Cagrilintide and CagriSema in Human Clinical Trials: Populations, Endpoints and Findings

A trial-by-trial account of the published clinical literature on the amylin analogue cagrilintide alone and as the fixed combination with semaglutide: populations, designs, durations, primary endpoints, results as reported, adverse events and limitations.

By Published Updated

Two distinct things are described in this literature and they are frequently conflated. Cagrilintide is a single molecule: a long-acting analogue of the pancreatic hormone amylin [2]. CagriSema is a fixed combination of cagrilintide and semaglutide, co-administered as one once-weekly subcutaneous injection and studied as a single product [6]. A result reported for the combination is not a result for cagrilintide, and the published trials are careful about the distinction in a way that secondary coverage often is not.

This article describes the published human record for both, trial by trial: population, design, duration, primary endpoint, results as reported, adverse events, and limitations. Several of these trials contain cagrilintide-alone and semaglutide-alone arms, which is what makes the separation possible at all, and those arms are given the same attention as the combination arms.

Two boundaries apply throughout. Every study below tested a pharmaceutical investigational product administered under clinical supervision in screened populations under registered protocols. And nothing below is guidance of any kind on handling any material, a comparison of products, or a recommendation.

What amylin is, and what a long-acting analogue changes

In vitro research

Amylin is a 37-amino-acid hormone co-secreted with insulin from pancreatic beta cells. Its pharmacology, physiology and receptor biology have been reviewed at length: it acts at receptor complexes formed by the calcitonin receptor together with receptor activity-modifying proteins, and its described physiological roles include slowing of gastric emptying and central effects on food intake [1]. Native human amylin is also strongly amyloidogenic, which is the practical obstacle to developing it as a therapeutic.

Cagrilintide was described in 2021 as an acylated, solubilised long-acting analogue engineered around that obstacle: sequence changes that suppress aggregation, with a lipid side chain that binds serum albumin and extends duration to support once-weekly administration [2].

The consequence for reading the clinical trials is that cagrilintide engages a receptor family entirely separate from the GLP-1 receptor. That is the stated rationale for combining the two — two mechanisms rather than more of one — and it is a rationale, not a finding.

The phase 1 and phase 2 record

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

Phase 1b: the combination's first human study

96 individuals aged 18 to 55 with a body-mass index of 27.0 to 39.9 kg/m² and otherwise healthy were recruited at a single centre in the United States and randomly assigned 3:1 within six sequential overlapping cohorts to once-weekly subcutaneous cagrilintide (0.16 to 4.5 mg) or matched placebo, each combined with once-weekly semaglutide 2.4 mg, with no lifestyle intervention. Both components were co-escalated over 16 weeks, held at target for 4 weeks, and followed for 5 weeks. The primary endpoint was the number of treatment-emergent adverse events [3, 10].

95 participants were exposed. Mean age was 40.6 years, 59% were men and 54% were Black or African American. 566 adverse events were reported in 92 participants — 97% of those on cagrilintide and 96% of those on placebo — of which 207 (37%) were gastrointestinal disorders; most were mild to moderate. Exposure was proportional to the cagrilintide amount and did not affect semaglutide exposure or elimination. Cagrilintide half-life was 159–195 hours and semaglutide 145–165 hours [3].

The trial's value is pharmacokinetic: it establishes that co-administration does not alter semaglutide exposure. It was not designed to measure efficacy, it enrolled otherwise healthy volunteers, and at 11 to 12 participants per cohort it can detect only common adverse events.

Phase 2 amount-finding for cagrilintide alone

706 adults aged at least 18 without diabetes, with a body-mass index of at least 30 kg/m² or at least 27 kg/m² with hypertension or dyslipidaemia, were randomised 6:1 at 57 sites in ten countries to once-weekly subcutaneous cagrilintide (0.3, 0.6, 1.2, 2.4 or 4.5 mg), once-daily liraglutide 3.0 mg, or volume-matched placebo. Treatment ran 26 weeks including up to 6 weeks of escalation, with 6 weeks of follow-up off treatment. The primary endpoint was percentage change in body weight from baseline to week 26. Masking covered active versus pooled placebo but not different active treatments [4, 11].

Mean percentage reductions in body weight under the trial-product estimand were 6.0% to 10.8% (6.4–11.5 kg) across the cagrilintide groups against 3.0% (3.3 kg) with placebo, estimated treatment differences of 3.0% to 7.8%, p<0.001. Cagrilintide 4.5 mg gave 10.8% against 9.0% with liraglutide 3.0 mg, an estimated difference of 1.8%, p=0.03. Permanent discontinuation occurred in 73 participants (10%), similarly across groups, mostly for adverse events (4%). Gastrointestinal disorders and administration-site reactions were the most frequent adverse events; gastrointestinal events occurred in 41–63% of cagrilintide participants against 32% of placebo participants, primarily nausea at 20–47% against 18% [4].

Limitations. The active comparison against liraglutide was not masked between active treatments, and the margin over liraglutide — 1.8 percentage points at p=0.03 — is narrow. 26 weeks is short. The trial establishes that an amylin analogue alone produces a measurable effect, which is what a combination rationale requires, and nothing about durability.

Phase 2 of the combination in type 2 diabetes

92 adults with type 2 diabetes and a body-mass index of 27 kg/m² or higher, on metformin with or without an SGLT2 inhibitor, were randomised 1:1:1 at 17 sites in the United States to once-weekly subcutaneous CagriSema, semaglutide, or cagrilintide, all escalated to 2.4 mg, for 32 weeks. The primary endpoint was change in glycated haemoglobin from baseline. 64% were male and mean age was 58 years [5, 12].

Mean change in glycated haemoglobin to week 32 was −2.2 percentage points with CagriSema, −1.8 with semaglutide and −0.9 with cagrilintide. The combination was significantly better than cagrilintide alone (difference −1.3 points; 95% CI −1.7 to −0.8; p<0.0001) but not significantly better than semaglutide alone (−0.4 points; −0.8 to 0.0; p=0.075). Mean change in body weight was −15.6% with CagriSema against −5.1% with semaglutide and −8.1% with cagrilintide, with the combination significantly better than both (both p<0.0001). Adverse events were reported by 68%, 71% and 80% of the three groups respectively [5].

This is the trial that separates the two claims most cleanly at phase 2, and it separates them in opposite directions: on the glycaemic endpoint the combination did not beat semaglutide alone; on body weight it did. With 30 or 31 participants per arm, it is small for either conclusion.

REDEFINE 1: phase 3a in overweight or obesity without diabetes

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

Population, design and endpoint. 3,417 adults without diabetes, with a body-mass index of 30 or higher or 27 or higher with at least one obesity-related complication, randomised 21:3:3:7 to cagrilintide-semaglutide (2.4 mg each), semaglutide 2.4 mg alone, cagrilintide 2.4 mg alone, or placebo, all with lifestyle intervention, for 68 weeks in a multicentre double-blind phase 3a trial. Group sizes were 2,108, 302, 302 and 705. Coprimary endpoints were relative change in body weight and a reduction of 5% or more at week 68 for the combination against placebo, under the treatment-policy estimand [6, 13].

Results as reported. Estimated mean percent change in body weight to week 68 was −20.4% with the combination against −3.0% with placebo — estimated difference −17.3 percentage points, 95% CI −18.1 to −16.6, P<0.001. The combination group was more likely than placebo to reach reductions of 5%, 20%, 25% and 30% or more, all P<0.001. Gastrointestinal adverse events — nausea, vomiting, diarrhoea, constipation or abdominal pain — affected 79.6% of the combination group and 39.9% of the placebo group and were described as mainly transient and mild to moderate [6].

Limitations. The coprimary comparison is against placebo. The semaglutide-alone and cagrilintide-alone arms hold 302 participants each against 2,108 in the combination arm, so the trial is powered to answer the placebo question and only descriptively addresses the question most readers arrive with — how much the amylin component adds. Four in five participants in the combination arm reported a gastrointestinal adverse event. The endpoint is anthropometric across 68 weeks, and no clinical outcome was counted.

REDEFINE 2: phase 3a in type 2 diabetes

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

Population, design and endpoint. 1,206 adults in 12 countries with a body-mass index of 27 or more, glycated haemoglobin of 7 to 10% and type 2 diabetes, randomised 3:1 to once-weekly cagrilintide-semaglutide (2.4 mg each) or placebo with lifestyle intervention for 68 weeks — 904 and 302 participants. The two primary endpoints were percent change in body weight and the proportion reaching a reduction of at least 5% [7, 14].

Results as reported. Estimated mean change in body weight to week 68 was −13.7% against −3.4%, an estimated difference of −10.4 percentage points (95% CI −11.2 to −9.5; P<0.001). More participants reached reductions of 5%, and of at least 10%, 15% and 20%, all P<0.001 for the stated comparisons. Glycated haemoglobin of 6.5% or less was reached by 73.5% of the combination group against 15.9% of placebo. Gastrointestinal adverse events were reported by 72.5% against 34.4%, most transient and mild or moderate [7].

Limitations. There is no active comparator in this trial — the design is combination against placebo only — so it cannot address what the amylin component contributes in a diabetes population. As in every trial of this family, the effect size in the diabetes population is smaller than in the population without diabetes, and the trial documents the difference without explaining it.

The trials against semaglutide alone

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

REDEFINE 5. 331 participants at 21 sites in Japan and one in Taiwan, aged at least 18, with a body-mass index of at least 27 kg/m² and at least two obesity-related complications, or at least 35 kg/m² with at least one, with or without type 2 diabetes, randomised 1:1 to cagrilintide-semaglutide or semaglutide (both escalated to 2.4 mg) with lifestyle intervention for 68 weeks. 68% were male and 24% had type 2 diabetes. The primary endpoint was relative change in body weight at week 68 under the trial-product estimand, with missing data imputed [8, 16].

Estimated mean change in body weight was −18.4% with the combination against −11.9% with semaglutide — estimated treatment difference −6.5 percentage points, 95% CI −8.4 to −4.6, p<0.0001. Adverse events were reported by 87% and 84% of the two groups, most commonly gastrointestinal disorders at 53% and 51%. 10% discontinued the combination and 6% semaglutide. One death occurred, in the semaglutide group, not judged treatment-related [8].

REIMAGINE 2. 2,713 participants in 30 countries with inadequately controlled type 2 diabetes (glycated haemoglobin 7.0–10.5%) on metformin with or without an SGLT2 inhibitor and a body-mass index of 25 kg/m² or more, randomised 8:8:2:8:8:1:1 across six active arms and matched placebo for 68 weeks: cagrilintide-semaglutide at 2.4 mg each, semaglutide 2.4 mg, cagrilintide 2.4 mg, cagrilintide-semaglutide at 1.0 mg each, semaglutide 1.0 mg, and placebo. The primary endpoint was change in glycated haemoglobin at week 68 for the combination at 2.4 mg each against semaglutide 2.4 mg. Mean baseline glycated haemoglobin was 8.2%; 95.7% completed the study and 87.6% were on treatment at week 68 [9, 17].

Mean glycated haemoglobin change was −1.91 percentage points with the combination against −1.75 with semaglutide 2.4 mg — estimated treatment difference −0.16 percentage points, 95% CI −0.27 to −0.05, p=0.0035. Adverse events were reported by 86.9% of the combination group, 81.2% of the semaglutide 2.4 mg group, 82.2% of the cagrilintide 2.4 mg group and 70.5% of the placebo group [9].

Limitations of both. REDEFINE 5 enrolled 331 participants in two east Asian territories and is not a general population. REIMAGINE 2's primary result is statistically significant and small: 0.16 percentage points of glycated haemoglobin, against a comparator that is itself highly effective. Neither trial counted a clinical event, and both stop at 68 weeks.

What the evidence base does not establish

What the amylin component contributes, quantitatively. The trials that include a semaglutide-alone arm are the ones that can address this, and they give a mixed answer: no significant glycaemic advantage over semaglutide at phase 2 [5], a 6.5-point body-weight advantage in a 331-participant east Asian trial [8], and a 0.16-point glycaemic advantage in a 2,713-participant trial [9]. REDEFINE 1's semaglutide arm was not sized to settle it [6].

Any clinical outcome. No published trial of cagrilintide or the combination has counted deaths, myocardial infarctions, strokes or kidney failure as a primary endpoint. REDEFINE 3 enrols a population with cardiovascular disease [15] and has not reported.

Anything beyond 68 weeks. Every phase 3a trial above ran 68 weeks, and the phase 2 trials 26 and 32 weeks. Nothing describes a second year, and nothing describes what follows discontinuation.

Tolerability in the long run. Gastrointestinal adverse events affected 72.5% to 79.6% of participants in the phase 3a combination arms [6, 7]. The publications describe these as mainly transient and mild to moderate, which is a characterisation of the events, not of what proportion of a population would remain on treatment indefinitely.

Comparison with anything but semaglutide and liraglutide. The only active comparators in this published record are liraglutide 3.0 mg at phase 2 [4] and semaglutide [5, 8, 9]. No trial has compared the combination with a dual or triple receptor agonist.

Regulatory position. Cagrilintide and the cagrilintide-semaglutide combination are investigational and approved nowhere. An approval held by one component of a combination confers nothing on the combination.

All of the research described in this article is research into pharmaceutical product candidates, conducted by their sponsor under registered protocols, using investigational material manufactured to a regulatory standard and administered under clinical supervision in defined populations. None of it is research into, or evidence about, research-grade material supplied for laboratory use.

Frequently Asked Questions

What is the difference between cagrilintide and CagriSema?
Cagrilintide is a single long-acting amylin analogue [2]. CagriSema is a fixed combination of cagrilintide and semaglutide co-administered as one once-weekly subcutaneous injection, and its trials report the combination rather than either component alone [6]. Several trials include cagrilintide-alone and semaglutide-alone arms precisely so the two can be separated [6, 9].
What did the REDEFINE 1 trial report?
In 3,417 adults without diabetes randomised 21:3:3:7 to cagrilintide-semaglutide, semaglutide alone, cagrilintide alone or placebo for 68 weeks, the estimated mean percent change in body weight to week 68 was −20.4% with the combination against −3.0% with placebo, an estimated difference of −17.3 percentage points (95% CI −18.1 to −16.6; P<0.001). Gastrointestinal adverse events affected 79.6% of the combination group and 39.9% of the placebo group [6].
Has CagriSema been compared directly with semaglutide alone?
Yes, in three published trials. REDEFINE 1 included a semaglutide-alone arm of 302 participants [6]. REDEFINE 5 randomised 331 participants in Japan and Taiwan 1:1 against semaglutide 2.4 mg and reported −18.4% against −11.9% at 68 weeks [8]. REIMAGINE 2 randomised 2,713 participants with type 2 diabetes and reported a glycated haemoglobin difference of −0.16 percentage points against semaglutide 2.4 mg (P=0.0035) [9].
What does cagrilintide do on its own in trials?
In a 26-week phase 2 amount-finding trial of 706 participants without diabetes, mean percentage reductions in body weight were 6.0% to 10.8% across cagrilintide groups against 3.0% with placebo, and 10.8% with cagrilintide 4.5 mg against 9.0% with liraglutide 3.0 mg (estimated difference 1.8%, p=0.03) [4]. In a 32-week phase 2 trial in type 2 diabetes, cagrilintide alone changed glycated haemoglobin by −0.9 percentage points against −1.8 for semaglutide alone [5].
Is CagriSema approved by the FDA?
No. Cagrilintide and the cagrilintide-semaglutide combination are investigational and are not approved for any indication in the United States or elsewhere. Semaglutide is separately approved, but an approval held by one component confers nothing on a combination product.
What adverse events are reported in cagrilintide and CagriSema trials?
Gastrointestinal events dominate every published trial: 79.6% against 39.9% on placebo in REDEFINE 1 [6], 72.5% against 34.4% in REDEFINE 2 [7], and 41–63% against 32% across cagrilintide groups in the phase 2 amount-finding trial, chiefly nausea [4]. Administration-site reactions were also among the most frequent events in that trial [4].
How long have cagrilintide and CagriSema trials run?
The phase 3a trials ran 68 weeks [6, 7, 8, 9]. The phase 2 trials ran 26 and 32 weeks [4, 5], and the phase 1b combination study ran 20 weeks of treatment with 5 weeks of follow-up [3]. No published trial of the combination has reported a clinical outcome endpoint.

References

  1. Amylin: Pharmacology, Physiology, and Clinical Potential Pharmacological Reviews; 2015. PMID 26071095 doi:10.1124/pr.115.010629
  2. Development of Cagrilintide, a Long-Acting Amylin Analogue Journal of Medicinal Chemistry; 2021. PMID 34288673 doi:10.1021/acs.jmedchem.1c00565
  3. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial Lancet; 2021. PMID 33894838 doi:10.1016/S0140-6736(21)00845-X
  4. 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 Lancet; 2021. PMID 34798060 doi:10.1016/S0140-6736(21)01751-7
  5. 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 Lancet; 2023. PMID 37364590 doi:10.1016/S0140-6736(23)01163-7
  6. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity The New England Journal of Medicine; 2025. PMID 40544433 doi:10.1056/NEJMoa2502081
  7. Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes The New England Journal of Medicine; 2025. PMID 40544432 doi:10.1056/NEJMoa2502082
  8. Efficacy and safety of co-administered cagrilintide and semaglutide versus semaglutide alone in adults with overweight or obesity with or without type 2 diabetes in Japan and Taiwan (REDEFINE 5): a multicentre, randomised, active-controlled, phase 3a trial The Lancet Diabetes & Endocrinology; 2026. PMID 42009015 doi:10.1016/S2213-8587(25)00402-4
  9. Cagrilintide-semaglutide (CagriSema) versus semaglutide or cagrilintide in people with type 2 diabetes (REIMAGINE 2): a randomised, double-blind, placebo-controlled and active-controlled, phase 3 trial The Lancet Diabetes & Endocrinology; 2026. PMID 42251859 doi:10.1016/S2213-8587(26)00125-7
  10. A Research Study of How NNC0174-0833 Taken With Semaglutide Works in People Who Are Overweight or Obese. NCT03600480
  11. Research Study Investigating How Well NNC0174-0833 Works in People Suffering From Overweight or Obesity.. NCT03856047
  12. Research Study to Look at How Well Cagrilintide Together With Semaglutide Works in People With Type 2 Diabetes. NCT04982575
  13. A Research Study to See How Well CagriSema Helps People With Excess Body Weight Lose Weight. NCT05567796
  14. A Research Study to See How Well CagriSema Helps People With Type 2 Diabetes and Excess Body Weight Lose Weight. NCT05394519
  15. REDEFINE 3: A Research Study to See the Effects of CagriSema in People Living With Diseases in the Heart and Blood Vessels. NCT05669755
  16. A Research Study to See How Well CagriSema Helps People in East Asia With Excess Body Weight Lose Weight. NCT05813925
  17. A Research Study to See How Well CagriSema Compared to Semaglutide, Cagrilintide and Placebo Lowers Blood Sugar and Body Weight in People With Type 2 Diabetes Treated With Metformin With or Without an SGLT2 Inhibitor. NCT06065540

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