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glucagon-like peptide 1 (GLP-1) receptor agonist; incretin mimetic; GLP-1 mimetic; GLP-1 agonist; glutide; GLP-1RA

Indications: - treatment of diabetes mellitus type-2 - GLP-1 agonists promote weight reduction in patients with or without diabetes mellitus [1] - risk reduction for cardiovascular disease in patients with diabetes mellitus type 2 (ACC recommendation) [13] - in patients with diabetes mellitus type-2 & asthma, metformin cuts odds of asthma attacks by 30%; adding a GLP-1 receptor agonist reduces odds by another 40% [36] Contraindications: - pancreatitis - history of pancreatitis is relative contraindication - family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia-2 (MEN2) - gastroparesis [20] - does not reduce hospitalization due to heart failure [19] - NLY01 investigational for treatment of Parkinson's disease (see Mechanism of action below) failed to reach primary efficacy endpoint [26] Dosage: SC weekly * oral semaglutide (Rybelsus) [15] Dosage adjustment with renal failure: - no adjustment needed for once weekly injection Adverse effects: - nausea/vomiting [7] - increased risk of chronic renal failure [7] - increased risk for pancreatitis? [3]; no [4,5] - probably no increased risk for pancreatitis [4,5] - increased risk of pancreatitis when used for weight loss [22] - no increased risk of pancreatic cancer [8] - delayed gastric emptying, gastroparesis* - risk of residual gastric contents on day of elective surgery [31] - risk of gastric food retention 17% with EGD alone but none when EGD combined with colonoscopy [34] - increased risk of gastroparesis when used for weight loss [22] - increased risk of bowel obstruction when used for weight loss [22] - not associated with increased risk for hospitalization due to heart failure [9] - cases of postmarketing acute cholecystitis with GLP-1 mimetics [18] - increased risk of gallbladder disease & disorder of the bile ducts [10] - may increase risk for cholangiocarcinoma [14] - increased risk of gallbladder or biliary diseases, especially when used at higher doses, for longer durations, & for weight loss [17] - no increased risk for breast cancer [11] - increased risk of overall thyroid cancer (RR=1.52) but not papillary thyroid cancer or medullary thyroid cancer [23] - not increased risk of thyroid cancer [28] - no increased risk of mortality [12] - alopecia, pulmonary aspiration, suicidal ideation (potential) [24] - FDA clears GLP-1 receptor agonists of suicidal risk, but continues review [24] - pulmonary aspiration during general anesthesia or deep sedation [35] - no increased risk of suicide in patients without mental illness [32] - questions remain regarding use in patient with depression [32] * Black box warning of contraindication for personal of family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia-2 (MEN2) (based on rodent studies where GLP-1 receptors on parfollicular cells induced C-cell proliferation & develpment of C-cell tumors) [20] * prone to retained gastric contents on upper GI endoscopy [21] - 8-hour solid-food fast & 2-hour liquid fast prior to the procedure, - delay procedure if nausea, vomiting, or abdominal distension [29] Drug interactions: - hypoglycemia when used in combination with sulfonylurea [7] - GLP-1 agonists (incretin mimetics) delay gastric emptying time which can decrease level & affect of concomitantly administered oral medications including acetaminophen [16] Laboratory: - a commercially available test for 40 genetic variants identifies people with the "hungry gut" obesity phenotype who will respond best to GLP-1 receptor agonists for weight management [30] Mechanism of action: - glucagon-like peptide 1 receptor agonist - mimicks action of incretin (gliptins also act through incretin effects) - stimulates glucose-related insulin secretion - inhibits glucagon secretion - slows gastric emptying - diminishes appetite in patients with type 2 diabetes - increases satiety - can lower Hgb A1c about 1.5% [2] - increases activity of cholangiocytes [10] - anti-inflammatory [25] - a brain-penetrant, pegylated, long-lasting version of exenatide (NLY01) reduces microglia activation [26] Clinical trials: - no long term outcome data Notes: - tirzepatide is most effective GLP-1 agonist for both glycemic control & weight loss - semaglutide is second most effective GLP-1 agonist for both indications - dulaglutide (1.5 mg) associated with greatest decrease in HgbA1c relative to placebo (1.4%), followed by once-weekly exenatide, & taspoglutide [6] - taspoglutide associated with largest weight loss (1.3 kg), followed by exenatide & dulaglutide - dulaglutide & exenatide were associated with highest risk for symptomatic hypoglycemia [6] - once weekly semaglutide lowers A1c more than flozin as add on to metformin - oral semaglutide compares favorably with subcutaneous liraglutide for glycemic control & weight loss [15]

Interactions

drug interactions drug adverse effects (more general classes)

Related

gliptin; dipeptidyl peptidase-4 inhibitor; DPP-4 inhibitor glucagon-like peptide 1 receptor; GLP-1 receptor; GLP-1-R; GLP-1R (GLP1R) incretin

Specific

albiglutide (Tanzeum) dulaglutide (Trulicity) efpeglenatide exenatide (Byetta, AC2993, extendin-4, Gilly, Lizzie, Bydureon) liraglutide (Victoza, Saxenda) lixisenatide (Adlyxin, Lyxumia) retatrutide semaglutide (Ozempic, Rybelsus, Wegovy) tirzepatide (Mounjaro, Zepbound)

General

parenteral hypoglycemic agent

References

  1. Vilsboll T et al. Effects of glucagon-like peptide-1 receptor agonists on weight loss: Systematic review and meta-analyses of randomised controlled trials. BMJ 2012 Jan 11; 344:d7771. PMID: 22236411
  2. Prescriber's Letter 19(6): 2012 CHART: Drugs for Type 2 Diabetes ALGORITHM: Stepwise Approach to Selecting Treatments for Type 2 Diabetes (ADA) GUIDELINES: Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach (2012) Detail-Document#: 280614 (subscription needed) http://www.prescribersletter.com
  3. Singh S et al Glucagonlike Peptide 1-Based Therapies and Risk of Hospitalization for Acute Pancreatitis in Type 2 Diabetes Mellitus. A Population-Based Matched Case-Control Study. JAMA Intern Med. 2013;():1-6. PMID: 23440284 http://archinte.jamanetwork.com/article.aspx?articleid=1656537
  4. Egan AG et al Pancreatic Safety of Incretin-Based Drugs - FDA and EMA Assessment. N Engl J Med 2014; 370:794-797February 27, 2014 PMID: 24571751 http://www.nejm.org/doi/full/10.1056/NEJMp1314078
  5. Li L et al. Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: Systematic review and meta-analysis of randomised and non-randomised studies. BMJ 2014 Apr 15; 348:g2366. PMID: 24736555 - Faillie JL et al. Incretin based drugs and risk of acute pancreatitis in patients with type 2 diabetes: Cohort study. BMJ 2014 Apr 24; 348:g2780 PMID: 24764569
  6. Zaccardi F et al Benefits and Harms of Once-Weekly Glucagon-like Peptide-1 Receptor Agonist Treatments: A Systematic Review and Network Meta-analysis. Ann Intern Med. Published online 8 December 2015 PMID: 26642233 http://annals.org/article.aspx?articleid=2474362 - Montori VM, Rodriguez-Gutierrez R The Triumph of Innovation and the Hard Work of Caring for Patients With Diabetes. Ann Intern Med. Published online 8 December 2015 PMID: 26641027 http://annals.org/article.aspx?articleid=2474364
  7. Medical Knowledge Self Assessment Program (MKSAP) 17, American College of Physicians, Philadelphia 2015
  8. Azoulay L, Filion KB, Platt RW et al Incretin based drugs and the risk of pancreatic cancer: international multicentre cohort study. BMJ 2016;352:i581 PMID: 26888382 Free Article http://www.bmj.com/content/352/bmj.i581 - Bolen SD, Maruthur NM The safety of incretin based drug treatments for type 2 diabetes. BMJ 2016;352:i801 PMID: 26888024 http://www.bmj.com/content/352/bmj.i801
  9. Filion KB, Azoulay L, Platt RW et al A Multicenter Observational Study of Incretin-based Drugs and Heart Failure. N Engl J Med 2016; 374:1145-1154. March 24, 2016 PMID: 27007958 http://www.nejm.org/doi/full/10.1056/NEJMoa1506115
  10. Faillie JL, Yu OH, Yin H et al Association of Bile Duct and Gallbladder Diseases With the Use of Incretin-Based Drugs in Patients With Type 2 Diabetes Mellitus. JAMA Intern Med. Published online August 01, 2016 PMID: 27478902 http://archinte.jamanetwork.com/article.aspx?articleid=2540538 - Butler PC Glucagon-Like Peptide 1 Drugs as Second-Line Therapy for Type 2 Diabetes.' JAMA Intern Med. Published online August 01, 2016 PMID: 27479247 http://archinte.jamanetwork.com/article.aspx?articleid=2540531
  11. Hicks BM, Yin H, Yu OH et al Glucagon-like peptide-1 analogues and risk of breast cancer in women with type 2 diabetes: population based cohort study using the UK Clinical Practice Research Datalink. BMJ 2016;355:i5340 PMID: 27797785 Free Article http://www.bmj.com/content/355/bmj.i5340 - Bolen SD, Maruthur NM Glucagon-like peptide-1 receptor agonists and risk of breast cancer. BMJ 2016;355:i5519 PMID: 27797789 http://www.bmj.com/content/355/bmj.i5519
  12. Liu J, Li L, Deng K et al Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis. BMJ. 2017 Jun 8;357:j2499. Review. PMID: 28596247 Free PMC Article
  13. Writing Committee, Das SR, Everett BM, Birtcher KK et al 2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease. A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. Nov 2018 PMID: 30497881 http://www.onlinejacc.org/content/early/2018/11/23/j.jacc.2018.09.020
  14. Abrahami D, Douros A, Yin H et al Incretin based drugs and risk of cholangiocarcinoma among patients with type 2 diabetes: population based cohort study. BMJ 2018;363:k4880 PMID: 30518618 https://www.bmj.com/content/363/bmj.k4880
  15. Pratley R, Amod A, Hoff ST et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): A randomised, double-blind, phase 3a trial. Lancet 2019 Jul 6; 394:39. PMID: 31186120 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31271-1/fulltext - Holst JJ. Which to choose, an oral or an injectable glucagon-like peptide-1 receptor agonist? Lancet 2019 Jul 6; 394:4. PMID: 31186119 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31350-9/fulltext
  16. Windle ML Fast Five Quiz: Acetaminophen Medscape. July 22, 2021 https://reference.medscape.com/viewarticle/954960_2
  17. He L, Wanf J, Ping F et al Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases. A Systematic Review and Meta-analysis of Randomized Clinical Trials. JAMA Intern Med. Published online March 28, 2022 PMID: 35344001 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2790392 - Halder S, Lipska KJ Glucagon-Like Peptide-1 Receptor Agonists - How Safe Are They? JAMA Intern Med. Published online March 28, 2022 PMID: 35344015 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2790398
  18. Woronow D, Chamberlain C, Niak A et al Acute Cholecystitis Associated With the Use of Glucagon-Like Peptide-1 Receptor Agonists Reported to the US Food and Drug Administration. JAMA Intern Med. Published online August 29, 2022 PMID: 36036939 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2795476
  19. Medical Knowledge Self Assessment Program (MKSAP) 19 A merican College of Physicians, Philadelphia 2022
  20. NEJM Knowledge+ Endocrinology
  21. Kobori T et al. Association of glucagon-like peptide-1 receptor agonist treatment with gastric residue in an esophagogastroduodenoscopy. J Diabetes Investig 2023 Jun; 14:767. PMID: 36919944 PMCID: PMC10204182 Free PMC article https://onlinelibrary.wiley.com/doi/10.1111/jdi.14005
  22. Sodhi M, Rezaeianzadeh R, Kezouh A et al Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss. JAMA. Published online October 5, 2023 PMID: 37796527 https://jamanetwork.com/journals/jama/fullarticle/2810542
  23. Silverii GA, Monami M, Gallo M et al Glucagon-like peptide-1 receptor agonists and risk of thyroid cancer: A systematic review and meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2023 Nov 29. PMID: 38018310
  24. O'Mary L FDA Evaluating Three Side Effects Reported With Weight Loss Drugs. Medscape. January 05, 2024 https://www.medscape.com/s/viewarticle/fda-investigates-three-side-effects-reported-weight-loss-2024a10000e4 - Monaco K FDA Clears Wegovy, Other GLP-1 Drugs of Suicidality Risk for Now. Preliminary evaluation reassures, while the agency's review continues. MedPage Today January 11, 2024 https://www.medpagetoday.com/primarycare/obesity/108223
  25. Lenharo M Obesity drugs have another superpower: taming inflammation Nature News. Jan 26, 2024 https://www.nature.com/articles/d41586-024-00118-4
  26. McGarry A et al. Safety, tolerability, and efficacy of NLY01 in early untreated Parkinson's disease: A randomised, double-blind, placebo-controlled trial. Lancet Neurol 2024 Jan; 23:37. PMID: 38101901 https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(23)00378-2/fulltext
  27. Yao H et al. Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: Systematic review and network meta-analysis. BMJ 2024 Jan 29; 384:e076410. PMID: 38286487 PMCID: PMC10823535 Free PMC article https://www.bmj.com/content/384/bmj-2023-076410
  28. Pasternak B et al. Glucagon-like peptide 1 receptor agonist use and risk of thyroid cancer: Scandinavian cohort study. BMJ 2024 Apr 10; 385:e078225 PMID: 38683947 PMCID: PMC11004669 https://doi.org/10.1136/bmj-2023-078225
  29. Hashash JG et al. AGA Rapid Clinical Practice Update on the management of patients taking GLP-1 receptor agonists prior to endoscopy: Communication. Clin Gastroenterol Hepatol 2024 Apr; 22:705 PMID: 37944573 https://www.cghjournal.org/article/S1542-3565(23)00869-8/fulltext
  30. McNamara D Genetic Test Can Predict Response to Semaglutide for Weight Loss. Medscape May 21, 2024 https://www.medscape.com/viewarticle/genetic-test-can-predict-response-semaglutide-weight-loss-2024a10009k6
  31. Sen S et al. Glucagon-like peptide-1 receptor agonist use and residual gastric content before anesthesia. JAMA Surg 2024 Jun; 159:660. PMID: 38446466 PMCID: PMC10918573 (available on 2025-03-06) https://jamanetwork.com/journals/jamasurgery/fullarticle/2815663
  32. Ueda P, Soderling J, Wintzell V et al GLP-1 Receptor Agonist Use and Risk of Suicide Death. JAMA Intern Med. 2024 Sep 3:e244369. PMID: 39226030 PMCID: PMC11372654 Free PMC article. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2823083 - Wadden TA et al. Psychiatric safety of semaglutide for weight management in people without known major psychopathology: Post hoc analysis of the STEP 1, 2, 3, and 5 trials. JAMA Intern Med 2024 Sep 3; [e-pub] PMID: 39226070 PMCID: PMC11372653 Free PMC article. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2823084 - Schoretsanitis G et al. Disproportionality analysis from World Health Organization data on semaglutide, liraglutide, and suicidality. JAMA Netw Open 2024 Aug; 7:e2423385. PMID: 39163046 PMCID: PMC11337067 Free PMC article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2822453
  33. Henderson J The Data Are Clear: Patients Regain Weight After Stopping GLP-1 Drugs. Other than staying on drug, there's no evidence-based strategy to maintain weight loss. MedPage Today September 26, 2024 https://www.medpagetoday.com/special-reports/exclusives/112138
  34. Nasser J, Hosseini A, Barlow G et al Food Retention at Endoscopy Among Adults Using Glucagon-Like Peptide-1 Receptor Agonists. JAMA Netw Open. 2024 Oct 1;7(10):e2436783. PMID: 39352703 PMCID: PMC11445686 Free PMC article. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2824290
  35. Larkin M FDA Updates GLP-1 Label With Pulmonary Aspiration Warning Medscape. Nov 6, 2024 https://www.medscape.com/viewarticle/fda-updates-glp-1-label-pulmonary-aspiration-warning-2024a1000k84
  36. Lee B, Man KKC, Wong E, Tan T, Sheikh A, Bloom CI. Antidiabetic Medication and Asthma Attacks. JAMA Intern Med. 2024 Nov 18. PMID: 39556360 https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2826086