An Overlook of Cagrilintinide and Semaglutide as it Progresses Through Phase 3 Trials

Type 2 diabetes (T2D) affects around 11.6% of the American population and continues to be a popular focus for pharmaceutical companies.¹ For example, Novo Nordisk focuses on therapeutic areas such as diabetes, hemophilia, and obesity. Their product semaglutide (Ozempic; Wegovy) has become a well-known medication among the general public, mostly for its possibility to induce weight loss. Semaglutide is an anti-diabetic injectable medication that works as a glucagon-like peptide-1 (GLP-1) receptor agonist (RA).² This article dives into another medication, cagrilintide, which acts in conjunction with semaglutide.

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Cagrilintide is an amylin analog. Amylin is a peptide that is co-secreted from the pancreas with insulin and serves as a satiety signal. It works slightly differently from semaglutide since the glucagon-like peptide is released from the gut which serves to decrease gastric emptying and to prevent glucose spikes. CagriSema is a subcutaneous injectable combination of cagrilintide and semaglutide that is currently in phase 3 trials.

While GLP-1 RAs are effective for weight loss, recent findings show combination therapies may be effective as well. A systemic review comparing semaglutide to other GLP-1 RAs and to CagriSema revealed that the combination product allowed for more weight loss, with patients losing nearly 14 kg. Study findings also hinted at improved glycemic control, with patients dropping nearly 1.8% in HbA_1c at least 12 weeks post initiation.³ The observed adverse effects (AEs) were similar to those of other GLP-1 RAs, including gastrointestinal issues and diarrhea. The combination product had a slightly higher odds ratio at 6.60 compared wait semaglutide at 2.37 for diarrhea. Patients taking the newer medication may be more likely to experience diarrhea compared with those on semaglutide. The odds ratio in context of discontinuation for cagrilintide/semaglutide was lower than the comparable counterparts. Patients taking this may be less likely to discontinue it compared to those taking the alternative GLP-1 RAs.

Past phase 2 studies involved a comparison of the combination to its individual components, semaglutide and cagrilintide. The combination product allowed for a larger drop in HbA_1c, about 2.18% over 32 weeks in people with T2D.⁴ The weight among participants decreased by 15.6%, and semaglutide showed a reduction of 5.1%. Phase 3 trials are currently underway, with studies in larger populations and more varied patient characteristics. These trials will target primary outcomes like weight loss, T2D, and cardiovascular events over a time period of 4.5 years.⁵

According to investigators of the previous trials, CagriSema shows similar glucose control and improved weight loss compared to its individual components, cagrilintide and semaglutide. However, the expected gastrointestinal discomfort still remains, along with other possible AEs. Considering that many patients with T2D also present with metabolic comorbidities like obesity, this combination product can be a useful alternative. Further research involving effects on liver, thyroid, and renal function can also provide useful information prior to approval. Larger studies and phase 3 results may be insightful before using this new medication as a first-line treatment for treating T2D.

REFERENCES

1. Center for Disease Control and Prevention (15 May 2024). National Diabetes Statistics Report. https://www.cdc.gov/diabetes/php/data-research/index.html

2. Ozempic. Semaglutide [package insert]. Plainsboro, NJ: Novo Nordisk; 2017.

3. Yao H, Zhang A, Li D, et al. Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis. BMJ. 2024;384:e076410. Published 2024 Jan 29. doi:10.1136/bmj-2023-076410

4. Gogineni P, Melson E, Papamargaritis D, Davies M. Oral glucagon-like peptide-1 receptor agonists and combinations of entero-pancreatic hormones as treatments for adults with type 2 diabetes: where are we now?. Expert Opin Pharmacother. 2024;25(7):801-818. doi:10.1080/14656566.2024.2356254

5. A Research Study to See the Effects of CagriSema in People Living With Diseases in the Heart and Blood Vessels (REDEFINE 3). Identifier: NCT05669755. Updated 19 September 2024. https://clinicaltrials.gov/study/NCT05669755