GLP-1 receptor agonist
Glucagon-like peptide-1 receptor agonists, also known as GLP-1 receptor agonists (GLP-1-RA) or incretin mimetics, are agonists of the GLP-1 receptor. This class of medications is used for the treatment of type 2 diabetes[1][2] Some drugs are also approved for obesity. One of their advantages over older insulin secretagogues, such as sulfonylureas or meglitinides, is that they have a lower risk of causing hypoglycemia.[3] GLP-1 has a short duration of action, so to overcome this limitation several modifications in either the drugs or the formulations are being developed.[4]
The 2022 ADA standards of medical care in diabetes include GLP-1-RA as a first line pharmacological therapy for type 2 diabetes, specifically in patients with atherosclerotic cardiovascular disease or obesity.[5]
Health effects
A 2021 meta-analysis found a 12% reduction in all-cause mortality when GLP-1 analogs are used in the treatment of type 2 diabetes, as well as significant improvements in cardiovascular and renal outcomes.[6] A JAMA article meta-analysis in 2018 (covering studies concerning GLP-1 agonists, DPP-4 inhibitors, and SGLT2 inhibitors) showed GLP-1 agonists were associated with lower stroke risk than controls.[7]
Preclinical research has suggested the possibility that the drugs may increase the risk of pancreatitis and pancreatic cancer.[8] Analyses of human trials have not found an increased risk of pancreatitis but are insufficiently powered to rule out an effect on pancreatic cancer.[9][10][11]
Studies in rodents have shown GLP1 mediated thyroid c-cell hyperplasia.[12]
A 2020 Cochrane systematic review did not find enough evidence of reduction of all-cause mortality, serious adverse events, cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, end-stage renal disease nor health-related quality of life when comparing metformin monotherapy to Glucagon-like peptide 1 analogues in the treatment of type 2 diabetes.[13]
Approved
- exenatide (brand names Byetta and Bydureon, manufactured by AstraZeneca), approved in 2005/2012
- liraglutide (Victoza for diabetes, Saxenda for obesity, manufactured by Novo Nordisk), approved in 2010[14]
- lixisenatide (Lyxumia in Europe, Adlyxin in the United States, manufactured by Sanofi), approved in 2016[15]
- albiglutide (Tanzeum, manufactured by GSK), approved in 2014[16]
- dulaglutide (Trulicity, manufactured by Eli Lilly), approved in 2014[17]
- semaglutide (Ozempic and Rybelsus for diabetes, Wegovy for obesity, manufactured by Novo Nordisk), approved in 2017[18]
- tirzepatide (Mounjaro, manufactured by Eli Lilly), approved in 2022[19]
Under investigation
- taspoglutide, phase III halted Sept 2010[1]
- efpeglenatide[20]
Mechanism
These agents work by activating the GLP-1R, rather than inhibiting the breakdown of GLP-1 as do DPP-4 inhibitors, and are generally considered more potent.[21]
References
- ^ a b Baggio LL (2008). "Glucagon-like Peptide-1 Analogs Other Than Exenatide". Medscape Diabetes & Endocrinology.
- ^ Ali ES, Hua J, Wilson CH, Tallis GA, Zhou FH, Rychkov GY, Barritt GJ (September 2016). "The glucagon-like peptide-1 analogue exendin-4 reverses impaired intracellular Ca(2+) signalling in steatotic hepatocytes". Biochimica et Biophysica Acta. 1863 (9): 2135–2146. doi:10.1016/j.bbamcr.2016.05.006. PMID 27178543.
- ^ "Standards of medical care in diabetes--2012". Diabetes Care. 35 Suppl 1: S11–S63. January 2012. doi:10.2337/dc12-s011. PMC 3632172. PMID 22187469.
- ^ Das A, Geetha KM, Hazarika I (29 August 2019). "Contemporary Updates on the Physiology of Glucagon like Peptide-1 and Its Agonist to Treat Type 2 Diabetes Mellitus". International Journal of Peptide Research and Therapeutics. 26 (3): 1211–1221. doi:10.1007/s10989-019-09927-y. S2CID 202854512.
- ^ Draznin B, Aroda VR, Bakris G, Benson G, Brown FM, Freeman R, et al. (January 2022). "9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022". Diabetes Care. 45 (Suppl 1): S125–S143. doi:10.2337/dc22-S009. PMID 34964831.
- ^ Sattar N, Lee MM, Kristensen SL, Branch KR, Del Prato S, Khurmi NS, et al. (October 2021). "Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials". The Lancet. Diabetes & Endocrinology. 9 (10): 653–662. doi:10.1016/s2213-8587(21)00203-5. PMID 34425083.
- ^ Zheng SL, Roddick AJ, Aghar-Jaffar R, Shun-Shin MJ, Francis D, Oliver N, Meeran K (April 2018). "Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis". Jama. 319 (15): 1580–1591. doi:10.1001/jama.2018.3024. hdl:10044/1/60316. PMC 5933330. PMID 29677303.
- ^ Pinto LC, Falcetta MR, Rados DV, Leitão CB, Gross JL (February 2019). "Glucagon-like peptide-1 receptor agonists and pancreatic cancer: a meta-analysis with trial sequential analysis". Scientific Reports. 9 (1): 2375. doi:10.1038/s41598-019-38956-2. PMID 30787365.
- ^ Forsmark CE (2016). "Incretins, Diabetes, Pancreatitis and Pancreatic Cancer: What the GI specialist needs to know". Pancreatology. 16 (1): 10–13. doi:10.1016/j.pan.2015.11.009. PMID 26795258.
- ^ Nreu B, Dicembrini I, Tinti F, Mannucci E, Monami M (July 2020). "Pancreatitis and pancreatic cancer in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonists: an updated meta-analysis of randomized controlled trials". Minerva Endocrinologica. doi:10.23736/S0391-1977.20.03219-8. PMID 32720500.
- ^ Boniol M, Franchi M, Bota M, Leclercq A, Guillaume J, van Damme N, et al. (February 2018). "Incretin-Based Therapies and the Short-term Risk of Pancreatic Cancer: Results From Two Retrospective Cohort Studies". Diabetes Care. 41 (2): 286–292. doi:10.2337/dc17-0280. PMID 29146599. S2CID 207368560.
- ^ Bjerre Knudsen L, Madsen LW, Andersen S, Almholt K, de Boer AS, Drucker DJ, et al. (April 2010). "Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation". Endocrinology. 151 (4): 1473–1486. doi:10.1210/en.2009-1272. PMID 20203154.
- ^ Gnesin F, Thuesen AC, Kähler LK, Madsbad S, Hemmingsen B, et al. (Cochrane Metabolic and Endocrine Disorders Group) (June 2020). "Metformin monotherapy for adults with type 2 diabetes mellitus". The Cochrane Database of Systematic Reviews. 6 (6): CD012906. doi:10.1002/14651858.CD012906.pub2. PMC 7386876. PMID 32501595.
- ^ "FDA Approves New Treatment for Type 2 Diabetes". Food and Drug Administration.
- ^ "FDA approves Adlyxin to treat type 2 diabetes". Food and Drug Administration. 2019-09-10.
- ^ "FDA Approves Weekly Injectable Diabetes Drug: Albiglutide".
- ^ "FDA Approves Weekly Injectable Diabetes Drug: Dulaglutide". Food and Drug Administration.
- ^ Longer Acting GLP-1 Receptor Agonists and the Potential for Improved Cardiovascular Outcomes. 2013
- ^ Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, et al. (August 2021). "Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes". The New England Journal of Medicine. 385 (6): 503–515. doi:10.1056/NEJMoa2107519. PMID 34170647. S2CID 235635529.
- ^ Gerstein HC, Sattar N, Rosenstock J, Ramasundarahettige C, Pratley R, Lopes RD, et al. (September 2021). "Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes". The New England Journal of Medicine. 385 (10): 896–907. doi:10.1056/NEJMoa2108269. PMID 34215025. S2CID 235723092.
- ^ "GLP-1 Receptor Agonists vs. DPP-4 Inhibitors for Type 2 Diabetes".