Cagrilintide Peptide: Mechanism, Research, and Benefits

Understanding Cagrilintide Peptide

Cagrilintide is a long-acting amylin analog, which means that it imitates the effects of the natural hormone amylin, which is involved in the regulation of blood sugar levels, hunger, and fullness.  Both on its own and in conjunction with semaglutide, which is a GLP-1 (glucagon-like peptide-1) receptor agonist, it is now being developed as a treatment for obesity and type 2 diabetes. This means that it is being developed as a treatment for both conditions. Cagrilintide influences appetite regions in the brain, reducing cravings and making it simpler to make smart dietary choices. Stabilizes Blood Sugar Levels: By functioning in combination with insulin, it helps smooth out blood sugar fluctuations, reducing the risk of insulin resistance.

Mechanism of Action of Cagrilintide Peptide

In Alzheimer's disease, neuronal damage is caused by an intracellular process, and it is hypothesized that this mechanism is analogous to that process. The aggregatory character of this protein was a crucial consideration that needed to be taken into account when creating an amylin analog. Numerous alterations were made to the structure of amylin in order to get around this feature. Through the presence of 14E and 17R mutations, the amylin-analog Cagrilintide is able to generate a salt bridge, which in turn helps to stabilize the structure of the central helix. It incorporates mutations of 25P, 28P, and 29P, which have the effect of reducing the protein's tendency to form fibrils and β-sheets. Additionally, the incorporation of a C-terminal proline enhances the protein's ability to bind to the CTR channel.  It is important to note that the potency of Cagrilintide has not changed in comparison to amylin as a result of these alterations. 

Extending the half-life of an amylin-analog medicine in comparison to the first-generation treatment, Pramlintide, which is administered through injection three times per day, was the second obstacle that needed to be overcome.  

In the process of developing the GLP-1 (glucagon-like peptide 1)  receptor agonist Semaglutide, the technique that was utilized to increase the drug's half-life was to promote both covalent and non-covalent binding of Semaglutide to albumin. This was accomplished by adding a fatty acid attachment to Semaglutide.  

This effective method, which enabled Semaglutide to be administered once every week among individuals struggling to check its efficacy and safety, was also utilized in the process of developing Cagrilintide by the pharmaceutical company.  When compared to the medicine of the first generation, Pramlintide, the half-life of Cagrilintide is extended as a result of the incorporation of an N-terminal C20 fatty acid.  

In clinical trials, the half-life of Cagrilintide ranged from 159 to 195 hours (0.16–4.5 mg), and the elimination half-life ranged from 7 to 8 days. This indicates that Cagrilintide is suitable for once-weekly doses to be administered for good overall health. 

Research Evidence

Participants in the trial comparing Cagrilintide with Liraglutide included 706 individuals who were at least 18 years old, did not have diabetes or metabolic disorder, and had a body mass index of at least 30 kg/m2 or at least 27 kg/m2 with either hypertension or dyslipidemia.  Subjects were randomly assigned to receive either once-weekly Cagrilintide, once-daily Liraglutide, or a volume-matched placebo through subcutaneous self-injections. 

The ratio of the randomization was 6:1.  Five different doses of Cagrilintide (0.3, 0.6, 1.2, 2.4, or 4.5 mg) were compared to a single dose of Liraglutide (3.0 mg) or a volume-matched placebo for each of the six placebo groups.  The trial consisted of a treatment period that lasted for a total of 26 weeks, which included a dose-escalation period that lasted for six weeks, as well as a follow-up period that lasted for six weeks without any therapy.  

In light of the fact that AOMs are recommended in conjunction with lifestyle interventions, all of the participants were provided with dietary and physical activity counseling with the objective of achieving a deficit of 500 calories per day and 150 minutes of continuous physical activity per week.  Measurement of the percentage change in body weight from the beginning of the study to the completion of the 26th week was the major objective of the study.  

Following the completion of the 26-week treatment period, the average percentage of weight loss from the beginning of the study was higher with all doses of Cagrilintide (0.3–4.5 mg, 6.0%–10.8%) compared to the placebo (3.0%).  In addition, although the placebo group saw a plateau in weight loss in the 18th week, the weight loss that occurred with Cagrilintide remained throughout the whole duration of the study, which reached 26 weeks.  

The reductions in weight were also substantially bigger with Cagrilintide 4.5 mg as opposed to Liraglutide 3.0 mg, with the former achieving a weight loss of 10.8% and the latter achieving 9.0% (P = 0.03).  When compared to lifestyle management alone, our findings demonstrate that the weight loss advantages of Cagrilintide (4.5 mg) and Liraglutide (3 mg) are clinically superior.  In addition, metabolic health with the decrease in triglycerides and very-low-density cholesterol produced by Cagrilintide 2.4 and 4.5 mg was considerably greater than that produced by the pooled placebo, and they were comparable to that produced by Liraglutide 3.0 mg.   

A certain amount of weight was regained in the 32nd week, following the termination of treatment in the 26th week.  At week 32, the average weight loss with Cagrilintide 0.3–4.5 mg varied from -5.0% to 9.8%, which was significantly lower than the range of -6.1% to 10.8% that was observed at week 26.  Overall, the results of this trial demonstrated that Cagrilintide at doses ranging from 0.3 to 4.5 milligrams for a period of 26 weeks resulted in a dose-dependent and clinically significant reduction in weight in people who were struggling with obesity or overweight.

Research Application

Novo Nordisk is developing a new investigational medication called CagriSema, which is the combination of Cagrilintide and Semaglutide, to help people lose weight and treat type 2 diabetes. During the course of a clinical trial, the administration of CagriSema to individuals with type 2 diabetes led to improvements in glycemic control that were clinically significant (including clinical glucose monitoring metrics). In comparison to cagrilintide, the mean change in HbA1c with CagriSema was significantly higher; however, this was not the case with semaglutide.  CagriSema treatment resulted in much more weight loss compared to semaglutide and cagrilintide, and it was well tolerated by the patient's hormone secretion. The findings point to the necessity of doing phase 3 studies that are both longer and more extensive in order to investigate CagriSema in this community.

Research is still being done on phase 2 trials to determine how safe and effective it is for patients with type 2 diabetes and obesity. Cagrilintide, a long-acting amylin analog, and Semaglutide, a well-known GLP-1 receptor agonist, are the two drugs that makeup CagriSema.  These drugs may have synergistic effects on blood sugar regulation and weight loss since they operate through various bodily pathways. 

Research is being done on CagriSema as a possible therapy for type 2 diabetes and obesity.  

A research study to determine whether CagriSema can reduce kidney damage in individuals with type 2 diabetes (T2D), chronic kidney disease (CKD), and obesity or overweight. An investigation of the extent to which CagriSema reduces blood sugar and body weight in individuals with type 2 diabetes.  An investigation into the effects of CagriSema in comparison to a placebo in patients with painful diabetic peripheral neuropathy and type 2 diabetes. 

Weight Management: CagriSema's ability to help people with type 2 diabetes and obesity lose a substantial amount of weight is being studied.   At 57 locations across ten countries (Canada, Denmark, Finland, Ireland, Japan, Poland, Serbia, South Africa, the United Kingdom, and the United States of America), a group of researchers carried out a multicenter, randomised, double-blind, placebo-controlled, and active-controlled, dose-finding phase 2 trial. The trial was designed to determine the optimal dosage of the drug.    

The treatment phase of the experiment lasted for a total of 26 weeks, which included a dose-escalation phase that lasted for up to six weeks, and a follow-up phase that lasted for six weeks without any medication.  Regarding the allocated study treatment, both participants and investigators were masked with regard to the active treatment as opposed to the pooled placebo treatment; however, they were not masked with regard to the various active treatments.   

Treatment with cagrilintide resulted in considerable decreases in body weight in individuals who were overweight or obese, and the medication was well tolerated by these individuals. 

These discoveries provide credence to the idea of developing compounds that possess novel mechanisms of action for the purpose of weight management.  

Cardiovascular Outcomes: Studies are being conducted to determine how CagriSema affects cardiovascular events in people who have type 2 diabetes and/or obesity.  The potential of CagriSema to reduce kidney damage in individuals with type 2 diabetes (T2D), chronic kidney disease (CKD), and overweight or obesity is being studied.  

Research Design and Findings:  Numerous studies that compare CagriSema to a placebo or other active treatments are set up as randomized, double-blind, active-controlled trials.  Changes in body weight, cardiovascular events, and HbA1c (a marker of blood sugar management) are frequently the main results.  According to certain research, CagriSema significantly reduces body weight when compared to placebo or alternative therapies.

Future Application

Both on its own and in conjunction with the GLP-1 receptor analog Semaglutide, Cagrilintide has been demonstrated to be safe and well tolerated by patients using it.  With more weight reduction than any other currently licensed AOM, the complementary MOAs of amylin-analog and GLP-1 receptor agonists promise to be a promising combination therapy. As a result, they have the potential to further close the gap with the outcomes of bariatric surgery.  There are now two clinical trials that are being conducted to provide evidence that this prospective combination medication could be useful in the treatment of individuals who are overweight or obese.

References

1. https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.1c00565

2. https://journals.lww.com/cardiologyinreview/fulltext/2024/01000/cagrilintide__a_long_acting_amylin_analog_for_the.13.aspx

3. Enebo LB, Berthelsen KK, Kankam M, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial. Lancet. 2021;397:1736–1748.

4. Gadde KM, Martin CK, Berthoud HR, et al. Obesity: pathophysiology and management. J Am Coll Cardiol. 2018;71:69–84.

5. Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial Frias, Juan P et al. The Lancet, Volume 402, Issue 10403, 720 - 730

6. Once-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 Lau, David C W et al. The Lancet, Volume 398, Issue 10317, 2160 - 2172