-analysis with indirect comparisons. GI safety concerns noted.
9Cagrilintide is not associated with clinically relevant QTc prolongation: A thorough QT study in healthy participants.NCT05804162PMID 39279639
Gabe MBN et al. - Diabetes, Obesity and Metabolism (2024) - Thorough QT study (Phase 1 cardiac safety) - N=105 (cagrilintide 53, placebo 52)
Cagrilintide 4.5 mg (supratherapeutic dose) did not cause clinically relevant QTcF prolongation. Upper limits of 90% CIs were below 10 ms at all time points. QT assay sensitivity confirmed with moxifloxacin positive control.
Limitations: Healthy participants only. Assessed cagrilintide alone, not in combination with semaglutide.
10Synthetic target trial emulation and predictive modeling of amylin-pathway therapies for obesity and type 2 diabetes.PMID 41255585
Al-Harbi FA et al. - Metabolism Open (2025) - Computational modeling / target trial emulation - 7 RCTs, N=5786 (synthetic IPD reconstruction)
CagriSema superiority over amycretin SC confirmed (posterior probability >0.95). Longitudinal kinetics showed weight loss plateau at 52-68 weeks for obesity, 24-32 weeks for glycemic endpoints. Machine learning predicted treatment response with 82-87% accuracy.
Limitations: Synthetic (reconstructed) individual patient data, not original patient-level data. Computational modeling study. Model calibration slope 0.61 for efficacy.
11Long-acting amylin-related peptides as therapies for obesity and type 2 diabetes.PMID 41747885
Bailey CJ et al. - Peptides (2026) - Review - N/A (narrative review)
Comprehensive review of amylin-based therapies. Describes cagrilintide as a dual AMYR/CTR agonist co-formulated with semaglutide. Notes CagriSema achieves greater effects than either component alone. Reviews heterodimeric structure of amylin-calcitonin receptor complexes. Discusses GI side effects and potential benefits for fatty liver disease, kidney complications, and resistant hypertension.
Limitations: Narrative review, not systematic. Authors declare no conflict, but reviews Novo Nordisk products.
12Amylin and the renin-angiotensin system: risk or opportunity in amylin-based therapy?PMID 41207308
Muskiet MHA et al. - Lancet (2026) - Hypothesis / commentary - N/A
Hypothesizes that amylin receptor agonists can activate the renin-angiotensin system (RAS), potentially undermining cardiorenal benefits. Notes that CagriSema showed substantial BP reductions in Phase 3. Suggests concurrent RAS inhibitors may redirect amylin-induced RAS activation toward protective alternative pathway (Mas receptors).
Limitations: Hypothesis paper, not primary data. Multiple authors have industry conflicts.