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Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control excess body fat. These medications alter one of the fundamental processes of the human body, weight regulation, by: reducing appetite and consequently energy intake, increasing energy expenditure, redirecting nutrients from adipose to lean tissue, or interfering with the absorption of calories.
Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. It is co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.
Pramlintide is an injectable amylin analogue drug for diabetes, developed by Amylin Pharmaceuticals. Pramlintide is sold as an acetate salt.
The calcitonin receptor (CT) is a G protein-coupled receptor that binds the peptide hormone calcitonin and is involved in maintenance of calcium homeostasis, particularly with respect to bone formation and metabolism.
Enteroendocrine cells are specialized cells of the gastrointestinal tract and pancreas with endocrine function. They produce gastrointestinal hormones or peptides in response to various stimuli and release them into the bloodstream for systemic effect, diffuse them as local messengers, or transmit them to the enteric nervous system to activate nervous responses. Enteroendocrine cells of the intestine are the most numerous endocrine cells of the body. They constitute an enteric endocrine system as a subset of the endocrine system just as the enteric nervous system is a subset of the nervous system. In a sense they are known to act as chemoreceptors, initiating digestive actions and detecting harmful substances and initiating protective responses. Enteroendocrine cells are located in the stomach, in the intestine and in the pancreas. Microbiota play key roles in the intestinal immune and metabolic responses in these enteroendocrine cells via their fermentation product, acetate.
Obesogens are certain chemical compounds that are hypothesised to disrupt normal development and balance of lipid metabolism, which in some cases, can lead to obesity. Obesogens may be functionally defined as chemicals that inappropriately alter lipid homeostasis and fat storage, change metabolic setpoints, disrupt energy balance or modify the regulation of appetite and satiety to promote fat accumulation and obesity.
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Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, GLP-1DAs or incretin mimetics, are a class of drugs that reduce blood sugar and energy intake by activating the GLP-1 receptor. They mimic the actions of the endogenous incretin hormone GLP-1 that is released by the gut after eating.
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Cagrilintide is a long-acting analogue of amylin. It is being tested to treat obesity and type 2 diabetes by itself and in combination with semaglutide as cagrilintide/semaglutide.
Cagrilintide/semaglutide, marketed as CagriSema, is a combination of cagrilintide, a dual amylin and calcitonin receptor agonist, and semaglutide, a GLP-1 agonist. It is injected once weekly and is being tested in type 2 diabetes and obesity. Preliminary trial results found a greater weight loss compared to either medication alone. HbA1c was significantly improved compared to cagrilintide alone and non-significantly better than semaglutide alone. In a Phase II trial, weight loss averaged -15.6 percent after 32 weeks, making CagriSema comparable in efficacy to tirzepatide. A future trial sponsored by Novo Nordisk is comparing tirzepatide and CagriSema head-to-head. As of 2023, CagriSema is in a Phase III trial.
The amylin receptors (AMYRs) are heterodimers of the calcitonin receptor that are bound to by amylin with high affinity and consist of AMY1, AMY2, and AMY3. Amylin mimetics that are agonists at the amylin receptors are being developed as therapies for diabetes and obesity, and one, pramlintide, has been FDA approved. The AMY1 receptor may be activated by both amylin and the calcitonin gene-related peptide (CGRP) and could play a role in the effects of CGRP receptor antagonists developed for migraine. Dual agonists of the amylin and calcitonin receptors (DACRAs) are under development for obesity. Amylin and its receptors are believed to play a role in Alzheimer's disease.
NNC9204-1706 or NN9423 is a GLP-1/GIP/glucagon receptor triple agonist developed by Novo Nordisk. It was evaluated in a clinical trial; adverse effects such as "dose-dependent increases in heart rate and reductions in reticulocyte count, increases in markers of inflammation and hepatic disturbances, and impaired glucose tolerance at the highest dosages" meant that the drug was declared to have an inadequate safety profile and discontinued.
Petrelintide is an amylin analogue dosed once weekly, developed by Zealand Pharma for the treatment of type 2 diabetes and obesity. Preclinical data suggests it may be more effective in combination with semaglutide.
Glucagon receptor agonists are a class of drugs under development for the treatment of obesity, non-alcoholic fatty liver disease, and congenital hyperinsulinism.
GLP1 poly-agonist peptides are a class of drugs that activate multiple peptide hormone receptors including the glucagon-like peptide-1 (GLP-1) receptor. These drugs are developed for the same indications as GLP-1 receptor agonists—especially obesity, type 2 diabetes, and non-alcoholic fatty liver disease. They are expected to provide superior efficacy with fewer adverse effects compared to GLP-1 mono-agonists, which are dose-limited by gastrointestinal disturbances. The effectiveness of multi-receptor agonists could possibly equal or exceed that of bariatric surgery. The first such drug to receive approval is tirzepatide, a dual agonist of GLP-1 and GIP receptors.
References
- ↑ Larsen, A. T.; Mohamed, K. E.; Sonne, N.; Bredtoft, E.; Andersen, F.; Karsdal, M. A.; Henriksen, K. (December 2022). "Does receptor balance matter? - Comparing the efficacies of the dual amylin and calcitonin receptor agonists cagrilintide and KBP-336 on metabolic parameters in preclinical models". Biomedicine & Pharmacotherapy. 156: 113842. doi: 10.1016/j.biopha.2022.113842 . ISSN 1950-6007. PMID 36242844.
- ↑ Henriksen, Kim; Broekhuizen, Karen; de Boon, Wadim M. I.; Karsdal, Morten A.; Bihlet, Asger R.; Christiansen, Claus; Dillingh, Marlous R.; de Kam, Marieke; Kumar, Raj; Burggraaf, Jacobus; Kamerling, Ingrid M. C. (December 2021). "Safety, tolerability and pharmacokinetic characterisation of DACRA KBP‐042 in healthy male subjects". British Journal of Clinical Pharmacology. 87 (12): 4786–4796. doi: 10.1111/bcp.14921 . ISSN 0306-5251. S2CID 235093884.
- ↑ Andreassen, K. V.; Larsen, A. T.; Sonne, N.; Mohamed, K. E.; Karsdal, M. A.; Henriksen, K. (1 November 2021). "KBP-066A, a long-acting dual amylin and calcitonin receptor agonist, induces weight loss and improves glycemic control in obese and diabetic rats". Molecular Metabolism. 53: 101282. doi: 10.1016/j.molmet.2021.101282 . ISSN 2212-8778. PMC 8313742 . PMID 34214708.
- ↑ Larsen, Anna Thorsø; Gydesen, Sofie; Sonne, Nina; Karsdal, Morten Asser; Henriksen, Kim (7 January 2021). "The dual amylin and calcitonin receptor agonist KBP-089 and the GLP-1 receptor agonist liraglutide act complimentarily on body weight reduction and metabolic profile". BMC Endocrine Disorders. 21 (1): 10. doi: 10.1186/s12902-020-00678-2 . ISSN 1472-6823. PMC 7791885 . PMID 33413317.
- ↑ Melander, Simone A.; Larsen, Anna T.; Elhady Mohamed, Khaled; Karsdal, Morten A.; Henriksen, Kim (20 June 2023). "840-P: Dual Amylin and Calcitonin Receptor Agonist Treatment Improves Blood Pressure and Glucose Control in ZSF1 Rats". Diabetes. 72 (Supplement_1). doi:10.2337/db23-840-P. S2CID 259415731.
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