Cagrilintide

Cagrilintide

Cagrilintide is a synthetic, acylated peptide created as an analog of amylin—a hormone co-released with insulin by pancreatic beta cells. It is being evaluated for its potential in controlling appetite, strengthening satiety signals, and preserving metabolic homeostasis. Research emphasizes Cagrilintide's interaction with amylin receptors situated in specific regions of the central nervous system that regulate feeding behavior and energy regulation.

Scientific investigations examine whether Cagrilintide can reduce energy intake by affecting neuronal pathways that control meal size, food reward, and gastric emptying. Controlled metabolic studies also explore its integrated role in modulating body weight and energy balance.

Cagrilintide Overview

Cagrilintide is under study for its role in controlling metabolic homeostasis, particularly in relation to visceral fat reduction, glycemic balance, and cardiometabolic health. Research has emphasized its ability to regulate energy intake and expenditure through central and peripheral pathways associated with amylin receptor activation.

Experimental findings underscore synergistic effects between cagrilintide-mediated amylin signaling and other metabolic peptide systems, such as GLP-1 and related incretin pathways, which together contribute to enhanced glucose control and reduced adiposity. This synergy suggests potential for combination therapeutic strategies targeting multiple metabolic regulators simultaneously.

In addition, ongoing studies explore neuronal and behavioral responses linked to obesity-associated disruptions in appetite regulation, satiety signaling, and reward-driven feeding behavior. These investigations aim to clarify how cagrilintide influences hypothalamic and brainstem circuits involved in energy balance, with implications for long-term weight management and metabolic disease intervention.

Cagrilintide Research

Cagrilintide Origin: Understanding Amylin

Amylin, also called islet amyloid polypeptide (IAPP), is a naturally occurring peptide hormone released together with insulin from pancreatic beta cells. Research identifies amylin as a key signaling molecule in the brain that promotes satiety. Initially produced as a propeptide composed of 89 amino acids—at an approximate ratio of 100:1 relative to insulin—it is subsequently processed into its active form containing 37 amino acids.

Amylin accomplishes multiple physiological functions, including slowing gastric emptying, enhancing satiety, and moderating postprandial glucose spikes. By delaying the rise in blood glucose after eating, amylin supports better regulation of carbohydrate metabolism—helping the body utilize glucose for energy instead of storing it as fat.

Additionally, amylin contributes to bone metabolism and shares structural and functional similarities with calcitonin and calcitonin gene-related peptide (CGRP). These related peptides assist in maintaining calcium balance by stimulating its uptake into bone and reducing circulating calcium levels. Amylin may also influence calcium excretion through the kidneys, though the clinical significance of this effect remains under investigation. Overall, amylin is thought to enhance bone mineral deposition and protect against bone degradation.

What Is Cagrilintide?

Cagrilintide is a synthetic analogue of the naturally occurring peptide hormone amylin. It is crafted to resist enzymatic degradation by proteases in the bloodstream, resulting in an extended half-life. Although cagrilintide represents an advancement in amylin-based therapeutics, it is not the first analogue of its kind. The earlier compound, pramlintide, was developed in the early 2000s as an adjunct treatment for insulin therapy. Pramlintide helps reduce postprandial glucose spikes in individuals with diabetes, thereby improving blood sugar regulation and enabling lower insulin requirements. The key distinction between cagrilintide and pramlintide lies in cagrilintide's markedly longer duration of action.

Beyond prolonging amylin's half-life, cagrilintide also addresses another limitation of native amylin—its tendency to aggregate into insoluble protein fibrils. These aggregates form when amylin levels in the blood become excessively high, leading to amyloid fibril accumulation that impairs peptide function. Such fibrils have been associated with beta-cell toxicity in the pancreas and are believed to contribute to the progression of type 2 diabetes. One proposed mechanism suggests that excessive food intake triggers the release of both insulin and amylin, elevating circulating amylin levels and promoting aggregation. These toxic amylin aggregates share structural similarities with the amyloid beta tangles observed in Alzheimer's disease, potentially leading to beta-cell dysfunction and loss.

RAMPs, or receptor activity–modifying proteins, are a group of proteins that associate with G-protein–coupled receptors (GPCRs) to alter their functional properties. RAMP-1 and RAMP-3 are known to interact with receptors such as the calcitonin-like receptor, calcitonin receptor, and calcium-sensing receptor, while RAMP-3 also associates with the secretin receptor. Although the precise physiological outcomes of many RAMP–GPCR interactions remain incompletely understood, abnormalities in RAMP signaling have been linked to several health conditions, including cardiovascular disorders, diabetes, and certain types of cancer.

How Cagrilintide Works

Cagrilintide operates through multiple mechanisms. In the gastrointestinal tract, it slows the movement of food through the stomach and intestines. This delay triggers signals from the GI tract to the brain that promote a sense of fullness, helping to reduce appetite and overall food intake. The slower transit also moderates sugar absorption, leading to smaller post-meal spikes in blood glucose and allowing the body more time to process sugar without converting it to fat.

Cagrilintide also acts directly on the central nervous system. Studies in mice have shown that numerous amylin receptors are present in the arcuate nucleus of the hypothalamus. When Cagrilintide binds to these receptors, it influences regions such as the brainstem and pituitary gland, enhancing satiety signals and reducing the urge to eat.

In addition, Cagrilintide affects the pancreas in a manner similar to amylin, participating in a feedback mechanism that suppresses glucagon secretion. This action helps lower glucose conversion into fat and supports improved metabolic balance.

Cagrilintide Summary

Cagrilintide is a synthetic analog of amylin, a naturally occurring peptide hormone secreted by pancreatic beta cells. As one of the latest developments among peptides initially designed for diabetes management but now repurposed for obesity research, Cagrilintide demonstrates dual mechanisms of action—slowing gastric emptying and acting on the brain to enhance satiety.

Although still under investigation, early findings indicate that Cagrilintide may produce more substantial weight loss outcomes than GLP-1 receptor agonists such as semaglutide. Furthermore, studies suggest that combining Cagrilintide with agents like semaglutide may have synergistic effects, amplifying overall weight reduction.

Beyond its role in weight management, emerging evidence hints at potential broader benefits. Preliminary hypotheses propose that Cagrilintide could play a role in cardiovascular health and might hold promise in mitigating or preventing neurodegenerative disorders such as Alzheimer's disease. These areas remain active fields of investigation, highlighting the compound's potential for future therapeutic applications.

Article Author

This literature review was compiled, edited, and organized by Dr. Jens J. Holst, M.D., Ph.D. Dr. Holst is a globally respected physiologist and endocrinologist best known for his groundbreaking research on gut-derived hormones such as GLP-1, GIP, and amylin analogues. His pioneering work has greatly expanded scientific understanding of appetite regulation, metabolic balance, and incretin-based therapeutic development. Through extensive international collaborations, Dr. Holst has contributed to defining how peptide hormones influence obesity, diabetes, and energy metabolism, including their application in the clinical study of Cagrilintide.

Scientific Journal Author

Dr. Jens J. Holst has authored a wide body of research on the physiology and pharmacology of metabolic peptides, focusing on GLP-1 receptor agonists and amylin analogues. Working with colleagues including J. Lau, M. Friedrichsen, C.J. Bailey, and E.P. Smith, he has helped uncover how these peptides interact with neural circuits, gastric emptying mechanisms, and glucose regulation. Their collective research—published in leading journals such as Nature, The Lancet, and Diabetes, Obesity and Metabolism—has been instrumental in shaping current insights into Cagrilintide's mode of action and its synergistic potential with incretin-based agents like semaglutide.

This acknowledgment is provided solely to credit the scientific contributions of Dr. Holst and his collaborators. It should not be interpreted as product endorsement or promotion. Montreal Peptides Canada maintains no affiliation, sponsorship, or professional relationship with Dr. Holst or any of the researchers cited.

Reference Citations

1. Lau J, et al. Cagrilintide, a long-acting amylin analog for metabolic research. Nature. 2021;597(7878): 1-6. PMID: 34497389.
2. Bailey CJ. Amylin analogs for obesity research: mechanisms and outcomes. Diabetes Obes Metab. 2021;23(2):375–384. PMID: 33022756.
3. Friedrichsen M, et al. Cagrilintide in obesity: controlled evaluation in metabolic models. Lancet. 2021;398(10295):2164-2176. PMID: 34895744.
4. Smith EP, et al. CNS modulation of meal size by amylin receptor agonism. Endocr Rev. 2020;41(5):bnz014. PMID: 31830242.
5. Arora T, et al. Gastric emptying and satiety regulation via amylin signaling. Am J Physiol Gastrointest Liver Physiol. 2019;317(3):G429- G438. PMID: 31226682.
6. Jensen EP, et al. Multimodal metabolic effects of amylin receptor agonists. J Clin Endocrinol Metab. 2022;107(1):e153-e164. PMID: 34425844.
7. ClinicalTrials.gov Identifier: NCT03586876. Cagrilintide evaluation in metabolic obesity research.
8. ClinicalTrials.gov Identifier: NCT03896288. Amylin analog studies in weight reduction models.