incretin mimetic; glucagon-like peptide 1 (GLP-1) receptor agonist; GLP-1 mimetic; glutide; GLP-1RA
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Indications
- treatment of diabetes mellitus type-2
- incretin mimetics 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]
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*
- 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]
- 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]
* 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]
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]
- drug interaction(s) of acetaminophen in combination with GLP1-agonist
- drug interaction(s) of fluoroquinolones with hypoglycemic agents
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]
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]
More general terms
More specific terms
- albiglutide (Tanzeum)
- dulaglutide (Trulicity)
- efpeglenatide
- exenatide (Byetta, AC2993, extendin-4, Gilly, Lizzie, Bydureon)
- liraglutide (Victoza, Saxenda)
- lixisenatide (Adlyxin, Lyxumia)
- semaglutide (Ozempic, Rybelsus, Wegovy)
- tirzepatide (Mounjaro, Zepbound)
Additional terms
References
- ↑ 1.0 1.1 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: https://www.ncbi.nlm.nih.gov/pubmed/22236411
- ↑ 2.0 2.1 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#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=280614&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 3.0 3.1 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. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23440284 <Internet> http://archinte.jamanetwork.com/article.aspx?articleid=1656537
- ↑ 4.0 4.1 4.2 Egan AG et al Pancreatic Safety of Incretin-Based Drugs - FDA and EMA Assessment. N Engl J Med 2014; 370:794-797February 27, 2014 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24571751 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMp1314078
- ↑ 5.0 5.1 5.2 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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/24764569 - ↑ 6.0 6.1 6.2 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26642233 <Internet> 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26641027 <Internet> http://annals.org/article.aspx?articleid=2474364 - ↑ 7.0 7.1 7.2 7.3 Medical Knowledge Self Assessment Program (MKSAP) 17, American College of Physicians, Philadelphia 2015
- ↑ 8.0 8.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26888382 Free Article <Internet> 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26888024 <Internet> http://www.bmj.com/content/352/bmj.i801 - ↑ 9.0 9.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27007958 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1506115
- ↑ 10.0 10.1 10.2 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27478902 <Internet> 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27479247 <Internet> http://archinte.jamanetwork.com/article.aspx?articleid=2540531 - ↑ 11.0 11.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27797785 Free Article <Internet> 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27797789 <Internet> http://www.bmj.com/content/355/bmj.i5519 - ↑ 12.0 12.1 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: https://www.ncbi.nlm.nih.gov/pubmed/28596247 Free PMC Article
- ↑ 13.0 13.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/30497881 <Internet> http://www.onlinejacc.org/content/early/2018/11/23/j.jacc.2018.09.020
- ↑ 14.0 14.1 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: https://www.ncbi.nlm.nih.gov/pubmed/30518618 https://www.bmj.com/content/363/bmj.k4880
- ↑ 15.0 15.1 15.2 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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/31186119 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31350-9/fulltext - ↑ 16.0 16.1 Windle ML Fast Five Quiz: Acetaminophen Medscape. July 22, 2021 https://reference.medscape.com/viewarticle/954960_2
- ↑ 17.0 17.1 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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/35344015 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2790398 - ↑ 18.0 18.1 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: https://www.ncbi.nlm.nih.gov/pubmed/36036939 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2795476
- ↑ 19.0 19.1 Medical Knowledge Self Assessment Program (MKSAP) 19 A merican College of Physicians, Philadelphia 2022
- ↑ 20.0 20.1 20.2 NEJM Knowledge+ Endocrinology
- ↑ 21.0 21.1 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: https://www.ncbi.nlm.nih.gov/pubmed/36919944 PMCID: PMC10204182 Free PMC article https://onlinelibrary.wiley.com/doi/10.1111/jdi.14005
- ↑ 22.0 22.1 22.2 22.3 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: https://www.ncbi.nlm.nih.gov/pubmed/37796527 https://jamanetwork.com/journals/jama/fullarticle/2810542
- ↑ 23.0 23.1 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: https://www.ncbi.nlm.nih.gov/pubmed/38018310
- ↑ 24.0 24.1 24.2 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 - ↑ 25.0 25.1 Lenharo M Obesity drugs have another superpower: taming inflammation Nature News. Jan 26, 2024 https://www.nature.com/articles/d41586-024-00118-4
- ↑ 26.0 26.1 26.2 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: https://www.ncbi.nlm.nih.gov/pubmed/38101901 https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(23)00378-2/fulltext
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/38286487 PMCID: PMC10823535 Free PMC article https://www.bmj.com/content/384/bmj-2023-076410