CagriSema

REDEFINE 1: obesity without diabetes, 3,417 adults, 68 weeks

The largest published CagriSema trial randomised 3,417 adults without diabetes who had a body mass index of 30 or higher, or 27 or higher with at least one obesity-related complication, in a 21:3:3:7 ratio to CagriSema 2.4 mg/2.4 mg, semaglutide 2.4 mg alone, cagrilintide 2.4 mg alone, or placebo, all with lifestyle intervention. The arms held 2,108, 302, 302 and 705 participants (PMID: 41328546). The co-primary endpoints were the relative change in body weight and the proportion losing 5% or more by week 68, both against placebo, and both were met. Estimated mean body weight change was 20.4% with CagriSema against 3.0% with placebo (estimated difference 17.3 percentage points in favour of CagriSema, 95% CI 16.6 to 18.1, p less than 0.001) on the treatment-policy estimand. More participants on CagriSema reached losses of 5%, 20%, 25% and 30% or more. Gastrointestinal adverse events affected 79.6% of the CagriSema group and 39.9% of the placebo group and were mostly transient and mild to moderate (PMID: 40544433).

Two further analyses of REDEFINE 1 have been published. A secondary post hoc analysis looked at absolute anthropometric targets rather than percentage weight loss and concluded that the proportion of participants reaching a BMI under 27 and a waist-to-height ratio under 0.53 at week 68 was greater with CagriSema than with semaglutide, cagrilintide or placebo (PMID: 42503495). That paper carries a correction published on 20 October 2026 (PMID: 42897974) whose content could not be retrieved, so its individual percentages are left out of this guide. A blood pressure analysis reported changes from baseline to week 68 of 10.9 mmHg systolic and 5.4 mmHg diastolic with CagriSema against 2.8 and 1.7 mmHg with placebo; 63.0% of the CagriSema group and 32.0% of the placebo group reached blood pressure targets, and among participants taking antihypertensive medication during the trial, 39.6% on CagriSema and 18.8% on placebo reduced or stopped it (PMID: 41328546).

REDEFINE 2: obesity with type 2 diabetes, 1,206 adults, 68 weeks

REDEFINE 2 randomised 1,206 adults with type 2 diabetes, a BMI of 27 or more and HbA1c of 7 to 10% in a 3:1 ratio to CagriSema 2.4 mg/2.4 mg or placebo for 68 weeks. Both primary endpoints were met: estimated mean body weight change was 13.7% against 3.4% with placebo (estimated difference 10.4 percentage points in favour of CagriSema, 95% CI 9.5 to 11.2, p less than 0.001), and more patients reached a 5% loss. HbA1c of 6.5% or less was reached by 73.5% on CagriSema and 15.9% on placebo. Gastrointestinal adverse events were reported by 72.5% and 34.4% respectively (PMID: 40544432).

REDEFINE 5: east Asian population, 331 adults, 68 weeks

REDEFINE 5 was the first phase 3 trial whose primary endpoint compared CagriSema directly with semaglutide. It randomised 331 adults in Japan and Taiwan, with or without type 2 diabetes, 1:1 to CagriSema or semaglutide, both escalated to 2.4 mg, for 68 weeks. Estimated mean body weight change on the trial-product estimand was 18.4% with CagriSema against 11.9% with semaglutide (estimated treatment difference 6.5 percentage points in favour of CagriSema, 95% CI 4.6 to 8.4, p less than 0.0001), meeting the primary endpoint. Adverse events were reported by 87% and 84% of the two groups, most commonly gastrointestinal (PMID: 42009015).

REIMAGINE 1, 2 and 3: type 2 diabetes, 2026

Three phase 3 trials in type 2 diabetes were published in June 2026 and all met their primary endpoint, which in each case was HbA1c.

REIMAGINE 1 enrolled 189 adults whose diabetes was inadequately controlled on diet and exercise and compared CagriSema at 2.4 mg each and 1.0 mg each against matching placebo over 40 weeks. HbA1c fell 1.8 percentage points on the higher dose against 0.1 on placebo, and body weight fell 13.8% against 1.4% (PMID: 42251860).

REIMAGINE 2 was the largest of the three, randomising 2,713 adults on metformin with or without an SGLT2 inhibitor across six arms for 68 weeks: CagriSema and semaglutide each at 2.4 mg and at 1.0 mg, cagrilintide 2.4 mg, and pooled placebo. The primary comparison, CagriSema 2.4 mg each against semaglutide 2.4 mg, favoured the combination by a small margin: HbA1c fell 1.91 percentage points against 1.75 (estimated treatment difference 0.16 percentage points in favour of the combination, 95% CI 0.05 to 0.27, p = 0.0035). Adverse events were reported by 86.9% of the CagriSema group and 81.2% of the semaglutide group, most commonly gastrointestinal (PMID: 42251859).

REIMAGINE 3 added CagriSema to once-daily basal insulin in 274 adults over 40 weeks. HbA1c fell 2.33 percentage points on the 2.4 mg dose and 2.10 on the 1.0 mg dose against 0.66 on placebo, body weight fell 10% to 12%, and no severe hypoglycaemia was reported. One death occurred in the 1.0 mg group and was judged unrelated to treatment (PMID: 42251856).

Phase 2 in type 2 diabetes: 92 adults, 32 weeks

The phase 2 trial that justified the phase 3 program randomised 92 adults with type 2 diabetes and a BMI of 27 or more, on metformin with or without an SGLT2 inhibitor, 1:1:1 to CagriSema, semaglutide or cagrilintide, all escalated to 2.4 mg, for 32 weeks. The primary endpoint was HbA1c change. HbA1c fell 2.2 percentage points on CagriSema, 1.8 on semaglutide and 0.9 on cagrilintide; the difference against cagrilintide was significant (p less than 0.0001) but the difference against semaglutide was not (0.4 percentage points, p = 0.075), so the primary endpoint was met against one comparator only. Body weight fell 15.6% on CagriSema against 5.1% on semaglutide and 8.1% on cagrilintide, both differences significant. No level 2 or 3 hypoglycaemia and no fatal adverse events were reported (PMID: 37364590).

Phase 1b: the first human test of the pair, 96 adults

The combination was first given to people in a phase 1b multiple-ascending-dose trial at a single United States centre, which screened participants between 25 July 2018 and 17 December 2019 and was published in 2021. Ninety-six adults aged 18 to 55 with a BMI of 27.0 to 39.9 were randomised 3:1 within six cohorts to cagrilintide 0.16 to 4.5 mg or matching placebo, everyone on semaglutide 2.4 mg, with no lifestyle intervention. The primary endpoint was the number of treatment-emergent adverse events. Of 566 adverse events in 92 participants, 207 were gastrointestinal disorders, and most events were mild to moderate. At week 20, body weight fell 15.7% on cagrilintide 1.2 mg and 17.1% on cagrilintide 2.4 mg against 9.8% on pooled placebo plus semaglutide 2.4 mg (PMID: 33894838). Because every participant received semaglutide, this trial measured what cagrilintide adds, not what the pair does against nothing.

Cagrilintide alone: the phase 2 dose-finding trial, 706 adults

The amylin half has its own phase 2 trial, run at 57 sites in ten countries. It randomised 706 adults without diabetes 6:1 to once-weekly cagrilintide at 0.3, 0.6, 1.2, 2.4 or 4.5 mg, once-daily liraglutide 3.0 mg, or volume-matched placebo for 26 weeks. The primary endpoint, percentage change in body weight at week 26, was met: weight fell 6.0% to 10.8% across the cagrilintide doses against 3.0% on placebo, and 10.8% on cagrilintide 4.5 mg against 9.0% on liraglutide 3.0 mg (estimated treatment difference 1.8%, p = 0.03). Gastrointestinal adverse events occurred in 41% to 63% of cagrilintide groups against 32% on placebo, mostly nausea at 20% to 47% against 18% (PMID: 34798060).

Pooled analyses

A 2026 systematic review and meta-analysis of five randomised trials covering 4,746 unique participants compared CagriSema with semaglutide 2.4 mg under a harmonised trial-product estimand. CagriSema produced 6.89 percentage points more weight loss (95% CI 5.06 to 8.70), 7.16 kg more absolute weight loss, 2.41 kg/m2 more BMI reduction, 4.07 cm more waist circumference reduction, and roughly double the chance of reaching a 20% loss (RR 2.10, 95% CI 1.78 to 2.47). Injection-site reactions were more frequent (RR 3.14, 95% CI 1.42 to 6.96), and gastrointestinal adverse events were not significantly increased under the primary model (RR 1.09, 95% CI 0.97 to 1.21). The authors wrote that the evidence does not settle whether serious adverse events or neoplasms differ, and that durability, cardiovascular outcomes and body composition are undetermined (PMID: 42890523). A separate GRADE-assessed meta-analysis of seven trials in 8,069 people found CagriSema produced 7.58 kg more weight loss than semaglutide, 9.24 kg more than cagrilintide and 13.99 kg more than placebo, with no increase in serious adverse events (PMID: 42608559). A network meta-analysis of six trials in 4,642 people ranked high-dose injectable amycretin first for percentage weight loss, high-dose eloralintide second and high-dose CagriSema third, and reported that only high-dose CagriSema increased discontinuation for adverse events among the amylin-based agents studied (PMID: 42175595).

Running and unpublished trials

The cardiovascular outcomes trial, REDEFINE 3, randomised 7,076 adults with established cardiovascular disease and a BMI of 25.0 or higher, with or without type 2 diabetes, to CagriSema or placebo on top of standard care between January 2023 and December 2024 at 575 sites in 24 countries. Its safety objective is non-inferiority against placebo for cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, and its efficacy objective is superiority on those three plus revascularisation. Mean age at baseline was 66 years and 62% had a prior myocardial infarction. Only the design and baseline characteristics have been published (PMID: 42838477); ClinicalTrials.gov lists the trial as NCT05669755 with primary completion planned for September 2027.

Two phase 3 trials comparing CagriSema directly with tirzepatide are listed as completed on ClinicalTrials.gov with no results posted and no published report that could be retrieved: NCT06131437 in 809 adults with obesity and no diabetes, with an 84-week treatment period, and NCT06221969 in 1,024 adults with type 2 diabetes on metformin with or without an SGLT2 inhibitor. Until those appear, any direct comparison between CagriSema and tirzepatide rests on indirect evidence.

Device

A usability study had 85 adults with overweight or obesity and 65 adults with type 2 diabetes perform simulated injections with the CagriSema dual-chamber pen, a single-dose pre-filled autoinjector, after standardised training. All but one participant completed the injection, median training time was 3 minutes, and median time to prepare and inject was 15 seconds (PMID: 42366647).

Everything below comes from human trials of CagriSema or of its components unless stated.

Gastrointestinal events dominate. In REDEFINE 1, gastrointestinal adverse events affected 79.6% of the CagriSema group against 39.9% of the placebo group, and the trial reported them as mainly transient and mild to moderate (PMID: 40544433). In REDEFINE 2, in adults with type 2 diabetes, the figures were 72.5% and 34.4% (PMID: 40544432). A 2026 narrative review of gastrointestinal effects across this drug class tabulates nausea in 55.0% of the CagriSema arm of REDEFINE 1 against 12.6% on placebo, constipation in 30.7% against 11.6%, and discontinuation for adverse events in 6.0% (PMID: 42808923).

Against semaglutide alone the gastrointestinal penalty is smaller than it looks. A 2026 meta-analysis of five trials found gastrointestinal adverse events were not significantly more frequent with CagriSema than with semaglutide 2.4 mg under its primary model (RR 1.09, 95% CI 0.97 to 1.21), while injection-site reactions were about three times as frequent (RR 3.14, 95% CI 1.42 to 6.96) (PMID: 42890523). An earlier meta-analysis reached a different conclusion on nausea, reporting it more frequent with the combination than with semaglutide (RR 1.64, 95% CI 1.01 to 2.66) along with more administration-site conditions (RR 3.27, 95% CI 1.27 to 8.46) (PMID: 41834765). A network meta-analysis of amylin-based agents found that, among the agents it compared, only high-dose CagriSema increased discontinuation for adverse events (PMID: 42175595).

Hypoglycaemia. The phase 2 trial in type 2 diabetes reported no level 2 or level 3 hypoglycaemia (PMID: 37364590). REIMAGINE 3, which added CagriSema to basal insulin, reported no severe hypoglycaemia over 40 weeks (PMID: 42251856).

Serious events and deaths. REIMAGINE 3 reported one death, in the lower-dose group, attributed by the investigator to malignancy and judged unrelated to treatment (PMID: 42251856). REDEFINE 5 reported one death, in the semaglutide comparator group, also judged not treatment related (PMID: 42009015). The 2026 meta-analysis concluded that the available evidence is not sufficient to tell whether serious adverse events or neoplasms differ between CagriSema and semaglutide (PMID: 42890523).

Cardiac repolarisation. A thorough QT study in 105 healthy participants found no clinically relevant QTcF prolongation with cagrilintide escalated to 4.5 mg weekly (PMID: 39279639).

Blood pressure direction. In REDEFINE 1, systolic and diastolic blood pressure fell further on CagriSema than on placebo, and more participants reduced or stopped antihypertensive medication during the trial (PMID: 41328546). A 2025 Lancet hypothesis paper argues that amylin receptor agonists could activate the renin-angiotensin system, and proposes preclinical work, post hoc analyses stratified by use of renin-angiotensin system inhibitors, and biomarker studies to test whether that matters; the authors note the blood pressure reductions seen in phase 3 run the other way (PMID: 41207308).

What is not known. No published CagriSema trial has run longer than 68 weeks. Cardiovascular outcomes are being tested in REDEFINE 3, which has reported only its design (PMID: 42838477). Body composition and durability after stopping were listed as undetermined in the 2026 meta-analysis (PMID: 42890523).