Cagrilintide Combined with Semaglutide: a new Approach for Treatment of Obesity and type 2 Diabetes

Review Article | DOI: https://doi.org/10.31579/2693-4779/154

Cagrilintide Combined with Semaglutide: a new Approach for Treatment of Obesity and type 2 Diabetes

  • Nasser Mikhail *

Endocrinology Division, Department of Medicine, Olive View-UCLA Medical Center, David-Geffen UCLA Medical School, CA, USA.

*Corresponding Author: Nasser Mikhail, Endocrinology Division, Department of Medicine, Olive View-UCLA Medical Center, David-Geffen UCLA Medical School, CA, USA.

Citation: Nasser Mikhail, (2023), Cagrilintide Combined with Semaglutide: à new Approach for Treatment of Obesity and type 2 Diabetes, Clinical Research and Clinical Trials, 8(3); DOI:10.31579/2693-4779/154

Copyright: © 2023, Nasser Mikhail. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: 05 August 2023 | Accepted: 30 September 2023 | Published: 23 December 2023

Keywords: cagrilintide; semaglutide; cagrisema; obesity; diabetes

Abstract

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. 

Summary

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)>


 

 

 Cagrilintide  [9]CagriSema [10]
DesignPhase 2, double-blind, randomized, placebo and active controlled (liraglutide), multinational (10 countries) Phase 2, double-blind, randomized, multicenter in the USA
Duration of follow-up26 weeks32 weeks
Subject number and groups 706 subjects without diabetes, 7 groups92 patients with type 2 diabetes, 3 groups
Subject characteristicsMean age 52, 62% women, 77% Whites, 13% AsiansMean age 58, 36% women, 78% Whites, 16% Blacks
Baseline weight, BMI107.4 kg, 37.8 kg/m2105.7 kg, 35.5 kg/m2
Baseline HbA1c 5.6%8.4%
InterventionCagrinlitide (0.3, 0.6, 1.2, 2.4, 4.5 mg/week), liraglutide 3.0 mg, placeboCagrinlitide 2.4 mg, semaglutide 2.4 mg, CagriSema 2.4 + 2.4 mg
Primary outcomePercentage in weight loss from baselineChange in HbA1c from baseline
Secondary outcomesProportions of subjects losing ≥5% and ≥10% of weight, FPG, CGM parameters, safetyChanges in weight, FPG, CGM parameters, safety
Effect on weight-6.0 to -10.8

Conflict of interest

The author has no conflicts of interests to declare.   

References

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