Cagrilintide Peptide: Mechanism and Research Findings

Cagrilintide is a long-acting amylin analog — a synthetic peptide designed to mimic amylin, a hormone involved in the regulation of blood glucose, hunger and satiety. Published research has examined it both on its own and in combination with semaglutide, a GLP-1 (glucagon-like peptide-1) receptor agonist. Studies have investigated its activity at appetite-related signalling pathways in the brain and its effect on glucose regulation alongside insulin.

The summary below describes findings reported in the published literature. Cagrilintide is supplied for laboratory research use only and is not approved for human or veterinary use. No conclusions can be drawn regarding safety or efficacy in humans.

Mechanism of Action of Cagrilintide Peptide

Native amylin has a strong tendency to aggregate into fibrils and β-sheets, and this aggregation behaviour has been compared in the literature to intracellular processes implicated in neuronal damage. That aggregatory character was a central design constraint in developing a stable amylin analog, and several structural alterations were made to address it.

The 14E and 17R substitutions allow cagrilintide to form a salt bridge, which helps stabilise the central helix. The 25P, 28P and 29P substitutions reduce the tendency to form fibrils and β-sheets, and a C-terminal proline improves binding at the calcitonin receptor (CTR) channel. Reported potency is comparable to native amylin following these alterations.

A second design constraint was half-life. The first-generation amylin analog pramlintide requires injection three times daily. In the development of semaglutide, half-life was extended by adding a fatty acid moiety that promotes covalent and non-covalent binding to albumin, allowing once-weekly administration in trial protocols. The same albumin-binding approach was applied to cagrilintide through an N-terminal C20 fatty acid.

In clinical studies, the reported half-life of cagrilintide ranged from 159 to 195 hours across the 0.16–4.5 mg dose range, with an elimination half-life of 7 to 8 days — consistent with the once-weekly dosing used in those trial protocols.

Research Evidence

A published trial comparing cagrilintide with liraglutide enrolled 706 participants aged 18 or over, without diabetes or metabolic disorder, with a body mass index of at least 30 kg/m², or at least 27 kg/m² with either hypertension or dyslipidemia. Participants were randomised 6:1 to once-weekly cagrilintide, once-daily liraglutide, or a volume-matched placebo, administered by subcutaneous self-injection.

Five cagrilintide doses (0.3, 0.6, 1.2, 2.4 and 4.5 mg) were compared against liraglutide 3.0 mg and a volume-matched placebo across six placebo groups. The treatment period ran 26 weeks, including a six-week dose-escalation phase, followed by a six-week off-treatment follow-up. As part of the trial protocol, all participants received dietary and physical activity counselling targeting a 500 kcal/day deficit and 150 minutes of physical activity per week. The primary endpoint was percentage change in body weight from baseline to week 26.

At week 26, mean percentage weight change from baseline was greater across all cagrilintide doses (0.3–4.5 mg: 6.0%–10.8%) than placebo (3.0%). The placebo group plateaued at week 18, while the reduction observed with cagrilintide continued across the full 26 weeks.

Reductions were also greater with cagrilintide 4.5 mg than liraglutide 3.0 mg (10.8% versus 9.0%, P = 0.03). The trial reported greater weight reduction with both cagrilintide 4.5 mg and liraglutide 3.0 mg than with lifestyle management alone. Reductions in triglycerides and very-low-density cholesterol with cagrilintide 2.4 mg and 4.5 mg were greater than pooled placebo and comparable to liraglutide 3.0 mg.

Some weight was regained by week 32, following cessation of treatment at week 26. Mean change at week 32 ranged from -5.0% to -9.8% across the 0.3–4.5 mg range, against -6.1% to -10.8% at week 26. The trial reported a dose-dependent reduction in body weight over 26 weeks in participants with obesity or overweight.

Research Application

CagriSema, an investigational combination of cagrilintide and semaglutide, has been evaluated in trials measuring body weight and glycaemic endpoints. In one clinical trial, administration of CagriSema to participants with type 2 diabetes was associated with improvements in glycemic control measures, including continuous glucose monitoring metrics. Mean change in HbA1c was greater with CagriSema than with cagrilintide alone, though not relative to semaglutide. The authors noted the need for longer and larger phase 3 studies in this population.

Because cagrilintide and semaglutide act through different pathways, the combination has been studied for potential additive effects on glucose regulation and body weight endpoints. CagriSema remains under investigation in type 2 diabetes and obesity research.

Registered studies in this area have examined: the effect of CagriSema on markers of kidney damage in participants with type 2 diabetes, chronic kidney disease and obesity or overweight; the extent to which CagriSema affects blood glucose and body weight endpoints in participants with type 2 diabetes; and CagriSema compared with placebo in participants with painful diabetic peripheral neuropathy and type 2 diabetes.

A multicentre, randomised, double-blind, placebo-controlled and active-controlled dose-finding phase 2 trial was conducted across 57 sites in ten countries (Canada, Denmark, Finland, Ireland, Japan, Poland, Serbia, South Africa, the United Kingdom and the United States) to identify optimal dosage. The treatment phase ran 26 weeks including a dose-escalation phase of up to six weeks, followed by a six-week off-treatment period. Participants and investigators were masked to active treatment versus pooled placebo, but not between the different active treatments.

Cardiovascular endpoints have also been studied, including the effect of CagriSema on cardiovascular events in participants with type 2 diabetes and/or obesity. Trials in this area are generally randomised, double-blind and active-controlled, with change in body weight, cardiovascular events and HbA1c as common primary endpoints.

Future Application

The complementary mechanisms of amylin analogs and GLP-1 receptor agonists have made this combination an active area of metabolic research, and published dose-finding data have prompted further study. Ongoing clinical trials are examining the combination in participants with overweight or obesity. These findings support continued investigation of compounds with novel mechanisms of action in metabolic research.

Research use statement. Cagrilintide and CagriSema are investigational compounds. The material supplied by Power Peptides is intended for laboratory research use only and is not approved by the U.S. Food and Drug Administration for human or veterinary use. It is not a drug, food or cosmetic, and must not be used in humans or animals.

References

1. https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.1c00565

2. https://journals.lww.com/cardiologyinreview/fulltext/2024/01000/cagrilintide__a_long_acting_amylin_analog_for_the.13.aspx

3. Enebo LB, Berthelsen KK, Kankam M, et al. 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;397:1736–1748.

4. Gadde KM, Martin CK, Berthoud HR, et al. Obesity: pathophysiology and management. J Am Coll Cardiol. 2018;71:69–84.

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 Frias, Juan P et al. The Lancet, Volume 402, Issue 10403, 720 - 730

6. 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, David C W et al. The Lancet, Volume 398, Issue 10317, 2160 - 2172