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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.
Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. The initial product GLP-1 (1–37) is susceptible to amidation and proteolytic cleavage, which gives rise to the two truncated and equipotent biologically active forms, GLP-1 (7–36) amide and GLP-1 (7–37). Active GLP-1 protein secondary structure includes two α-helices from amino acid position 13–20 and 24–35 separated by a linker region.
The glucagon-like peptide-1 receptor (GLP1R) is a G protein-coupled receptor (GPCR) found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. It is a member of the glucagon receptor family of GPCRs. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.
Taranabant (codenamed MK-0364) is a cannabinoid receptor type 1 (CB1) inverse agonist that was investigated as a potential treatment for obesity due to its anorectic effects. It was discovered by Merck & Co.
Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, 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.
Dulaglutide, sold under the brand name Trulicity among others, is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. It is also approved in the United States for the reduction of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors. It is a once-weekly injection.
SGLT2 inhibitors, also called gliflozins or flozins, are a class of medications that modulate sodium-glucose transport proteins in the nephron, unlike SGLT1 inhibitors that perform a similar function in the intestinal mucosa. The foremost metabolic effect of this is to inhibit reabsorption of glucose in the kidney and therefore lower blood sugar. They act by inhibiting sodium-glucose transport protein 2 (SGLT2). SGLT2 inhibitors are used in the treatment of type 2 diabetes. Apart from blood sugar control, gliflozins have been shown to provide significant cardiovascular benefit in people with type 2 diabetes. Several medications of this class have been approved or are currently under development. In studies on canagliflozin, a member of this class, the medication was found to enhance blood sugar control as well as reduce body weight and systolic and diastolic blood pressure.
Semaglutide is an antidiabetic medication used for the treatment of type 2 diabetes and an anti-obesity medication used for long-term weight management. It was developed by Novo Nordisk in 2012 and approved for use in the US in 2017. It is a peptide similar to the hormone glucagon-like peptide-1 (GLP-1), modified with a side chain. It can be administered by subcutaneous injection or taken orally. It is sold under the brand names Ozempic (injectable) and Rybelsus (pill) for diabetes, and under the brand name Wegovy for weight loss.
Cotadutide is an experimental drug for the treatment of type 2 diabetes mellitus. It lowers blood glucose levels by mimicking the human hormones glucagon-like peptide 1 and glucagon, which play a role in blood sugar regulation. The drug is a peptide that is injected under the skin.
Tirzepatide, sold under the brand name Mounjaro among others, is an antidiabetic medication used for the treatment of type 2 diabetes and for weight loss. Tirzepatide is administered through subcutaneous injection.
Orforglipron (LY-3502970) is a non-peptide glucagon-like peptide-1 receptor agonist developed as a weight loss drug by Eli Lilly and Company. It is easier to produce than GLP-1 agonists on the market in 2023 and is expected to be cheaper.
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. As of 2023, CagriSema is in a Phase III trial.
Dual amylin and calcitonin receptor agonists (DACRAs) are a class of drugs that act as agonists at the amylin receptor and calcitonin receptor that are under development as therapies for obesity and type 2 diabetes. Examples are cagrilintide and the KBP family derived from salmon calcitonin, including KBP‐042, KBP-066A, KBP-089, and KBP-336.
Maridebart cafraglutide is an investigational drug developed by Amgen for the treatment of obesity. It is an agonist of the GLP-1 receptor and an antagonist of the GIPR. In a preliminary trial, AMG 133 resulted in a 14.5 percent weight loss after 12 weeks at the highest dose tested.
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.
Mazdutide is a dual agonist of the GLP-1 receptor and glucagon receptor. It is an analog of oxyntomodulin (OXM). The drug is developed by Eli Lilly and is currently in a Phase II study.
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.
Survodutide is an experimental peptide that works as a dual glucagon/GLP-1 receptor agonist. Unlike other dual GLP-1/glucagon dual agonists, it is an glucagon analog rather than an analog of oxyntomodulin. It is developed by Boehringer Ingelheim as a weight loss drug.
References
- ↑ Goldenberg, Ronald M.; Gilbert, Jeremy D.; Manjoo, Priya; Pedersen, Sue D.; Woo, Vincent C.; Lovshin, Julie A. (15 November 2023). "Management of type 2 diabetes, obesity, or nonalcoholic steatohepatitis with high‐dose GLP‐1 receptor agonists and GLP‐1 receptor‐based co‐agonists". Obesity Reviews. doi:10.1111/obr.13663.
- ↑ Goldenberg, Ronald M.; Teoh, Hwee; Verma, Subodh (November 2023). "Glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor co-agonists for cardioprotection, type 2 diabetes and obesity: a review of mechanisms and clinical data". Current Opinion in Cardiology. 38 (6): 539–545. doi:10.1097/HCO.0000000000001084.
- ↑ He, Kun; Wei, Fang; Chen, Hong; Zhang, Yanyan; Sheng, Zhen; Wen, Qing (20 June 2023). "763-P: Safety, Tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) of a Dual GLP-1/GIP Receptor Agonist (HRS9531) in Healthy Subjects—A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose (SAD and MAD) Study". Diabetes. 72 (Supplement_1). doi:10.2337/db23-763-P.