CagriSema
Also known as: Cagrilintide-semaglutide, CagriSema 2.4 mg/2.4 mg, Cagrilintide plus semaglutide, Amylin-GLP-1 combination
CagriSema is an investigational fixed-dose combination of cagrilintide, a long-acting amylin analog, and semaglutide, a GLP-1 receptor agonist, co-administered once weekly and studied in Phase 3 trials for obesity and type 2 diabetes.
Key Findings at a Glance
- • CagriSema is a two-peptide combination product, not a single molecule: the amylin analog cagrilintide plus the GLP-1 agonist semaglutide, each dosed at 2.4 mg once weekly.
- • In the Phase 3 REDEFINE 1 trial of 3,417 adults with overweight or obesity, CagriSema produced 20.4 percent mean weight loss at 68 weeks versus 3.0 percent with placebo.
- • In REDEFINE 2 (1,206 participants with type 2 diabetes), CagriSema produced 13.7 percent weight loss and brought 73.5 percent of participants to an HbA1c of 6.5 percent or below, versus 15.9 percent on placebo.
- • Gastrointestinal adverse events are the dominant side effect, affecting roughly 72 to 80 percent of participants across Phase 3 trials, and were mainly transient and mild-to-moderate.
CagriSema Overview & Molecular Profile
CagriSema is Novo Nordisk's investigational combination of two established peptides: cagrilintide 2.4 mg, an acylated long-acting amylin analog, and semaglutide 2.4 mg, the GLP-1 receptor agonist marketed as Wegovy and Ozempic. It is a two-molecule combination product, not a single compound, and is co-administered as once-weekly subcutaneous injections. The pairing targets two complementary appetite-regulation pathways at once: amylin receptors in the brainstem that dampen reward-driven eating, and GLP-1 receptors that govern homeostatic energy balance. In the Phase 3 REDEFINE 1 trial it produced 20.4% mean weight loss at 68 weeks in adults with overweight or obesity, and in REDEFINE 2 it produced 13.7% weight loss in participants who also had type 2 diabetes. CagriSema is not approved by any regulator as of 2026.
Mechanism of Action: Receptor Agonism & Metabolic Pathways
CagriSema combines two long-acting peptides with distinct receptor pharmacology. Cagrilintide activates amylin receptors, heterodimeric complexes of the calcitonin receptor with RAMP proteins, concentrated in the area postrema and nucleus tractus solitarius; this reduces meal size, slows gastric emptying, suppresses postprandial glucagon, and blunts hedonic, reward-driven food intake. Semaglutide activates GLP-1 receptors in the pancreas and hypothalamus, enhancing glucose-dependent insulin secretion, suppressing glucagon, delaying gastric emptying, and reducing homeostatic hunger. Both peptides carry fatty-acid side chains that bind circulating albumin, extending their half-lives to roughly one week and enabling once-weekly co-administration. Because the two pathways converge on appetite through separate neural circuits, the combination produces greater weight loss than either agent achieves alone, as demonstrated in both Phase 2 and Phase 3 trials.
CagriSema Pharmacokinetics: Two Albumin-Binding Peptides on One Weekly Clock
CagriSema's once-weekly schedule is an engineered coincidence: both components were independently designed to circulate for about a week through fatty-acid-mediated albumin binding, so the amylin analog and the GLP-1 analog can be co-administered on the same interval without either peptide outrunning the other. Phase 1b co-administration data confirm the two peptides neither interact nor diverge in exposure.
Engineering Two Week-Long Half-Lives
Each component solved a different short-half-life problem with the same chemical strategy: lipidation for albumin binding.
- • The Amylin Problem: Native amylin aggregates into amyloid fibrils, and the first-generation analog pramlintide requires three daily injections because of its short half-life; cagrilintide was developed as a stable, lipidated, long-acting amylin analogue specifically to escape both constraints (PMID 34288673).
- • The Semaglutide Solution: Semaglutide was selected from a design program aimed at once-weekly dosing through increased albumin affinity and full metabolic stability — two amino acid substitutions (Aib8, Arg34) plus fatty-acid derivatization at Lys26 — and showed a plasma half-life of 46.1 hours after intravenous dosing and a mean residence time of 63.6 hours after subcutaneous dosing in mini-pigs (PMID 26308095).
- • Measured Human Half-Lives: In the Phase 1b co-administration trial, cagrilintide showed a half-life of 159-195 hours with a median tmax of 24-72 hours, and semaglutide 2.4 mg a half-life of 145-165 hours with a median tmax of 12-24 hours — both squarely in the once-weekly range (PMID 33894838).
No Pharmacokinetic Interaction in Combination
The combination's clinical viability required proof that two albumin-binding peptides would not displace or distort each other.
- • Dose-Proportional Cagrilintide Exposure: Across the 0.16-4.5 mg weekly cagrilintide range on a fixed semaglutide 2.4 mg background, exposure was proportional to dose, with AUC0-168h of 926-24,271 nmol·h/L and Cmax of 6.14-170 nmol/L (PMID 33894838).
- • Semaglutide Exposure Unchanged: Co-administered cagrilintide did not affect semaglutide exposure or elimination; semaglutide AUC0-168h stayed in a tight 12,757-15,305 nmol·h/L band with Cmax of 96.4-120 nmol/L across all cohorts (PMID 33894838).
- • Matched Disposition: Plasma clearance and volume of distribution for both peptides were similar across treatment groups, and the 4-week co-escalation intervals used in the program align each dose step with the roughly 4-5 weeks these ~7-day half-lives need to approach steady state (PMID 33894838).
From Exposure to Phase 3 Effect
The co-administration pharmacokinetics translated into an orderly exposure-response relationship that carried into the pivotal program.
- • Early Exposure-Response Signal: At week 20 of the Phase 1b trial, cagrilintide 1.2 and 2.4 mg added to semaglutide 2.4 mg produced mean bodyweight reductions of 15.7% and 17.1% versus 9.8% for pooled placebo cohorts — dose-ordered incremental effect on a constant semaglutide exposure (PMID 33894838).
- • Component-Level Confirmation: Once-weekly cagrilintide alone produced dose-dependent weight loss of 6.0-10.8% across 0.3-4.5 mg at 26 weeks versus 3.0% with placebo, with the 4.5 mg dose exceeding daily liraglutide 3.0 mg — the standalone exposure-effect relationship that justified carrying 2.4 mg into the combination (PMID 34798060).
- • Phase 3 Translation: REDEFINE 1 carried the 2.4 mg/2.4 mg once-weekly regimen into 3,417 participants and recorded -20.4% mean weight change at 68 weeks versus -3.0% with placebo, with active-control arms of each component alone confirming the combination's additive pharmacology (PMID 40544433).
Research-Observed Effects
Phase 3 Weight Loss in Obesity (REDEFINE 1)
Extensive ResearchIn REDEFINE 1, a 68-week, double-blind Phase 3a trial in 3,417 adults with overweight or obesity without diabetes, once-weekly cagrilintide 2.4 mg plus semaglutide 2.4 mg produced an estimated mean body-weight change of -20.4% versus -3.0% with placebo (estimated difference -17.3 percentage points; 95% CI -18.1 to -16.6; P<0.001). Participants on the combination were significantly more likely than those on placebo to reach weight-loss thresholds of 5%, 20%, 25%, and 30% (P<0.001 for all comparisons). The trial also randomized participants to semaglutide alone and cagrilintide alone as active-control arms. Gastrointestinal adverse events affected 79.6% of combination participants versus 39.9% on placebo and were mainly transient and mild-to-moderate in severity.
Weight and Glucose Control in Type 2 Diabetes (REDEFINE 2)
Extensive ResearchIn REDEFINE 2, a 68-week Phase 3a trial across 12 countries, 1,206 adults with a BMI of 27 or more, type 2 diabetes, and HbA1c of 7-10% were randomized 3:1 to the combination or placebo. Mean body-weight change was -13.7% with CagriSema versus -3.4% with placebo (estimated difference -10.4 percentage points; 95% CI -11.2 to -9.5; P<0.001), and significantly more participants achieved weight reductions of at least 5%, 10%, 15%, and 20%. An HbA1c of 6.5% or below was reached by 73.5% of CagriSema participants versus 15.9% on placebo, demonstrating dual efficacy on weight and glycemia in the more metabolically complex diabetes population. Gastrointestinal adverse events occurred in 72.5% versus 34.4% and were mostly transient and mild or moderate.
Superiority Over Component Agents
Extensive ResearchA 32-week Phase 2 trial in 92 adults with type 2 diabetes directly compared CagriSema against each component alone. Weight change was -15.6% with the combination versus -5.1% with semaglutide alone and -8.1% with cagrilintide alone (P<0.0001 against both). HbA1c fell by 2.2 percentage points with the combination versus 1.8 with semaglutide and 0.9 with cagrilintide, statistically superior to cagrilintide (P<0.0001) but not significantly different from semaglutide (P=0.075), an honest limitation of the small sample size. Continuous glucose monitoring showed time in range of 88.9% with the combination versus 76.2% and 71.7% with the single agents, and no level 2 or 3 hypoglycemia occurred in any group.
Complementary Dual-Pathway Appetite Suppression
Moderate ResearchThe mechanistic rationale for CagriSema is that amylin and GLP-1 suppress appetite through separate neural circuits. Amylin receptor activation in the area postrema and lateral parabrachial nucleus reduces the rewarding value of food and promotes earlier satiation, while GLP-1 receptor activation in hypothalamic centers regulates energy homeostasis. Phase 2 cagrilintide monotherapy data established that amylin agonism alone produces meaningful weight loss (6.0-10.8% across 0.3-4.5 mg doses at 26 weeks versus 3.0% with placebo, with the 4.5 mg dose exceeding liraglutide 3.0 mg), confirming that the combination's efficacy reflects two active mechanisms rather than one peptide carrying the other.
Tolerability Profile
Moderate ResearchAcross the REDEFINE program, gastrointestinal adverse events were the dominant tolerability issue, affecting 79.6% of participants in REDEFINE 1 and 72.5% in REDEFINE 2, versus roughly a third of placebo participants; events were predominantly transient and mild-to-moderate. In the Phase 2 diabetes trial, adverse event rates were similar across all three treatment arms (68-80%), gastrointestinal events were mostly mild or moderate, and no level 2 or 3 hypoglycemic events and no fatal adverse events were reported. These data characterize a side-effect burden consistent with the GLP-1 and amylin agonist classes rather than a new safety signal from the combination.
Research Protocol Doses Reported in Published Literature
Research Disclaimer: Doses reported below are from published preclinical research protocols. CagriSema is not approved for human use by the FDA or any regulatory agency. This information is provided for research reference only and does not constitute a dosing recommendation.
| Route | Dose | Frequency | Notes |
|---|---|---|---|
| Subcutaneous (Phase 3 – obesity and T2D) | cagrilintide 2.4 mg + semaglutide 2.4 mg | Once weekly | Co-administered as two injections in REDEFINE trials with gradual dose escalation; investigational, not approved as of 2026 |
All doses above are reported from published research protocols using laboratory subjects. Refer to the cited studies in the Research Studies section above for original source data.
Research Studies & References
Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity
Garvey WT, et al.
New England Journal of Medicine (2025)
The REDEFINE 1 Phase 3a trial randomized 3,417 adults without diabetes who had a BMI of 30 or higher, or 27 or higher with at least one obesity-related complication, to cagrilintide 2.4 mg plus semaglutide 2.4 mg, either agent alone, or placebo, all with lifestyle intervention, for 68 weeks. The estimated mean body-weight change was -20.4% with the combination versus -3.0% with placebo (estimated difference -17.3 percentage points; 95% CI -18.1 to -16.6; P<0.001), and combination participants were significantly more likely to reach 5%, 20%, 25%, and 30% weight-loss thresholds. Gastrointestinal adverse events affected 79.6% of the combination group and 39.9% of the placebo group and were mainly transient and mild-to-moderate. The investigators concluded that cagrilintide-semaglutide provided significant and clinically relevant body-weight reductions compared with placebo.
Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes
Davies MJ, et al.
New England Journal of Medicine (2025)
The REDEFINE 2 Phase 3a trial, conducted in 12 countries, randomized 1,206 adults with a BMI of 27 or more, type 2 diabetes, and HbA1c of 7-10% in a 3:1 ratio to once-weekly CagriSema (2.4 mg each component) or placebo for 68 weeks. Mean body-weight change was -13.7% versus -3.4% (estimated difference -10.4 percentage points; 95% CI -11.2 to -9.5; P<0.001), with significantly more combination participants reaching 5%, 10%, 15%, and 20% weight reductions. An HbA1c of 6.5% or less was achieved by 73.5% of the CagriSema group versus 15.9% on placebo. Gastrointestinal adverse events were reported by 72.5% versus 34.4%, mostly transient and mild or moderate, confirming efficacy in the population with both obesity and type 2 diabetes.
Efficacy 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
Frias JP, Deenadayalan S, Erichsen L, et al.
The Lancet (2023)
This 32-week Phase 2 trial at 17 US sites randomized 92 adults with type 2 diabetes and BMI of 27 or higher, on metformin with or without an SGLT2 inhibitor, to CagriSema, semaglutide alone, or cagrilintide alone (each escalated to 2.4 mg). HbA1c change was -2.2 percentage points with the combination versus -1.8 with semaglutide and -0.9 with cagrilintide (significantly greater than cagrilintide, P<0.0001; not versus semaglutide, P=0.075). Body-weight change was -15.6% versus -5.1% and -8.1% respectively (P<0.0001 against both single agents), and continuous glucose monitoring time in range reached 88.9% versus 76.2% and 71.7%. Mild or moderate gastrointestinal adverse events were most common, no level 2 or 3 hypoglycemia occurred, and no fatal adverse events were reported.
Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial
Lau DCW, Erichsen L, Francisco-Ziller N, et al.
The Lancet (2021)
This dose-finding Phase 2 trial at 57 sites in 10 countries randomized 706 adults without diabetes to once-weekly cagrilintide (0.3 to 4.5 mg), once-daily liraglutide 3.0 mg, or placebo for 26 weeks. Cagrilintide produced dose-dependent weight reductions of 6.0-10.8% versus 3.0% with placebo (estimated treatment difference range 3.0-7.8%; P<0.001), and the 4.5 mg dose exceeded liraglutide 3.0 mg (10.8% versus 9.0%; P=0.03). Gastrointestinal adverse events occurred in 41-63% of cagrilintide participants versus 32% on placebo, primarily nausea. The trial established the amylin analog component's standalone efficacy and informed the 2.4 mg dose carried into the CagriSema combination program.
Comparative Research
Explore in-depth research analyses and comparative studies featuring CagriSema.
Frequently Asked Questions
Is CagriSema a single peptide?
No. CagriSema is a fixed-dose combination of two separate peptide drugs: cagrilintide, a long-acting amylin analog, and semaglutide, a GLP-1 receptor agonist. In the Phase 3 REDEFINE trials the two were co-administered as once-weekly subcutaneous injections of 2.4 mg each. This distinguishes it from single-molecule multi-agonists such as tirzepatide (GLP-1/GIP) and retatrutide (GLP-1/GIP/glucagon), which are one peptide engineered to activate multiple receptors.
How much weight loss did CagriSema produce in Phase 3 trials?
In REDEFINE 1 (3,417 adults with overweight or obesity without diabetes), CagriSema produced an estimated mean weight change of -20.4% at 68 weeks versus -3.0% with placebo, a difference of -17.3 percentage points (P<0.001). In REDEFINE 2 (1,206 adults who also had type 2 diabetes), weight change was -13.7% versus -3.4% (P<0.001). Participants on the combination were significantly more likely than those on placebo to reach every weight-loss threshold tested, including 20%, 25%, and 30% in REDEFINE 1.
Why combine an amylin analog with a GLP-1 agonist?
Amylin and GLP-1 suppress appetite through different neural circuits. GLP-1 receptor activation primarily regulates homeostatic energy balance through hypothalamic centers, while amylin receptor activation in the area postrema reduces hedonic, reward-driven eating. The Phase 2 diabetes trial showed the practical payoff: weight loss of -15.6% with the combination versus -5.1% with semaglutide alone and -8.1% with cagrilintide alone, significantly greater than either component. Each peptide is individually active; the combination stacks two complementary mechanisms.
What did REDEFINE 2 show for blood sugar control?
In REDEFINE 2, adults with type 2 diabetes (baseline HbA1c 7-10%) treated with CagriSema for 68 weeks were far more likely to reach an HbA1c of 6.5% or below: 73.5% versus 15.9% on placebo, alongside the -13.7% versus -3.4% weight result. In the earlier Phase 2 diabetes trial, HbA1c fell 2.2 percentage points with the combination versus 1.8 with semaglutide alone, and continuous glucose monitoring time in range reached 88.9% with no level 2 or 3 hypoglycemic events reported.
What are the main side effects of CagriSema?
Gastrointestinal adverse events dominate, as expected from both drug classes: nausea, vomiting, diarrhea, constipation, and abdominal pain affected 79.6% of CagriSema participants in REDEFINE 1 (versus 39.9% on placebo) and 72.5% in REDEFINE 2 (versus 34.4%). The events were mainly transient and mild-to-moderate in severity, and gradual dose escalation is used to improve tolerability. In the Phase 2 diabetes trial, no severe hypoglycemia and no fatal adverse events were reported.
Is CagriSema approved by the FDA?
No. As of 2026, CagriSema is an investigational combination that has completed Phase 3 trials (REDEFINE 1 and REDEFINE 2, both published in the New England Journal of Medicine in 2025) but is not approved by the FDA or any other regulatory agency. Its component semaglutide is separately approved as Ozempic, Wegovy, and Rybelsus; cagrilintide alone is also investigational.
How does CagriSema compare with tirzepatide and retatrutide?
The approaches differ structurally. Tirzepatide is a single peptide activating GLP-1 and GIP receptors; retatrutide is a single peptide activating GLP-1, GIP, and glucagon receptors. CagriSema instead combines two separate peptides targeting GLP-1 and amylin pathways. Cross-trial comparisons are imperfect, but REDEFINE 1's -20.4% at 68 weeks sits near the top of reported Phase 3 pharmacotherapy results, alongside retatrutide's -24.2% at 48 weeks in a smaller Phase 2 trial. No head-to-head trial between these agents has been published.
What evidence supports the cagrilintide component on its own?
The Phase 2 dose-finding trial by Lau and colleagues (Lancet 2021) randomized 706 adults to cagrilintide 0.3-4.5 mg weekly, liraglutide 3.0 mg daily, or placebo for 26 weeks. Cagrilintide produced dose-dependent weight loss of 6.0-10.8% versus 3.0% with placebo, and the 4.5 mg dose significantly exceeded liraglutide (10.8% versus 9.0%; P=0.03). This demonstrated that amylin receptor agonism alone produces clinically meaningful weight reduction and justified carrying a 2.4 mg dose into the combination program.
Related Peptides
View allCagrilintide
Cagrilintide is a long-acting acylated amylin analog developed by Novo Nordisk, designed for once-weekly subcutaneous administration and studied both as monotherapy and in combination with semaglutide (CagriSema) for obesity and type 2 diabetes management.
Semaglutide (GLP-1)
Semaglutide is a long-acting GLP-1 (glucagon-like peptide-1) receptor agonist that mimics the incretin hormone GLP-1, regulating blood glucose levels, appetite, and body weight through multiple metabolic pathways.
Tirzepatide (GLP-1/GIP)
Tirzepatide is a first-in-class dual GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 receptor agonist, providing synergistic metabolic effects for diabetes and obesity research.
Retatrutide (Triple Agonist)
Retatrutide is a first-in-class triple hormone receptor agonist targeting GLP-1, GIP, and glucagon receptors simultaneously, producing the most profound metabolic effects seen in obesity research to date.