New Weight Loss Combo

A combined pharmacological therapy, cagrilintide and semaglutide, showed efficacy in bodyweight reduction without lifestyle changes.

Weight management is essential in reducing risk factors of many chronic diseases, such as cardiovascular disease, obesity, type 2 diabetes, asthma, sleep apnea, etc. Weight reduction of at least 5% of current weight, or even >10%, is highly recommended in managing dangerous chronic diseases mentioned above. Many studies have been conducted to ascertain effective and safe pharmaceutical products supporting weight loss. Recently, Dr. Lone B. Enebo and his colleagues published their discovery about a drug combination that can contribute to weight management: cagrilintide and semaglutide 2.4mg. 

Cagrilintide (international non-proprietary name: NNC0174-0833) is a long-acting amylin analog undergoing clinical trials, investigated for weight management. This medication possesses non-selective agonistic effects on native amylin and calcitonin receptors. Native amylin is secreted simultaneously with insulin by the pancreas to defer gastric emptying and interrupt glucagon release after food intake. This hormone can also reduce energy intake, regulate appetite, induce satiety and satiation. The weight loss effect of semaglutide is widely known and has been proved by multiple studies. Semaglutide has been demonstrated to reduce appetite, induce satiety, and improve control of eating behaviors and food choices, consequentially tapering off ad libitum energy intake. Thanks to those mechanisms of action, cagrilintide and semaglutide hypothetically can significantly impact weight loss if used as a combined therapy. Dr. Enebo and his colleagues conducted a randomized, placebo-controlled study. This research focused on analyzing the effectiveness in weight loss, safety, tolerability, pharmacokinetics, and pharmacodynamics of cagrilintide and semaglutide combined therapy.  

Ninety-five participants took part in treatment trials and were included in the final statistical analysis. Inclusion criteria were mainly 18-55 years of age, women of non-childbearing potential, men on appropriate contraception, BMI 27-39.9kg/m², otherwise healthy. Exclusion criteria focused on individuals of 40 or older who had 10-year ASCVD risk > 5%. The research team randomized qualified participants to multiple arms, including six sequential overlapping cohorts and placebos. Treatment cohorts took multiple-ascending doses of once-weekly subcutaneous cagrilintide (0.16mg, 0.3mg, 0.6mg, 1.2mg, 2.4mg, 4.5mg) in combination with once-weekly subcutaneous semaglutide 2.4mg. Placebo participants injected once-weekly subcutaneous cagrilintide without active ingredient with only excipients combined and semaglutide 2.4mg. Participants were directed to continue their usual daily routines and lifestyles in eating behavior, physical activity, work, and sleeping pattern during the entire study. Within 20 weeks of the treatment period, there were 16 weeks of dose co-escalation period, four weeks of the treatment period at target doses, and five weeks follow-up period. 

The primary endpoint was adverse events that emerged from the trials from week 0 (at baseline) to the end of week 25 (follow-up period). Secondary endpoints focused on pharmacokinetic parameters of the two drugs: area under the plasma concentration-time curve from 0-168 h (AUC0–168 h) and maximum concentration (Cmax) both measured at steady state. The exploratory endpoint was bodyweight reduction. 

After 20 weeks of trial, the result showed that participants taking cagrilintide 1.2mg and 2.4mg achieved greater percentage weight loss than participants taking placebo. Higher cagrilintide doses induce continuous and greater bodyweight reductions compared with lower doses. Participants who took cagrilintide 1.2 mg with semaglutide 2.4mg reduced average 6% body weight [95% CI −9.9 to −2.0]. Individuals who took cagrilintide 2.4 mg with semaglutide 2.4mg lost average 7.4% body weight [95% CI -11.2 to -3.5]. Cagrilintide 4.5mg with semaglutide 2.4mg helped reduce 7.4% bodyweight [95% CI -12.8 to -2.1]. 

Reported adverse events included gastrointestinal disorders, nausea, vomiting, dyspepsia, etc. Cagrilintide was frequently reported to cause decreased appetite. Cagrilintide doses >1.2 mg with semaglutide 2.4 mg also were noted to cause early satiety. Cagrilintide doses did not interfere with semaglutide serum concentration and elimination. Plasma clearance and volume of distribution of the two drugs were congruent among trial cohorts. 

The findings from this study contribute another promising pharmacological option for weight management that may not require bariatric surgery. The combined therapy of cagrilintide and semaglutide 2.4 mg showed positive effects on body weight reduction with an acceptable safety profile. The study design of randomized, placebo blinded increases the internal validity of study results. Dividing trials into cohorts trying multiple-ascending doses of cagrilintide provides a complete overview of weight loss efficacy. This study also had a few limitations. Endogenous amylin was initially listed as an exploratory pharmacodynamic endpoint. However, the research team was not able to acquire suitable assays and could not analyze endogenous amylin. There were a few deviations between baseline and the end of week 20 in clinical laboratory tests, vital signs, ECG, physical examinations, but were not fully addressed. Before this combined therapy is applied widely, more trials should be done in larger population sizes and longer times to assess the therapy’s efficacy and safety. 

Practice Pearls: 

• The combined therapy of cagrilintide and semaglutide 2·4 mg showed positive effects on body weight reduction with an acceptable safety profile. 
• This combined therapy is a promising pharmacological option for weight management without bariatric surgery. 
• More trials are needed to fully assess the therapy’s efficacy and safety before being widely introduced to the public. 

Enebo, Lone B, et al. “Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Concomitant Administration of Multiple Does of Cagnlintide with Semaglultide for Wt. Management.       ” The Lancet,  22 Apr. 2021,  

Thi Vietthi Huynh, 2022 PharmD Candidate, Lake Erie College of Osteopathic Medicine – School of Pharmacy.