Cagrilintide

Cagrilintide is a long-acting analogue of amylin, a naturally occurring peptide that is released in conjunction with insulin. Cagrilintide has shown promise in animal trials as a treatment for obesity and type 2 diabetes. It has been studied for benefits not just in type 2 diabetes, but for liver damage, alcohol-related liver disease, and heart/blood vessel disease. There is some speculation about the role of this peptide in Alzheimer’s disease as well, but no research has been published in that particular sub-domain, yet. Many trials, however, have looked at the combination of cagrilintide and semaglutide in the treatment of obesity and type 2 diabetes. The two proteins appear to work synergistically to provide more robust and more permanent weight loss effects.

Sequence: XKCNTATCATQRLAEFLRHSSNNFGPILPPTNVGSNTP
Molecular Formula: C₁₉₄H₃₁₂N₅₄O₅₉S_2.xC₂H₄O₂
Molecular Weight: 4409.01 g/mol
PubChem SID: 171397054
CAS Number: 1415456-99-3
Synonyms: AT42613, AM833[1]

Cagrilintide Origin: What Is Amylin?

Amylin (also called islet amyloid polypeptide or IAPP) is a natural peptide that is released along with insulin from beta cells in the pancreas. Research shows that it is an important signaling molecule in the brain where it produces feelings of satiety. Amylin is released as a propeptide that is 89 amino acids in length at a ratio of about 100:1 to insulin. Like insulin, amylin is processed to produce a smaller active molecule that is just 37 amino acids in length.

Amylin has several effects including slowing gastric emptying, promoting feelings of satiety in the brain, and preventing spikes in glucose levels following food consumption. Amylin basically slows down the rise in blood sugar levels following eating. This helps to control the utilization of sugar and allows it to be more readily processed into an energy source rather than being converted to fat.

Amylin has also been shown to act on bone metabolism and has both structural and functional relationships with calcitonin and CGRP. All these peptides help to reduce levels of calcium in the blood by stimulating its uptake in bone. It may also affect the rate of calcium loss in the kidneys, though to what degree this is significant is currently unclear[2]. In short, amylin can be thought of as increasing the deposition rates of bone or as protecting bone against degradation.

In animal trials where the amylin gene is silenced, the result is a reduction of appetite and lower calorie intake. Amylin is degraded by the same enzymes that degrade insulin[3]. Cagrilintide, however, is designed to be resistant to these enzymes, giving it a longer half-life and thus more potent and long-lived effects.

Though theoretical at this point, it is worth pointing out that amylin has been linked to the amyloid beta plaques observed in Alzheimer’s disease. The long and short of it is that too much amylin occurs in conjunctions with insulin resistance and diabetes. Because amylin is self-dimerizing, too much of it leads to fibril formation. It is thought that the interaction of these fibrils with beta amyloid in the brain may be the reason that amyloid plaques develop, though a causal link remains elusive.

What Is Cagrilintide?

Cagrilintide is a synthetic analogue of the naturally occurring protein amylin. It is designed to be resistant to degradation by proteases in the blood and thus has a longer half-life. Cagrilintide is not the first amylin analogue to be developed. That distinction belongs to pramlintide, which was developed in the early years of the 21st century. Pramlintide was established as an adjuvant to insulin treatment, allowing for the use of less insulin in controlling blood sugar. Essentially, it reduces the glucose spike that many diabetics face after eating and therefore leads to improved blood sugar control. The main factor that sets cagrilintide apart from pramlintide is its significantly longer half-life.

Extending amylin’s half-life is not the only benefit that cagrilintide provides. The synthetic peptide also prevents a common problem of amylin which is protein aggregation. Aggregation of amylin occurs when the peptide is present at extremely elevated levels in the bloodstream and renders the protein useless. Amyloid fibrils have been linked to toxic effects on beta cells in the pancreas and are thought to contribute to the development of type 2 diabetes. The hypothesis is that excess food consumption leads to increased release of both insulin and amylin. This, in turn, leads to levels of amylin that are too high, and this leads to aggregation. The toxic amylin tangles, not all that different from the amyloid beta tangles observed in Alzheimer’s disease then cause beta cell death in the pancreas and thus the inability of the organ to produce enough insulin[4].

Cagrilintide is really a marvel of modern design, having been developed in such a way as to minimize the sort-comings of natural amylin. Amylin is perfectly suited for what it does when released by the pancreas but is woefully unsuitable for exogenous administration. To overcome the tendency of amylin to form fibrils, scientists added proline residues to the C-terminal end of amylin. An amide residue added to the same end improves receptor binding. Then, to improve penetration of the peptide into the brain, a fatty acid residue was added to the N-terminal end[5]. Together, these alterations to native amylin allow for improved binding at RAMP-1 and RAMP-3 receptors.

RAMP receptors (receptor activity-modifying proteins) are a family of proteins that interact with G-protein coupled receptors to modify their function. RAMP-1 and -3 interact with the calcitonin-like receptor, calcitonin receptor, and calcium sensing receptor. RAMP-3 interacts with the secretin receptor. The exact functional consequences of many of these interactions are unclear, but RAMP receptor dysfunction has been implicated in a number of diseases including cardiovascular disease, diabetes, and cancer[6]. 

How Does Cagrilintide Work?

Cagrilintide has several mechanisms of action. In the stomach and intestine, cagrilintide acts to slow the transit of food. This stimulates the GI tract to send signals to the brain indicating fullness. This tempers the hunger response and results in decreased food intake. Slowing transit of food through the GI tract also slows the rate of sugar absorption. This helps to flatten spikes in blood sugar and gives the body time to process the sugar load so that it does not have to convert as much of it to fat.

Cagrilintide also has a direct effect on the central nervous system. Research in mice reveals that there are many amylin receptors in the arcuate nucleus of the brain. Binding in this area has direct effects on the brain stem and pituitary gland that help to create feelings of satiety and decrease the drive to consume food.

Finally, cagrilintide operates in the pancreas, much as amylin would, in a feedback loop that helps to decrease the release of glucagon. This reduces the conversion of glucose into fat[7].

Cagrilintide: The Research on Obesity

There have been two major trials featuring cagrilintide and they are worth reviewing to understand the overall effect of the peptide. When administered once per week, cagrilintide is associated with weight loss of 6-11% of total body mass over just six weeks when compared to placebo. These are rates that are greater than are seen with liraglutide, which was included as a positive control in the trial. Overall, rates of side effects were approximately the same for cagrilintide and liraglutide[8].

In the second trial, cagrilintide was combined with semaglutide, producing weight loss effects that were more robust than either peptide alone. In fact, the effects were more substantial than would have been expected if the effects were simply additive. Thus, researchers believe that cagrilintide and semaglutide work synergistically, producing a weight loss as high as 17.1% over a period of 20 weeks[9]. A 17% weight loss in someone who weighs 200 pounds amounts to 34 pounds….in just 5 months!

Cagrilintide in Diabetes

Cagrilintide, and similar agents like pramlintide, can dramatically reduce insulin resistance and lower hemoglobin A1C levels via the inhibition of glucagon secretion. In fact, research into these peptide treatments has revealed a 2.2% decrease in A1C levels over very short time frames[10], [11].

Cagrilintide, has been noted that it needs to only be administered once per week. This improvement not only makes the cagrilintide more acceptable in terms of administration, but also makes the peptide more effective. Its long half-life means better blood sugar control over a long period of time and, in the case of weight loss, means a more sustained tempering of appetite.

Cagrilintide in Alzheimer’s Disease

The link between blood sugar control and cognitive dysfunction has long been known. For instance, diabetes is associated with impaired memory, attention and processing speed even in younger individuals. Hyperglycemia (high blood sugar) may activate protein kinase C and directly damage brain cells. It may also increase overall levels of inflammation and oxidative stress leading to both general cognitive decline as well as other maladies associated with diabetes such as heart and kidney disease.

Studies show the relationship between blood sugar and cognitive function again and again. Both high and low levels of blood glucose are a problem for the brain, but the focus here is on hyperglycemia. In a four-year study of elderly women, for instance, chronic elevation of blood sugar is correlated with increased risk of both mild cognitive impairment and dementia[12], [13]. Interestingly, the research indicates that high blood sugar may lead lower levels of glucose in the brain. This is problematic because the brain relies almost exclusively on glucose for energy. This tracks with yet another study indicating that insulin resistance in the brain is a key pathogenic mechanism in diabetic cognitive dysfunction[14], [15]. Overall, what these studies indicate is that the inability of the brain to utilize glucose, even when (and perhaps especially when) there is too much of it in the blood is a key factor in the development of dementia.

Research similarly indicates that amylin levels may also be linked to cognitive dysfunction. As with blood sugar, high and low levels of amylin in the blood are problematic for brain function. Data from the Framingham Heart Study indicates that cognitive function has a u-shaped connection to amylin levels, with both too-low and too-high levels being linked to increased rates of cognitive dysfunction and risk for  Alzheimer’s disease[16].

The link between blood sugar levels, diabetes, and Alzheimer’s disease is by no means new. In fact, in the past Alzheimer’s disease was sometimes referred to as type 3 diabetes. That nomenclature has made a comeback recently as the connection between blood sugar and cognitive dysfunction is being investigated anew. The link between amylin and cognitive function is gaining renewed attention as well.

Amylin readily crosses the blood-brain barrier and shares several features in common with beta amyloid, which is the main component of the amyloid plaques so strongly associated with Alzheimer’s disease.  Both beta amyloid and amylin have similar beta-sheet secondary structures, bind to the same receptors in the brain, and are degraded by the same protease. Though a direct link between amylin and beta amyloid has yet to be established, high suspicion remains that there is a connection. Research in 2014, for instance, revealed a strong correlation between levels of amylin in the blood and the levels of amyloid plaque precursors in the brain. This relationship is so strong that it remains even after controlling for age, gender, ethnicity, BMI, severity of diabetes, stroke, kidney function, lipid levels, and the presence of the ApoE4 DNA marker associated with Alzheimer’s disease. Even more remarkable is the finding that administration of synthetic amylin into mouse models of Alzheimer’s disease leads to the removal of amyloid plaques from the brain and increased levels of it in the blood[17]. Interestingly, what may be going on is that too much amylin leads to crosslinking in the blood. This prevents amylin from crossing the blood-brain barrier and may therefore allow beta amyloid to build up and create amyloid plaques.

All of this seems to suggest a strong link between amylin and the development of cognitive dysfunction. While a great deal more research needs to be done, there is hope that cagrilintide and similar peptides may offer a treatment or preventative for Alzheimer’s disease. This area of research is currently under active investigation and is wide open to the ambitious researcher. Yet, no research has been published investigating the role of cagrilintide in clearing amyloid beta from the brain or in preventing/treating cognitive dysfunction.

Cagrilintide Summary

Cagrilintide is a synthetic analogue of amylin, a naturally occurring protein released by the pancreas. It is the newest edition to the group of peptides originally developed to treat diabetes but repurposed to combat obesity. Like semaglutide and similar peptides, it seems to both slow gastric motility and function in the brain to increase feelings of satiety. While still in the research phase, cagrilintide appears to provide even more dramatic weight loss benefits than the GLP-1 receptor analogues (e.g. semaglutide). Research has shown that when combined with peptides like semaglutide, the effects of cagrilintide appear to synergistically lead to even greater weight loss.

The benefits of cagrilintide outside of improved weight loss are currently theoretical, but there is reason to believe that it may be beneficial in both heart disease and perhaps even in the treatment/prevention of Alzheimer’s disease and other forms of dementia. That area of research is currently ripe for further investigation.

The above literature was researched, edited and organized by Dr. Logan, M.D. Dr. Logan holds a doctorate degree from Case Western Reserve University School of Medicine and a B.S. in molecular biology.

Dr. Thomas Lutz studied veterinary medicine at the University of Berlin, FRG, and did his veterinary doctoral thesis at the University of Zurich on epithelial electrolyte transport. He completed a PhD at the University of Queensland in Brisbane, Australia, on the pathophysiology of feline diabetes mellitus. He became Professor in Veterinary Physiology at the University of Zurich in 2004. His research focuses on the neuroendocrine control of eating, the pathophysiology of obesity and on the pathophysiology of obesity-related comorbidities like type 2 diabetes mellitus. Linked to that is a specific focus on weight lowering therapy and multi-organ crosstalk. 

Dr. Thomas Lutz is being referenced as one of the leading scientists involved in the research and development of Cagrilintide. In no way is this doctor/scientist endorsing or advocating the purchase, sale, or use of this product for any reason. There is no affiliation or relationship, implied or otherwise, between Peptide Sciences and this doctor. The purpose of citing the doctor is to acknowledge, recognize, and credit the exhaustive research and development efforts conducted by the scientists studying this peptide. Dr. Thomas Lutz is listed in [4] under the referenced citations.

1. PubChem, “Cagrilintide.” Accessed: Oct. 27, 2024. [Online]. Available: https://pubchem.ncbi.nlm.nih.gov/compound/171397054

2. R. A. Pittner et al., “Molecular physiology of amylin,” Journal of Cellular Biochemistry, vol. 55, no. S1994A, pp. 19–28, 1994, doi: 10.1002/jcb.240550004.

3. Y. Shen, A. Joachimiak, M. R. Rosner, and W.-J. Tang, “Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism,” Nature, vol. 443, no. 7113, p. 870, Oct. 2006, doi: 10.1038/nature05143.

4. T. A. Lutz, “Creating the amylin story,” Appetite, vol. 172, p. 105965, May 2022, doi: 10.1016/j.appet.2022.105965.

5. T. Kruse et al., “Development of Cagrilintide, a Long-Acting Amylin Analogue,” J. Med. Chem., vol. 64, no. 15, pp. 11183–11194, Aug. 2021, doi: 10.1021/acs.jmedchem.1c00565.

6. D. L. Hay and A. A. Pioszak, “Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles,” Annu Rev Pharmacol Toxicol, vol. 56, pp. 469–487, 2016, doi: 10.1146/annurev-pharmtox-010715-103120.

7. B. Dehestani, N. R. Stratford, and C. W. le Roux, “Amylin as a Future Obesity Treatment,” Journal of Obesity & Metabolic Syndrome, vol. 30, no. 4, p. 320, Dec. 2021, doi: 10.7570/jomes21071.

8. D. C. W. Lau et al., “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,” Lancet, vol. 398, no. 10317, pp. 2160–2172, Dec. 2021, doi: 10.1016/S0140-6736(21)01751-7.

9. L. B. Enebo 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, vol. 397, no. 10286, pp. 1736–1748, May 2021, doi: 10.1016/S0140-6736(21)00845-X.

10. C. J. Bailey, P. R. Flatt, and J. M. Conlon, “Recent advances in peptide-based therapies for obesity and type 2 diabetes,” Peptides, vol. 173, p. 171149, Mar. 2024, doi: 10.1016/j.peptides.2024.171149.

11. J. P. Frias et al., “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,” The Lancet, vol. 402, no. 10403, pp. 720–730, Aug. 2023, doi: 10.1016/S0140-6736(23)01163-7.

12. R. E. Warren and B. M. Frier, “Hypoglycaemia and cognitive function,” Diabetes Obes Metab, vol. 7, no. 5, pp. 493–503, Sep. 2005, doi: 10.1111/j.1463-1326.2004.00421.x

13. “Chronically high blood sugar linked to risk of cognitive impairment | UC San Francisco.” Accessed: Oct. 28, 2024. [Online]. Available: https://www.ucsf.edu/news/2006/08/97884/chronically-high-blood-sugar-linked-risk-cognitive-impairment

14. S. Zhang et al., “Cognitive dysfunction in diabetes: abnormal glucose metabolic regulation in the brain,” Front Endocrinol (Lausanne), vol. 14, p. 1192602, 2023, doi: 10.3389/fendo.2023.1192602.

15. Y. Yang, J.-J. Zhao, and X.-F. Yu, “Expert Consensus on Cognitive Dysfunction in Diabetes,” Curr Med Sci, vol. 42, no. 2, pp. 286–303, Apr. 2022, doi: 10.1007/s11596-022-2549-9.

16. H. Zhu et al., “Association of Plasma Amylin Concentration With Alzheimer Disease and Brain Structure in Older Adults,” JAMA Netw Open, vol. 2, no. 8, p. e199826, Aug. 2019, doi: 10.1001/jamanetworkopen.2019.9826.

17. W. Q. Qiu, M. Wallack, M. Dean, E. Liebson, M. Mwamburi, and H. Zhu, “Association between amylin and amyloid-β peptides in plasma in the context of apolipoprotein E4 allele,” PLoS One, vol. 9, no. 2, p. e88063, 2014, doi: 10.1371/journal.pone.0088063.

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