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

Gastrointestinal adverse events with cagrisema were more than with semaglutide or cagrilintide monotherapy, but serious adverse events and adverse events leading to discontinuation were minimal and similar between groups.

“Gastrointestinal AE with cagrisema were more than with semagutide or cagrilintide monotherapy, however the SAE and AE leading to medication discontinuation were minimal and similar between the groups [87, 90]”

The most frequently reported adverse events with cagrilintide 0.3-4.5 mg were gastrointestinal disorders, more common than in the placebo arm (41%-63% vs 32%), primarily nausea (20%-47% vs 18%).

“The most frequently reported adverse events with cagrilintide 0.3e4.5 mg were gastrointestinal disorders that were more common than in the M. Kokkorakis, M. Chakhtoura, C. Rhayem et al. Pharmacological Reviews 77 (2025) 100002 placebo arm (41%e63% vs 32%), primarily nausea (20%e47% vs 18%) (Appendix 3) (Lau et al, 2021).”

Monotherapy with cagrilintide, an amylin receptor agonist, produced a 10.6% weight loss at maximum titrated dose compared to placebo (2.8%) and liraglutide 3.0 mg (8.4%).

“Monotherapy with cagrilintide, an amylin receptor agonist produced a 10.6% weight loss at maximum titrated dose compared to placebo (2.8%) and liraglutide 3.0 mg (8.4%).58”

When co-administered with semaglutide (CagriSema), cagrilintide and semaglutide act synergistically to produce greater weight loss and improved glycemic control than either agent alone, without significantly increasing the incidence or severity of gastrointestinal adverse events.

“When co-administered with the GLP-1 receptor agonist semaglutide (CagriSema®), they act synergistically to produce greater weight loss and improved glycemic control than either agent alone, without significantly increasing the incidence or severity of gastrointestinal adverse events [72,73].”

In a phase 2 trial, cagrilintide produced mean weight reductions of -6.0% to -10.8% versus -3.0% with placebo.

“At the end of the study, the mean percentage weight reductions from baseline were greater with all doses of cagrilintide (0.3e4.5 mg, e6.0% to e10.8%) versus placebo (e3.0%; estimated treatment difference range 3.0%e7.8%;P < .001)(Fig. 4) (Lau et al, 2021).”

Cagrilintide is an amylin receptor agonist administered once weekly subcutaneously.

“Cagrilintide (once-weekly subcutaneous administration) is an amylin receptor agonist.150”

In a phase 2 trial, once weekly cagrilintide resulted in dose-dependent weight loss between 6 and 10.8% compared to 9% with liraglutide 3 mg and 3% with placebo.

“Cagrilintide is a newer long-acting amylin analogue - in a phase 2 trial, once weekly cagrilintide resulted in a dose-dependent WL between 6 and 10.8% compared to 9% with liraglutide 3 mg and 3% with placebo [87].”

Weight reductions were greater with cagrilintide 4.5 mg than with liraglutide 3.0 mg (−10.8% vs −9.0%; estimated treatment difference 1.8%, P = .03).

“Weight reductions were also greater with cagrilintide 4.5 mg versus liraglutide 3.0 mg (e10.8%vs e9.0%; estimated treatment difference 1.8%, P ¼ .03)(Lau et al, 2021).”

In a phase 2 trial of cagrilintide, mean percentage weight reductions from baseline were greater with all doses (0.3-4.5 mg, −6.0% to −10.8%) than with placebo (−3.0%; estimated treatment difference range 3.0%-7.8%; P < .001).

“At the end of the study, the mean percentage weight reductions from baseline were greater with all doses of cagrilintide (0.3e4.5 mg, e6.0% to e10.8%) versus placebo (e3.0%; estimated treatment difference range 3.0%e7.8%;P < .001)(Fig. 4) (Lau et al, 2021).”

The long-acting amylin analogue cagrilintide has recently been shown to reduce body weight by about 10% at doses of 2.4 mg and 4.5 mg injected subcutaneously once weekly during a 26-week study in overweight and obese individuals.

“A closely related long-acting amylin analogue, cagrilintide has recently been shown to reduce body weight by about 10% at doses of 2.4 mg and 4.5 mg injected subcutaneously once weekly during a 26-week study in overweight and obese individuals [41,42].”

In a phase 2 study, cagrilintide in doses 0.3 mg to 4.5 mg resulted in up to 10.8% WL in people with overweight/obesity without diabetes compared to 9% with liraglutide 3 mg and 3% WL with placebo.

“In a phase 2 study, cagrilintide in doses ranging from 0.3 mg to 4.5 mg resulted in up to 10.8% WL in people with overweight/obesity without diabetes compared to 9% with the GLP-1 RA liraglutide 3 mg and 3% WL with placebo [62].”

In a phase Ib trial, after 20 weeks, the group that received semaglutide 2.4 mg plus cagrilintide 2.4 mg weekly lost 17.1% weight, whereas the group that received semaglutide 2.4 mg monotherapy lost 9.8% weight.

“After 20 weeks, which included a 16-week dose titration, the group that received the combination of semaglutide 2.4 mg plus cagrilintide 2.4 mg weekly lost 17.1% weight, whereas the group that received monotherapy with semaglutide 2.4 mg weekly lost 9.8% weight (53).”

Gastrointestinal side effects and administration site reactions with cagrilintide were tolerable with slow dose titration.

“Gastrointestinal side effects and administration site reactions that were tolerable with slow dose titration, although fatigue appears to be a unique side effect of cagrilintide over GLP-1 receptor agonists [115].”

One phase 2 trial demonstrated that weekly injections of cagrilintide induced 10.8% weight loss over 26 weeks, compared with 9% with liraglutide and 3% with placebo, in participants with mean age 52.3 years and no upper age limit.

“One phase 2 trial demonstrated that weekly injections of cagrilintide induced 10.8% weight loss over 26 weeks, compared to 9% with liraglutide, and 3% with placebo (mean age 52.3 years, with no upper age limit).”

Fatigue appears to be a unique side effect of cagrilintide over GLP-1 receptor agonists.

“Gastrointestinal side effects and administration site reactions that were tolerable with slow dose titration, although fatigue appears to be a unique side effect of cagrilintide over GLP-1 receptor agonists [115].”