Cagrilintide is a long-acting amylin receptor agonist that lowers body weight and controls hyperglycemia through various actions. In a phase 2 trial of obese subjects, cagrilintide used in different subcutaneous doses once weekly was associated with a mean weight loss of 6-10.8% after 26 weeks, compared with 9.0% with the glucagon-like 1 receptor (GLP-1R) liraglutide (3 mg/d) and 3% with placebo at 26 weeks. In another phase 2 trial of obese patients with type 2 diabetes, the combination of cagrilintide 2.4 mg/week and the GLP-1R semaglutide 2.4 mg/week (referred to as CagriSema) was compared with each drug alone. At 32 weeks, reduction in glycated hemoglobin (HbA1c) levels with CagriSema (2.2%) was statistically superior to Cagrinlitide (0.9%), but not statistically greater than semaglutide (1.8%). Meanwhile, weight loss with CagriSema (15.6%) was statistically greater than both cagrilintide (8.1%) and semaglutide (5.1%). Higher proportions of patients (58%) randomized to CagriSema reported gastrointestinal (GI) adverse effects compared with those who received cagrinlitide (33%) and semaglutide (32%). In addition, level 1 hypoglycemia (blood glucose 55-69 mg/dl) occurred more frequently with CagriSema (7%) and cagrilintide (6%) versus 0% with semaglutide. In conclusion, reduction in obese patients with type 2 diabetes, preliminary data suggest that the combination of cagrilintide and semaglutide may exert a synergistic effect on weight loss but less than additive effect of HbA1c levels. This combination was associated with higher rates of GI adverse effects and mild hypoglycemia. Phase 3 clinical trials are urgently needed to clarify the efficacy and safety of this new approach for treatment of obesity and type 2 diabetes. 

Amylin is a 37 amino acid pancreatic hormone co-secreted with insulin from β-cells following meals [1]. This hormone exerts several actions that result in glycemic control including slowing of gastric emptying and suppression of postprandial glucagon release [1]. In addition, amylin may lower body weight by decreasing appetite and increasing satiety [2]. Pre-clinical data suggests that amylin may affect hedonic aspects in eating control and reduce the rewarding value of food [2]. The latter effects are mediated through receptors in the central nervous system such as the caudal hindbrain area postrema and the hypothalamic arcuate [2]. Moreover, while obesity is characterized by resistance to leptin, amylin may improve body responsiveness to leptin [3]. The first available amylin agonist was pramlintide, which is already approved for treatment of type 1 and type 2 diabetes in conjunction with insulin [4]. Yet, pramlintide has a short half-life (20-45 min) and therefore must be injected subcutaneously 3 times daily before meals. Furthermore, pramlintide causes only modest mean weight loss of 1.6 kg and HbA1c reduction of 0.34% compared with placebo [4]. Cagrilintide is a long-acting acylated agonist of amylin receptor [1]. The half-life of cagrilintide is 159-195 hours (approximately 6.6 to 8.1 days) making it suitable for once weekly subcutaneous administration [5]. Semaglutide is a GLP-1R agonist approved for treatment of type 2 diabetes (in doses 0.5-2.0 mg once weekly) and obesity (2.4 mg once weekly) [6,7]. The anti-diabetic actions of semaglutide include stimulation of insulin secretion, inhibition of glucagon secretion after meals and delay of gastric emptying [8]. Its anti-obesity effects are related to decrease appetite and induction of early satiety [8]. Despite some overlap in actions exists between cagrilintide and semaglutide, the combination of the 2 agonists was investigated to enhance their efficacy. Thus, preliminary data from a phase 1b trial showed that use of cagrilintide and semaglutide in obese subjects resulted in greater weight loss than semaglutide alone, 17% versus 10

after 20 weeks [5]. Subsequently, cagrilintide was evaluated as monotherapy for treatment of obesity in a phase 2 trial and in combination with semaglutide for treatment of obese patients with type 2 diabetes in another phase 2 trial [9,10]. Table 1 depicts the overview of these 2 trials. The main purpose of this article is to review efficacy and safety of cagrilintide with special emphasis on its combination with semaglutide. 

Cagrilintide monotherapy for treatment of obesity

In a 26-week phase 2 trial (n=706, 62% women, mean age 52 years), cagrilintide was evaluated in 5 groups of subjects receiving 0.3, 0.6, 1.2, 2.4, and 4.5 mg/week as treatment for obesity in comparison with liraglutide 3.0 mg/day, and placebo (table 1) [9]. The study was conducted in 57 sites from 10 countries. It was double-blinded, randomized, and placebo-controlled [9]. Subjects with diabetes were excluded. Baseline body weight and body mass index (BMI) were 10.7.4 kg and 37.8% kg/m2, respectively [9]. All participants received dietary and exercise counselling aiming at 500-kcal deficit per day. At 26 weeks, mean percentage reductions in weight (the primary outcome) were 6.0% to 10.8% in the cagrilintide groups compared with 9.0% in the liraglutide group, and 3.0% with placebo [9].  Compared with placebo, weight loss achieved with all doses of cagrilintide was statistically significant, estimated difference range was 3.0% to 7.8% (P<0>

Cagrilintide combined with semaglutide (CagriSema) for treatment of type 2 diabetes

In a recent small phase 2 trial (n=92), 3 groups of patients with type 2 diabetes were randomized to receive cagrilintide co-administered with semaglutide (the authors called this combination CagriSema), cagrilintide or semaglutide, both in doses escalated to 2.4 mg once weekly (table 1) [10]. The 2 drugs were injected subcutaneously in the same time in 2 separate sites in the abdomen. Patients were also obese with mean weight of 105.7 kg and BMI of 35.5 kg/m2 (table 1) [10]. Background diabetes therapy included metformin and sodium-glucose transporter-2 inhibitor (SGLT2i) in 73% and 27% of patients, respectively [10]. At 32 weeks, the mean change in HbA1c levels from baseline (the primary endpoint) was -2.2%, -1.8%, and -0.9% with CagriSema, semaglutide, and cagrilintide, respectively (table 1) [10]. Estimated difference in HbA1c reduction between CagriSema and cagrilintide was statistically significant: -1.3% (95% CI, -1.7 to -0.8; p< 0 p=0.075)>.

The author has no conflicts of interests to declare.