Amylin analogue reduces body weight in individuals with overweight and obesity

One-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

Literature - Lau DCW, Erichsen L, Francisco AM et al., - The Lancet 2021, S0140-6736(21)01751-7. doi: 10.1016/S0140-6736(21)01751-7

Introduction and methods


There are only few approved pharmacotherapies for weight management in individuals with overweight or obesity, and weight loss with these agents ranges from 3-9% relative to placebo at 1 year [1,2]. The STEP trial program showed that the GLP-1 receptor agonist semaglutide resulted in significant weight loss [3-5], but there is room for novel agents given the heterogeneity of obesity and the differential response to treatments.

Amylin is hormone produced in the β cells of the pancreas and secreted together with insulin in response to food intake. It creates a satiety signal, resulting in slowing gastric emptying and suppressing the post-prandial glucagon response. Cagrilintide is a long-acting, acylated amylin analogue and has shown to reduce food intake and bodyweight [6-8].

This study examined the effect of ascending doses of cagrilintide on bodyweight, safety and tolerability in participants with overweight or obesity. Also, changes in waist circumference and cardiometabolic parameters with cagrilintide were compared with placebo and the GLP-1RA liraglutide.

Study design

A multicenter, randomized, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial was conducted. The trial had a 26-week treatment period, including a dose-escalation period of up to 6 weeks, and a 6-week follow-up without treatment. Adult of non-childbearing potential with a BMI of ≥30 kg/m2, or ≥27 kg/m2 with hypertension or dyslipidemia were eligible. Individuals with diabetes were excluded. 706 Participants were randomized to subcutaneous injections of one-weekly cagrilintide (0.3, 0.6, 1.2, 2.4, or 4.5 mg), once-weekly liraglutide or volume-matched placebo. All participants were counselled on diet and physical activity.


Primary endpoint was the percentage change in bodyweight from baseline to week 26.

Main results

  • Bodyweight decreased progressively in all groups and did not reach a plateau by week 26.
  • At week 26, mean weight reductions were greater with all doses of cagrilintide (6.0-10.8% [6.4-11.5 kg]) compared with the pooled placebo (3.0%, [3.3 kg]) (estimated treatment difference range -3.0% to -7.8%, P<0.001).
  • Weight reductions with cagrilintide were dose-dependent and the reduction was greater with cagrilintide 4.5 mg (10.8%, {11.5 kg]) than with liraglutide 3.0 mg (9.0%, [9.6 kg]) (estimated treatment difference: -1.8%, P=0.03).
  • Adherence was high (mean compliance scores ranges from 0.95 to 0.97 across treatment groups).
  • Number of individuals achieving a categorical weight loss ≥5% or 10% at week 26 is higher in cagrilintide >0.3 mg dose groups compared to placebo (P<0.001).
  • Waist circumference reductions with cagrilintide 1.2-4.5 mg were dose-dependent greater than the pooled placebo and similar to that with liraglutide.
  • No changes in HbA1c and fasting glucose concentrations with cagrilintide was observed.
  • Reductions in triglycerides and VLDL-c were greater with cagrilintide 2.4 and 4.5 mg vs. pooled placebo and similar to reductions with liraglutide.
  • TFEQ-R18 scores improved in all treatment groups, with greater improvements with cagrilintide vs. pooled placebo in cognitive restraint, emotional eating and uncontrolled eating.
  • Number of individuals with adverse events was numerically higher in cagrilintide groups than with placebo and similar to that with liraglutide. 2-6% Of participants in the cagrilintide groups discontinued treatment because of adverse events compared to 7% in the liraglutide group and 3% in the placebo group. Most common adverse events were gastrointestinal disorders and administration-site reactions. There were few serious adverse events with cagrilintide and these were not dependent on dose.


Use of the amylin analogue cagrilintide in doses ranging from 0.3-4.5 mg for 26 weeks in addition to lifestyle interventions resulted in dose-dependent weight loss in adults with overweight or obesity. It was well tolerated. The authors write: ‘Cagrilintide presents an opportunity to expand the range of existing pharmacotherapies for weight management. Moreover, cagrilintide could be explored in combination with other agents for a potential additive weight-loss effect.’


1. Khera R, Murad MH, Chandar AK, et al. Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA 2016; 315: 2424–34.

2. Bessesen DH, Van Gaal LF. Progress and challenges in anti-obesity pharmacotherapy. Lancet Diabetes Endocrinol 2018; 6: 237–48.

3. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021; 384: 989–1002.

4. Wadden TA, Bailey TS, Billings LK, et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity. The STEP 3 randomized clinical trial. JAMA 2021; 325: 1403–13.

5. Rubino D, Abrahamsson N, Davies M, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA 2021; 325: 1414–25.

6. Kruse T, Dahl K, Schäffer L, et al. Development of cagrilintide, a long-acting amylin analogue. J Med Chem 2021; 64: 11183–94.

7. Dahl K, Hansen JL, Skyggebjerg RB, et al. Preclinical weight loss efficacy of AM833 in animal models of obesity. Obesity Week virtual meeting; Nov 2–6, 2020 (poster 330).

8. Raun K, John LM, Clausen TR, Dahl K. AM833 and GLP-1 analogues have distinct effects on gastric emptying and glucose tolerance in rats. Obesity Week virtual meeting. Nov 2–6, 2020; (poster 029).

Find this article online at The Lancet

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