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Cagrilintide

Tier 1 · Human trials
Also known as NNC0174-0833 · AM833 · CagriSema

The strongest evidence is Tier 1 from multiple randomised controlled human trials, including phase 2 and phase 3a studies of cagrilintide alone and as the CagriSema (cagrilintide-semaglutide) combination, plus a phase 1b PK study, a thorough QT trial, and meta-analyses/network meta-analyses. Supporting evidence spans Tier 2 (in vitro myotube mitochondrial study) and Tier 3 (consumer/pharmacy web material, expert-opinion reviews). Cagrilintide remains investigational and is not approved in the UK, EU or USA.

Half-life
~180 h
Routes
Subcutaneous injection (once-weekly)
Goals
Weight loss / obesity management · Glycemic control / type 2 diabetes · Metabolic health · Appetite regulation
Cost / mg
Not recorded

How it works

According to Novo Nordisk development papers and reviews, cagrilintide is a long-acting synthetic version of amylin, a hormone the pancreas releases alongside insulin after meals to signal fullness. Consumer and pharmacy web material describe it as designed to activate amylin receptors in the brainstem, aiming to reduce appetite, boost fullness, slow the stomach's emptying, suppress the post-meal release of glucagon and help regulate blood sugar. It is engineered for once-weekly injection. Reviews note it is frequently combined with the GLP-1 drug semaglutide (as CagriSema) because the two work through separate routes, which sources describe as complementary and potentially additive for appetite reduction and glucose control.

Overview

Overview

Cagrilintide (also known as NNC0174-0833 and AM833, and as a component of CagriSema) is described in a development paper by Novo Nordisk researchers19 and in reviews3,10 as a long-acting amylin receptor agonist developed for once-weekly subcutaneous injection. Pharmacy web material22 describes it as a long-acting amylin analogue developed for obesity and overweight treatment that binds amylin and calcitonin receptors. It remains investigational: consumer and pharmacy web sources21,22 state that cagrilintide and CagriSema are not yet approved in the UK, EU or USA and that cagrilintide is sold as a research peptide by gray-market retailers.

Cagrilintide monotherapy

Weight-loss trials of cagrilintide alone reported significant, dose-dependent effects. A 26-week phase 2 trial (17, also17) randomized 706 participants to once-weekly cagrilintide 0.3-4.5 mg and reported mean weight reductions of 6.0-10.8% (6.4-11.5 kg) versus 3.0% (3.3 kg) with placebo, with all doses significantly greater than placebo (estimated treatment differences 3.0-7.8%; p<0.001). The same trial reported cagrilintide 4.5 mg produced greater weight loss than liraglutide 3.0 mg (10.8% vs 9.0%; treatment difference 1.8%, p=0.03). The phase 2 authors17 noted that 5-10% weight loss is associated with health benefits, that ≥10% is often required to improve certain obesity-related complications, and that approved pharmacotherapies achieve 3-9% weight loss at 1 year relative to placebo.

A note of nuance: a meta-analysis of 5 RCTs with 2,780 participants6 reported that cagrilintide alone produced only a modest, non-significant HbA1c reduction versus placebo (MD -0.1%; 95% CI -1.4 to 1.0) and body weight reduction of -7.1 kg with a confidence interval crossing zero (95% CI -16.5 to 2.5), concluding cagrilintide conferred only modest metabolic benefits compared with semaglutide and CagriSema.

CagriSema (cagrilintide plus semaglutide)

Much of the strongest data concerns the combination. A review3 describes cagrilintide as a long-acting amylin receptor agonist with bodyweight- and glucose-lowering properties, combined with semaglutide (a GLP-1 receptor agonist), and explains that semaglutide increases insulin secretion while cagrilintide potentially enhances insulin sensitivity, so combining amylin and GLP-1 biology may provide complementary benefits over the monocomponents (12 echo this additive rationale).

  • A phase 3 trial randomizing 3,417 participants8 reported CagriSema (semaglutide 2.4 mg plus cagrilintide 2.4 mg) produced an estimated mean body weight change of -20.4% from baseline to week 68 versus -3.0% with placebo (difference -17.3 pp).
  • REIMAGINE 1, a phase 3a study in adults with type 2 diabetes (5,15-enrolled), reported cagrilintide-semaglutide 2.4 mg each produced an HbA1c change of -1.8 pp after 40 weeks versus -0.1 with placebo, with relative bodyweight change of -13.8% versus -1.4% with placebo.
  • A phase 3a trial in patients on basal insulin4 reported HbA1c reductions of 2.33% (2.4 mg each) and 2.10% (1.0 mg each) versus 0.66% with placebo at week 40, with bodyweight reductions of 10-12%.
  • A 68-week phase 3a trial of 1,206 patients7 reported -13.7% body weight change versus -3.4% with placebo, and 73.5% achieving HbA1c ≤6.5% versus 15.9% with placebo.
  • A review3 reports that in REDEFINE 2, cagrilintide 2.4 mg plus semaglutide 2.4 mg produced mean bodyweight reduction up to 15.7% and mean HbA1c reduction up to 2.1 pp after 68 weeks (this figure is cited within a review rather than a primary paper).
  • A phase 2 trial in type 2 diabetes16 reported CagriSema produced a mean HbA1c change of -2.2 pp, mean bodyweight change of -15.6%, and increased time in range from 45.9% to 88.9% at week 32.

A network meta-analysis of 76 trials and 39,246 participants15 reported CagriSema produced the highest weight loss versus placebo (mean difference -14.03 kg; 95% CI -17.05 to -11.00) with high confidence of evidence. Reviews10,11 describe early data suggesting CagriSema may lead to greater or comparable weight loss to tirzepatide (up to 22.5%); these comparisons are based on early/expected data rather than head-to-head trials.

Pharmacokinetics

A phase 1b RCT2 reported that cagrilintide exposure was proportional to dose and did not affect semaglutide exposure or elimination, that cagrilintide 0.16-4.5 mg had a half-life of 159-195 h with a median tmax of 24-72 h, and8 AUC0-168h ranging from 926 to 24,271 nmol×h/L with Cmax from 6.14 to 170 nmol/L. A review1 describes a plasma half-life of approximately 8 days (180 h) in humans.

What the research shows

172 findings extracted from the 25 sources cited below, strongest evidence first within each group. Every one links to the source it came from.

What human studies found

Based on 56 human trial findings, 1 human study finding and 4 expert opinion findings.

  • human trialCagrilintide and semaglutide 2.4 mg combination was studied in a randomised, placebo-controlled, phase 1b trial2

  • human trialStudy included 95 participants exposed to treatment (mean age 40.6 years, 59% men, 54% Black or African American)2

  • human trialSemaglutide has been shown to reduce the risk of cardiovascular events and chronic kidney disease events in large outcome studies in populations at high risk of these adverse outcomes with type 2 diabetes3

  • human trialSemaglutide has been shown to reduce liver fibrosis in people with metabolic dysfunction-associated steatohepatitis3

  • human trialIn REDEFINE 2, a combination of cagrilintide 2·4 mg plus semaglutide 2·4 mg as an adjunct to lifestyle intervention resulted in a mean bodyweight reduction of up to 15·7% and a mean HbA1c reduction of up to 2·1 percentage points after 68 weeks3

  • human trialCagrilintide-semaglutide (2.4 mg each) reduced HbA1c by 2.33% from baseline to week 404

  • human trialCagrilintide-semaglutide (1.0 mg each) reduced HbA1c by 2.10% from baseline to week 404

  • human trialPlacebo reduced HbA1c by 0.66% from baseline to week 404

Show 53 more findings

  • human trialEstimated treatment difference for cagrilintide-semaglutide (2.4 mg each) vs placebo was -1.68 percentage points (95% CI -1.95 to -1.41), p<0.00014

  • human trialEstimated treatment difference for cagrilintide-semaglutide (1.0 mg each) vs placebo was -1.44 percentage points (95% CI -1.71 to -1.17), p<0.00014

  • human trialCagrilintide-semaglutide provided bodyweight reductions of 10-12%4

  • human trialThe study enrolled 274 adults with type 2 diabetes with baseline mean HbA1c of 8.8%4

  • human trialREIMAGINE 1 was a randomised, double-blind, parallel-group, phase 3a study carried out at 42 sites in six countries5

  • human trialCagrilintide-semaglutide (2.4 mg each) produced estimated mean change in HbA1c of -1.8 percentage points after 40 weeks versus -0.1 percentage points with placebo5

  • human trialCagrilintide-semaglutide (1.0 mg each) produced estimated mean change in HbA1c of -1.5 percentage points after 40 weeks versus -0.1 percentage points with placebo5

  • human trialTreatment difference for cagrilintide-semaglutide (2.4 mg each) versus placebo was -1.7 percentage points (95% CI -2.0 to -1.3; p<0.0001) for HbA1c5

  • human trialTreatment difference for cagrilintide-semaglutide (1.0 mg each) versus placebo was -1.3 percentage points (95% CI -1.8 to -0.9; p<0.0001) for HbA1c5

  • human trialCagrilintide-semaglutide (2.4 mg each) produced relative bodyweight change of -13.8% versus -1.4% with placebo (estimated treatment difference -12.4 percentage points [95% CI -14.7 to -10.1]; p<0.0001)5

  • human trialCagrilintide-semaglutide (1.0 mg each) produced relative bodyweight change of -11.8% versus -1.4% with placebo (estimated treatment difference -10.4 percentage points [95% CI -12.9 to -8.0]; p<0.0001)5

  • human trial189 participants were enrolled and randomly assigned to cagrilintide-semaglutide (2.4 mg each; n=62), cagrilintide-semaglutide (1.0 mg each; n=63), or placebo (n=64)5

  • human trialStudy enrollment occurred between March 19 and December 5, 20245

  • human trialCagriSema produced the greatest HbA1c reduction versus placebo (MD, -1.5%; 95% CI, -2.4 to -0.7)6

  • human trialCagrilintide produced HbA1c reduction versus placebo (MD, -0.1%; 95% CI, -1.4 to 1.0)6

  • human trialCagrilintide achieved body weight reduction of -7.1 kg (95% CI, -16.5 to 2.5)6

  • human trialCagriSema achieved body weight reduction of -13.2 kg (95% CI, -20.2 to -6.0)6

  • human trialCagrilintide conferred only modest metabolic benefits compared to Semaglutide and CagriSema6

  • human trialCagrilintide and semaglutide have each been shown to induce weight loss as monotherapies7

  • human trialOnce-weekly cagrilintide-semaglutide (2.4 mg each) resulted in estimated mean body weight change of -13.7% from baseline to week 687

  • human trialPlacebo group showed estimated mean body weight change of -3.4% from baseline to week 687

  • human trialEstimated difference in weight change between cagrilintide-semaglutide and placebo was -10.4 percentage points (95% CI, -11.2 to -9.5; P<0.001)7

  • human trialMore patients in cagrilintide-semaglutide group achieved weight reduction of 5% or more compared to placebo (P<0.001)7

  • human trialPercentage of patients with glycated hemoglobin level of 6.5% or less was 73.5% in cagrilintide-semaglutide group and 15.9% in placebo group7

  • human trialCagrilintide at a dose of 2.4 mg has shown promising results in early-phase trials8

  • human trialThe combination of semaglutide at 2.4 mg and cagrilintide at 2.4 mg (CagriSema) produced an estimated mean percent change in body weight of -20.4% from baseline to week 688

  • human trialCagrilintide-semaglutide produced a body weight reduction of 17.3 percentage points more than placebo (-3.0%)8

  • human trialParticipants receiving cagrilintide-semaglutide were more likely than placebo to reach weight-loss targets of 5% or more, 20% or more, 25% or more, and 30% or more8

  • human trialCagrilintide-semaglutide provided significant and clinically relevant body-weight reductions in adults with overweight or obesity, as compared with placebo8

  • human trialCompleted phase 2 trials on incretin-based therapies (which would include cagrilintide as an amylin agonist component) showed a mean percent weight loss of 7.4% to 24.2%9

  • human trialEarly data for cagrisema suggests it may lead to greater weight loss than tirzepatide11

  • human trialCagrilintide has achieved adequate weight loss, reaching even more than 10% of the total weight in early clinical trials12

  • human trialClinical trials have confirmed the effectiveness of cagrilintide in comparison with glucagon-like peptide 1 receptor agonists12

  • human trialCagrilintide alone, as well as cagrilintide in combination with semaglutide have shown promising weight loss in clinical trials14

  • human trialCagriSema (semaglutide with cagrilintide) resulted in the highest weight loss compared to placebo in GLP-1RA treatments for type 2 diabetes15

  • human trialCombining the GLP-1 receptor agonist semaglutide with the long-acting amylin analogue cagrilintide has weight-loss benefits16

  • human trialCagriSema resulted in mean HbA change of -2.2 percentage points from baseline to week 3216

  • human trialCagriSema resulted in mean bodyweight change of -15.6% from baseline to week 3216

  • human trialCagriSema resulted in mean fasting plasma glucose change of -3.3 mmol/L from baseline to week 3216

  • human trialTime in range (3.9-10.0 mmol/L) increased from 45.9% at baseline to 88.9% at week 32 with CagriSema16

  • human trialPrior to this study, cagrilintide was shown to promote weight loss in a dose-dependent manner in preclinical studies and one clinical trial17

  • human trialCagrilintide led to clinically significant, dose-dependent weight loss that was greater with cagrilintide at all doses versus placebo17

  • human trialCagrilintide at 4.5 mg showed greater weight loss versus liraglutide 3.0 mg17

  • human trialMean percentage weight reductions from baseline with cagrilintide 0.3-4.5 mg were 6.0%-10.8% (6.4-11.5 kg) versus placebo 3.0% (3.3 kg)17

  • human trialCagrilintide 4.5 mg produced greater weight loss than liraglutide 3.0 mg (10.8% [11.5 kg] vs 9.0% [9.6 kg])17

  • human trialAll doses of cagrilintide (0.3-4.5 mg) produced significantly greater weight reductions versus placebo (estimated treatment difference range 3.0%-7.8%; p<0.001)17

  • human trialCagrilintide is currently in clinical trial with obesity as an indication19

  • human trialCagrilintide has induced significant weight loss when dosed alone or in combination with semaglutide19

  • human studyCagrisema combination is expected to achieve weight loss in the same range as tirzepatide (up to 22.5%)10

  • expert opinionEarly research suggests cagrilintide may amplify the effects of semaglutide when the two are combined in a treatment called CagriSema21

  • expert opinionCagrilintide showed meaningful weight loss in Phase 2 clinical trials22

  • expert opinionWhen paired with semaglutide, cagrilintide produced results that neither drug could achieve alone in a combination known as CagriSema22

  • expert opinionAmylin-based agents enhance satiety and glycemic outcomes23

How it works

Based on 9 human trial findings, 6 in vitro findings, 21 expert opinion findings and 3 theoretical findings.

  • human trialCagrilintide is a long-acting amylin receptor agonist with established bodyweight-lowering and glucose-lowering properties3

  • human trialSemaglutide increases insulin secretion and cagrilintide potentially enhances insulin sensitivity3

  • human trialThe combination of cagrilintide and semaglutide might provide additional treatment benefits compared with the monocomponents, with the targeting of both amylin and GLP-1 biology providing complementary effects3

  • human trialCagrilintide-semaglutide is a novel, once-weekly combination of the amylin receptor agonist cagrilintide and the GLP-1 receptor agonist semaglutide5

  • human trialCagrilintide is a long-acting amylin analogue6

  • human trialCagrilintide is a long-lasting synthetic amylin analog12

  • human trialAmylin, released with insulin from beta cells in the pancreas, induces its satiating effect via both the homoeostatic and hedonic regions of the brain14

  • human trialSemaglutide, a GLP-1 receptor agonist, reduces appetite via GLP-1 receptors in the hypothalamus and increases the production of insulin, and reduces glucagon secretion, delaying gastric emptying14

Show 31 more findings

  • human trialThe separate, but related mechanisms of action of an amylin-analog and a GLP-1 receptor agonist appear to have an additive effect on appetite reduction14

  • in vitroIn healthy myotubes, cagrilintide transiently reduced basal respiration by 21%-28% at 48 h (p < 0.05)20

  • in vitroIn healthy myotubes, cagrilintide reduced ATP production by 24%-31% at 48 h (p < 0.01)20

  • in vitroIn healthy myotubes, cagrilintide reduced Complexes I, III and IV protein expression at 48 h, which resolved by 5 days20

  • in vitroIn palmitic acid-treated myotubes, cagrilintide acutely worsened mitochondrial impairment with ATP production reduction by approximately 20%-25% at 48 h (p < 0.01)20

  • in vitroIn palmitic acid-treated myotubes, cagrilintide's mitochondrial impairment effects resolved by Day 520

  • in vitroIn human myotubes, cagrilintide caused transient reduction in respiration by 30%-62% at 48 h (p < 0.05)20

  • expert opinionCagrilintide is a long-acting amylin receptor agonist1

  • expert opinionAmylin is a major regulatory hormone for satiation and food intake perception in humans12

  • expert opinionCagrilintide is a novel long-acting amylin analogue that has the potential to be used for weight management due to its new mechanism of action17

  • expert opinionNatural amylin is a pancreatic hormone that induces satiety17

  • expert opinionCagrilintide is a long-acting amylin analogue17

  • expert opinionCagrilintide is a synthetic medication designed to mimic amylin, a hormone made by the pancreas that is released alongside insulin after meals to help signal fullness21

  • expert opinionCagrilintide works by activating amylin receptors in the brainstem21

  • expert opinionGLP-1 drugs work by activating GLP-1 receptors, mainly in the pancreas, brain, and gut21

  • expert opinionCagrilintide suppresses appetite through a separate signaling route than GLP-1s21

  • expert opinionCagrilintide is thought to slow gastric emptying (the movement of food out of the stomach)21

  • expert opinionCagrilintide is thought to suppress the release of glucagon after eating to reduce blood glucose levels21

  • expert opinionCagrilintide is thought to activate centers in the brain associated with appetite and reward to reduce how much you eat21

  • expert opinionCagrilintide works through the amylin receptor pathway, which is completely different from GLP-1 receptor agonists that target hormones released from the gut22

  • expert opinionAmylin (islet amyloid polypeptide, IAPP) is a 37-amino acid peptide hormone co-secreted by pancreatic beta cells alongside insulin in response to meals22

  • expert opinionNatural amylin slows gastric emptying, which helps moderate post-meal blood glucose rise22

  • expert opinionNatural amylin suppresses glucagon release, the hormone that signals the liver to release glucose22

  • expert opinionAmylin binds to receptors in the area postrema and brainstem to generate satiety signals22

  • expert opinionCagrilintide binds to amylin and calcitonin receptors22

  • expert opinionCagriSema (cagrilintide + semaglutide) enhances satiety and glycemic outcomes through complementary actions23

  • expert opinionAmylin is a neuroendocrine anorexigenic polypeptide hormone, which is co-secreted with insulin from β-cells of the pancreas in response to food consumption24

  • expert opinionAmylin inhibits homeostatic and hedonic feeding, induces satiety, and decreases body weight24

  • theoreticalAmylin has high propensity toward formation of amyloid fibrils19

  • theoreticalCagrilintide is a stable, lipidated long-acting amylin analogue19

  • theoreticalCagrilintide is a long-acting amylin analogue19

Dosing

Based on 5 human trial findings.

  • human trialSemaglutide is a GLP-1 receptor agonist approved as a once-weekly subcutaneous treatment for type 2 diabetes at a dose of up to 2·0 mg and for weight management at a dose of up to 7·2 mg3

  • human trialCagrilintide-semaglutide was administered once per week as a subcutaneous injection4

  • human trialCagriSema was administered as once-weekly subcutaneous injection escalated to 2.4 mg16

  • human trialCagrilintide was administered as once-weekly subcutaneous self-injections17

  • human trialTreatment period was 26 weeks including a dose-escalation period of up to 6 weeks17

How the body handles it

Based on 7 human trial findings, 2 human study findings and 2 expert opinion findings.

  • human trialExposure was proportional to cagrilintide dose and did not affect semaglutide exposure or elimination2

  • human trialCagrilintide 0.16−4.5 mg had a half-life of 159–195 h2

  • human trialCagrilintide had a median tmax of 24–72 h2

  • human trialSemaglutide 2.4 mg had a half-life of 145–165 h2

  • human trialSemaglutide 2.4 mg had a median tmax of 12–24 h2

  • human trialAUC0–168 h ranged from 926 nmol × h/L to 24,271 nmol × h/L with cagrilintide 0.16–4.5 mg2

  • human trialCmax ranged from 6.14 nmol/L to 170 nmol/L with cagrilintide 0.16–4.5 mg2

  • human studyplasma half-life of approximately 8 days (180 h) in humans1

Show 3 more findings

  • human studyPramlintide requires three daily injections due to its short half-life19

  • expert opinionNatural amylin has a short half-life and degrades rapidly in the bloodstream22

  • expert opinionThrough chemical modifications, cagrilintide was created with a half-life of approximately seven days for once-weekly dosing22

Safety and side effects

Based on 30 human trial findings and 4 expert opinion findings.

  • human trialOf 566 adverse events reported in 92 participants, 207 (37%) were gastrointestinal disorders2

  • human trialMost adverse events were mild to moderate in severity and the proportion of participants with one or more adverse event was similar across treatment groups2

  • human trialAdverse events were reported by 80% of participants receiving cagrilintide-semaglutide (2.4 mg each)4

  • human trialAdverse events were reported by 71% of participants receiving cagrilintide-semaglutide (1.0 mg each)4

  • human trialAdverse events were reported by 71% of participants receiving placebo4

  • human trialAdverse events were mostly mild or moderate gastrointestinal disorders4

  • human trialNo severe hypoglycaemia was reported in the study4

  • human trialOne death occurred in the cagrilintide-semaglutide (1.0 mg each) group, not related to treatment (due to malignancy)4

Show 26 more findings

  • human trialAdverse events were reported by 49 (79%) of 62 participants in the cagrilintide-semaglutide (2.4 mg each) group5

  • human trialNo significant differences were observed among Semaglutide, Cagrilintide, and CagriSema in terms of serious adverse events6

  • human trialNo significant differences were observed among treatments in terms of treatment discontinuation6

  • human trialGastrointestinal symptoms were more frequent with CagriSema (OR, 5.5; 95% CI, 3.1 to 13.0) compared with placebo6

  • human trialGastrointestinal adverse events were reported by 72.5% of patients in cagrilintide-semaglutide group and 34.4% in placebo group, most of which were transient and mild or moderate in severity7

  • human trialGastrointestinal adverse events affected 79.6% in the cagrilintide-semaglutide group and 39.9% in the placebo group8

  • human trialGastrointestinal adverse events including nausea, vomiting, diarrhea, constipation, or abdominal pain were mainly transient and mild-to-moderate in severity8

  • human trialAdverse gastrointestinal effects, particularly nausea, were more frequent with cagrilintide compared with pramlintide12

  • human trialCagrilintide does not result in clinically relevant prolongation of cardiac repolarization compared with placebo13

  • human trialCagrilintide did not result in clinically relevant QTcF prolongation13

  • human trialCagrilintide indicates no increased risk of ventricular tachyarrhythmias13

  • human trialGLP-1RAs induce gastrointestinal adverse events, with safety concerns especially warranted for high dose administration15

  • human trialAdverse events were reported by 68% of participants in the CagriSema group16

  • human trialMild or moderate gastrointestinal adverse events were most common16

  • human trialNo level 2 or 3 hypoglycaemia was reported with CagriSema16

  • human trialNo fatal adverse events were reported with CagriSema16

  • human trialTreatment with cagrilintide was well tolerated at all tested doses with an acceptable safety profile17

  • human trialThe most frequent adverse events were gastrointestinal disorders (nausea, constipation, and diarrhoea) and administration-site reactions17

  • human trial41%-63% of participants receiving cagrilintide 0.3-4.5 mg had gastrointestinal adverse events compared with 32% with placebo17

  • human trialNausea occurred in 20%-47% with cagrilintide versus 18% with placebo17

  • human trialPermanent treatment discontinuation occurred in 10% overall, mostly due to adverse events (4%)17

  • human trialCagrilintide can be safely administered concomitantly with semaglutide 2.4 mg18

  • expert opinionCagrilintide is not yet FDA approved21

  • expert opinionCagrilintide is still just a research peptide sold by gray-market retailers who are circumventing regulations21

  • expert opinionOn its own, cagrilintide might lead to less uncomfortable side effects like nausea or constipation, but more research is needed21

  • expert opinionCagrilintide and CagriSema are investigational treatments currently undergoing regulatory review and are not yet approved for use in the UK, EU, or USA22

What people use it for

Based on 10 human trial findings, 3 human study findings and 5 expert opinion findings.

  • human trialCagrilintide is a long-acting amylin analogue being investigated for weight management2

  • human trialREIMAGINE 1 study compared the effect of cagrilintide–semaglutide (2·4 mg each) and a combination of cagrilintide 1·0 mg plus semaglutide 1·0 mg in adults with type 2 diabetes inadequately controlled on diet and exercise3

  • human trialStudy participants were receiving stable once per day basal insulin with or without metformin4

  • human trialAdults aged 18 years or older with type 2 diabetes inadequately controlled with diet and exercise were randomly assigned to receive once-weekly subcutaneous cagrilintide-semaglutide5

  • human trialStudy duration was 68 weeks in a phase 3a double-blind randomized placebo-controlled trial7

  • human trialCagriSema is a GLP-1 RA/amylin agonist combination undergoing phase 3 trials for weight loss in adults with overweight/obesity9

  • human trialCagrilintide is a GLP-1/amylin receptor agonist (cagrisema) that has progressed to phase 3 trials as an obesity treatment11

  • human trialCagrilintide is being developed for the treatment of obesity and type 2 diabetes13

Show 10 more findings

  • human trialCagrilintide is an amylin-analog being developed in combination with the GLP-1 agonist semaglutide to achieve sustained weight loss in persons with overweight and obesity14

  • human trialThe trial evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of cagrilintide with semaglutide 2.4 mg for weight management18

  • human studyCagrilintide is a component of Cagrisema (cagrilintide 2.4mg plus semaglutide 2.4mg)10

  • human studyCagrilintide is used as part of a dual combination with semaglutide10

  • human studyPramlintide is commercially available for diabetes treatment as adjunct to insulin therapy19

  • expert opinionAmylin analogs are emerging as promising anti-obesity agents in non-DM subjects12

  • expert opinionCagrilintide aims to reduce appetite, boost fullness, and regulate blood sugar21

  • expert opinionCagrilintide is a long-acting analogue of amylin developed by Novo Nordisk designed to be administered once weekly via subcutaneous injection for obesity and overweight treatment22

  • expert opinionPramlintide (Symlin) is an existing amylin analogue that requires multiple daily injections for diabetes management22

  • expert opinionCagrilintide is an amylin analog with applications in diabetology, endocrinology, and metabolism disorders such as obesity24

Other findings

Based on 2 human trial findings, 1 in vitro finding and 1 theoretical finding.

  • human trialCagriSema is a combination of semaglutide with cagrilintide15

  • human trialThis was a randomised, controlled, phase 1b trial18

  • in vitroCagrilintide is an amylin analogue20

  • theoreticalCagrilintide was developed by Novo Nordisk researchers19

Points of contention

Where the evidence is unsettled, thin, or says less than the popular claim — worth knowing before you draw conclusions.

Contested

Cagrilintide alone shows modest glycemic and weight benefit, while the CagriSema combination is much stronger

The JCQ meta-analysis (Comparative Efficacy and Safety of Semaglutide, Cagrilintide, and CagriSema for the Treatment of Type 2 Diabetes Mellitus: A Bayesian Network Meta-Analysis) reported cagrilintide alone produced only a non-significant HbA1c reduction (MD -0.1%; 95% CI -1.4 to 1.0) and body weight reduction of -7.1 kg with a wide confidence interval crossing zero (95% CI -16.5 to 2.5), concluding cagrilintide conferred only modest metabolic benefits, whereas CagriSema achieved -13.2 kg. Weight-loss monotherapy trials (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, 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.) nonetheless reported significant dose-dependent weight loss for cagrilintide alone.

Limited evidence

In vitro data show cagrilintide transiently impairs muscle mitochondrial function

A tier-2 in vitro study (Mitochondrial Adaptations in Skeletal Muscle Following Incretin-Based Therapies: In Vitro.) found cagrilintide reduced myotube respiration, ATP production and respiratory complex expression at 48 h, worsening effects in palmitic acid-treated cells; effects resolved by 5 days. Clinical relevance is unestablished and this is a single cell-based study.

Single source

Comparison of CagriSema to tirzepatide is based on early/expected data only

Claims that CagriSema may produce greater or comparable weight loss to tirzepatide (up to 22.5%) come from reviews describing early data and expectations (What is the pipeline for future medications for obesity?, Weight management treatment in obesity.), not head-to-head trials.

Other

Cagrilintide is investigational and not approved; some sources are non-clinical web material

Consumer and pharmacy web sources (Cagrilintide Peptide for Weight Loss: What to Know, Cagrilintide: What It Is, How It Works & Weight Loss Benefits, tier 3) state cagrilintide/CagriSema are not yet approved in the UK, EU or USA and describe gray-market sale of cagrilintide as a research peptide. Mechanistic 'thought to' statements in these sources are expert opinion rather than trial findings.

Limited evidence

Some pivotal outcome figures are reported via reviews rather than the primary papers

REDEFINE 2 results (15.7% weight loss, 2.1 pp HbA1c over 68 weeks) are cited within a review (Efficacy and safety of once-weekly cagrilintide–semaglutide (CagriSema) in adults with type 2 diabetes inadequately controlled on diet and exercise (REIMAGINE 1): a randomised, double-blind, placebo-controlled, phase 3a study - ScienceDirect); the phase 2 incretin weight-loss range of 7.4%-24.2% (Emerging pharmacotherapies for obesity: A systematic review.) pools multiple incretin therapies, not cagrilintide alone.

Safety and side effects

Safety and tolerability

Across trials, the most consistently reported adverse events are gastrointestinal.

  • The phase 2 monotherapy trial5,17 reported cagrilintide was well tolerated at all tested doses with an acceptable safety profile, but the most frequent adverse events were gastrointestinal disorders (nausea, constipation, diarrhoea) and administration-site reactions; 41-63% of cagrilintide participants had gastrointestinal adverse events versus 32% with placebo, nausea occurred in 20-47% versus 18% placebo, and permanent treatment discontinuation was 10% overall (mostly due to adverse events, 4%).
  • The phase 1b combination trial2 reported that of 566 adverse events in 92 participants, 207 (37%) were gastrointestinal disorders, with most events mild to moderate and a similar proportion of participants affected across treatment groups.
  • REIMAGINE 111 reported adverse events in 49 (79%) of 62 participants in the cagrilintide-semaglutide 2.4 mg each group.
  • The basal-insulin phase 3a trial17 reported adverse events in 80% (2.4 mg each), 71% (1.0 mg each) and 71% (placebo), mostly mild or moderate gastrointestinal disorders, with no severe hypoglycaemia and one death in the 1.0 mg each group deemed unrelated to treatment (malignancy).
  • The large phase 3 CagriSema trial reported gastrointestinal adverse events in 79.6% of the combination group versus 39.9% of placebo (nausea, vomiting, diarrhea, constipation or abdominal pain), mainly transient and mild-to-moderate. The 68-week phase 3a trial reported gastrointestinal adverse events in 72.5% versus 34.4% with placebo. A phase 2 diabetes trial reported adverse events in 68% of the CagriSema group with no level 2 or 3 hypoglycaemia and no fatal adverse events.
  • The meta-analysis6 reported no significant differences among semaglutide, cagrilintide and CagriSema for serious adverse events or treatment discontinuation, but gastrointestinal symptoms were more frequent with CagriSema versus placebo (OR 5.5; 95% CI 3.1 to 13.0). A network meta-analysis15 noted GLP-1RAs induce gastrointestinal adverse events with safety concerns especially at high doses.
  • A study12 reported that adverse gastrointestinal effects, particularly nausea, were more frequent with cagrilintide compared with pramlintide.

Cardiac safety

A thorough QT trial with 105 participants13, using 4.5 mg once-weekly cagrilintide with a 400-mg oral moxifloxacin positive control, reported no clinically relevant QTcF prolongation, with upper limits of two-sided 90% CIs below 10 ms at all timepoints (12, 24, 48, 72 hours), indicating no increased risk of ventricular tachyarrhythmias.

Preliminary/limited-evidence signals

A tier-2 in vitro study20 found that cagrilintide transiently impaired mitochondrial function in healthy human myotubes (reduced respiration, ATP production and respiratory complex expression at 48 h) and worsened impairment in palmitic acid-treated cells; these effects resolved by 5 days. Clinical relevance is unestablished and this is a single cell-based study.

Regulatory status

Consumer and pharmacy web material21,22 note cagrilintide is not yet FDA approved, is still a research peptide sold by gray-market retailers circumventing regulations, and that cagrilintide and CagriSema are investigational treatments undergoing regulatory review, not yet approved in the UK, EU or USA. The consumer material21 suggests cagrilintide on its own might cause fewer side effects such as nausea or constipation, though it states more research is needed — this is expert opinion rather than a trial finding.

Reconstitution and handling

Dosing

No dose has been established for this compound. Cagrilintide is investigational and has no regulatory approval in the UK, EU or USA22, so the figures below are what clinical trials and other sources report — not guidance.

Doses used in clinical trials

  • Cagrilintide monotherapy: the 26-week phase 2 trial17 used once-weekly subcutaneous self-injections at 0.3, 0.6, 1.2, 2.4 or 4.5 mg, with up to a 6-week dose-escalation period.
  • The phase 1b pharmacokinetic study2,18 evaluated doses of 0.16, 0.30, 0.60, 1.2, 2.4 and 4.5 mg.
  • The thorough QT trial13 used 4.5 mg once-weekly subcutaneous cagrilintide.
  • As CagriSema, a Tier 1 phase 3 trial8 used cagrilintide 2.4 mg plus semaglutide 2.4 mg once weekly; the Tier 1 REIMAGINE 1 and basal-insulin phase 3a trials4,5 also studied a 1.0 mg each dose. Tier 1 CagriSema trials4,5,8 describe escalation to the 2.4 mg target dose.

Administration

All trials describe once-weekly subcutaneous injection17,22. Pharmacy material22 describes cagrilintide as engineered with a half-life of approximately seven days to enable once-weekly dosing. The phase 1b trial2 reported cagrilintide can be administered concomitantly with semaglutide 2.4 mg without affecting semaglutide exposure or elimination.

Context

For reference, sources note that pramlintide (Symlin), an existing amylin analogue, requires multiple daily injections due to its short half-life19,22; cagrilintide's lipidation and extended half-life are what enable weekly dosing. No trial has tested any protocol for use of gray-market research-peptide material, and reconstitution details for such material are not established in the provided sources.

Sources

Ordered by evidence quality — the strongest first.

  1. Cagrilintide is not associated with clinically relevant QTc ...(opens in a new tab)
    Tier 1Web · dom-pubs.onlinelibrary.wiley.com
  2. Safety, tolerability, pharmacokinetics, and ...(opens in a new tab)
    Tier 1Web · sciencedirect.com
  3. Efficacy and safety of once-weekly cagrilintide–semaglutide (CagriSema) in adults with type 2 diabetes inadequately controlled on diet and exercise (REIMAGINE 1): a randomised, double-blind, placebo-controlled, phase 3a study - ScienceDirect(opens in a new tab)
    Tier 1Web · sciencedirect.com · 2026
  4. Cagrilintide-semaglutide (CagriSema) as an add-on to basal insulin in adults with type 2 diabetes (REIMAGINE 3): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study(opens in a new tab)
    Tier 1Web · pubmed.ncbi.nlm.nih.gov · 2026
  5. Efficacy and safety of once-weekly cagrilintide-semaglutide (CagriSema) in adults with type 2 diabetes inadequately controlled on diet and exercise (REIMAGINE 1): a randomised, double-blind, placebo-controlled, phase 3a study - PubMed(opens in a new tab)
    Tier 1Web · pubmed.ncbi.nlm.nih.gov · 2026
  6. Comparative Efficacy and Safety of Semaglutide, Cagrilintide, and CagriSema for the Treatment of Type 2 Diabetes Mellitus: A Bayesian Network Meta-Analysis(opens in a new tab)
    Tier 1Web · doi.org · 2025
  7. Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2025
  8. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2025
  9. Emerging pharmacotherapies for obesity: A systematic review.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2025
  10. Weight management treatment in obesity.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2025
  11. What is the pipeline for future medications for obesity?(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2025
  12. Amylin analogs for the treatment of obesity without diabetes: present and future.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2024
  13. Cagrilintide is not associated with clinically relevant QTc prolongation: A thorough QT study in healthy participants.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2024
  14. Cagrilintide: A Long-Acting Amylin Analog for the Treatment of Obesity.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2024
  15. Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2024
  16. 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.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2023
  17. 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(opens in a new tab)
    Tier 1Web · doi.org · 2021
  18. a randomised, controlled, phase 1b trial(opens in a new tab)
    Tier 1Web · pubmed.ncbi.nlm.nih.gov · 2021
  19. Development of Cagrilintide, a Long-Acting Amylin Analogue.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2021
  20. Mitochondrial Adaptations in Skeletal Muscle Following Incretin-Based Therapies: In Vitro.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2026
  21. Cagrilintide Peptide for Weight Loss: What to Know(opens in a new tab)
    Tier 3Web · joinmidi.com
  22. Cagrilintide: What It Is, How It Works & Weight Loss Benefits(opens in a new tab)
    Tier 3Web · thecarepharmacy.com
  23. Novel GLP-1-based Medications for Type 2 Diabetes and Obesity.(opens in a new tab)
    Tier 3PubMed · pubmed.ncbi.nlm.nih.gov · 2026
  24. Amylin, Another Important Neuroendocrine Hormone for the Treatment of Diabesity.(opens in a new tab)
    Tier 3PubMed · pubmed.ncbi.nlm.nih.gov · 2024
  25. Original Article(opens in a new tab)
    Tier 4Web · sciencehub.novonordisk.com