semaglutide (Ozempic, Rybelsus, Wegovy)
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Indications
- treatment of diabetes mellitus type-2 (Ozempic FDA-approved Dec 2017)[3]
- 2.4 mg/week subcutaneous dose FDA-approved for weight reduction[15][20]
- hypoglycemic agent of choice (if not insulin) in patients with CKD4
- benefits obese patients with HFpEF[26]
- benefits obese patients with HFpEF & diabetes mellitus type-2[36]
- secondary prevention of cardiovascular disease
- reduces cardiovascular events in overweight or obese patient with cardiovascular disease (heart attack, stroke) but without diabetes mellitus (6.5% vs 8.0% over 40 months)[28] (FDA-approved[34])
- reduces second major cardiovascular event after myocardial infarction in obese patients without diabetes mellitus[33]
- in obese patients with HFpEF, semaglutide 2.4 mg improved symptoms, physical limitations, & exercise, & reduces inflammation & body weight across LVEF[29][31][37]
- reduces risk of renal complications & cardiovascular mortality in patients with type 2 diabetes & chronic kidney disease[38]
* semaglutide improves HgbA1c more than canagliflozin 1.5 vs 1.0%[8]
- semaglutide also associated with more weight reduction (5.3 vs 4.2 kg)
- may be useful as an adjunct to diet & exercise for weight reduction in non-diabetic overweight or obese adults[11] & adolescents[18]
- in conjunction with an intensive dietary-behavioral intervention, semaglutide more than doubles weight reduction[12]
- continuing weekly semaglutide after 20 weeks in young obese adults results in continued weight reduction vs weight gain if discontinued[14]
- 2.4 mg SC weekly normalizes glycemic control in most obese patients with prediabetes[17]
* may increase likelihood of NASH (stage F2 or F3 fibrosis) resolution, but does not inmprove fibrosis stage[10]
Contraindications
- pancreatitis
- history of pancreatitis is relative contraindication
- family history of medullary thyroid carcinoma or patients with Multiple Endocrine Neoplasia-2 (MEN2)[22]
- gastroparesis[23]
- does not reduce hospitalization due to heart failure[21]
Dosage
- 0.25 mg SC once weekly for 4 weeks, then increase to 0.5 mg once weekly
- if glycemic control is not achieved after at least 4 weeks on 0.5-mg dose, the dose may be increased to 1 mg once weekly
- investigational 2.4-mg dose weekly induces weight reduction of 10% of body weight in patients with type-2 diabetes[13]
- oral semaglutide (Rybelsus) 7 mg & 14 mg (FDA-approved Sept 2019)[6][9]
- doses as high as 50 mg safe & effective[24] Dosage adjustment with renal failure:
- no adjustment needed for once weekly injection
Adverse effects
- increased incidence of diabetic retinopathy complications, including blindness[1][22]
- gastrointestinal distress, nausea (44%)[25], gastroparesis[25]
- pancreatitis[27]
- ileus[27]
- may increase likelihood of neoplasms (no organ-specific pattern identified)[10]
- semaglutide is not associated with an increased risk of suicidal ideation[30]
Mechanism of action
- glucagon-like peptide-1 receptor agonist[1]
- may reduce cardiovascular events (mostly stroke) in type 2 diabetics with increased cardiovascular risk in industry-conducted trial[1]
- may be beneficial for weight reduction; 3 kg vs placebo[2]
- may reduce incidence of diabetic nephropathy
- may reduce HgbA1c[1]; 1.55% vs placebo[2]
Clinical trials
- 6 months, almost all participants achieved 5% weight loss, 1/2 lost >10%, & a 1/4 lost >15% of their body weight[16]
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
- may diminish HgbA1c as add on to metformin > dulaglutide by 0.4%[4]
- may diminish HgbA1c as add on to metformin > sitagliptin by 0.3-0.5%[5]
- oral semaglutide compares favorably with subcutaneous liraglutide for glycemic control & weight reduction[7]
- Medicare will cover semaglutide (Wegovy) under Part D for overweight or obese patients with preexisting cardiovascular disease to prevent heart attack or stroke[35]
- cost $10,000 annually (2019)
- cost for Wegovy (weight loss) is $1349 for 4 weekly injections[19]
- Novo Nordisk has not announced pricing on oral semiglutide
More general terms
References
- ↑ 1.0 1.1 1.2 1.3 1.4 Marso SP, Bain SC, Consoli A et al Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. September 16, 2016 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27633186 Free Article <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1607141
- ↑ 2.0 2.1 2.2 Sorli S, Harashima SI, Tsoukas GM et al Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes & Endocrinology. Jan 16, 2017 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28110911 <Internet> http://www.thelancet.com/journals/landia/article/PIIS2213-8587(17)30013-X/fulltext
Scheen AJ Semaglutide: a promising new glucagon-like peptide-1 receptor agonist. Lancet Diabetes & Endocrinology. Jan 16, 2017 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28110912 <Internet> http://www.thelancet.com/journals/landia/article/PIIS2213-8587(17)30012-8/fulltext (industry-funded study)
Novo Nordisk News Release. Dec. 5, 2016 Novo Nordisk Files for Regulatory Approval of Once-Weekly Semaglutide with the FDA for the Treatment of Type 2 Diabetes. http://press.novonordisk-us.com/2016-12-05-Novo-Nordisk-Files-for-Regulatory-Approval-of-Once-Weekly-Semaglutide-with-the-FDA-for-the-Treatment-of-Type-2-Diabetes - ↑ 3.0 3.1 Frieden J FDA Panel Urges Approval of Semaglutide for T2D. Vote was 16-0 with one abstention. MedPage Today. October 18, 2017 https://www.medpagetoday.com/Endocrinology/Diabetes/68642
Tucker ME FDA Approves Semaglutide for Type 2 Diabetes Medscape - Dec 05, 2017. https://www.medscape.com/viewarticle/889631
Windle ML. FDA New Drug and Biologic Approvals -- 2017 Year-in-Review Medscape - Jan 11, 2018. https://reference.medscape.com/viewarticle/890871
U.S. Food and Drug Administration. Novel Drug Approvals for 2017. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm537040.htm - ↑ 4.0 4.1 4.2 Pratley RE, Aroda VR, Lingvay I et al Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes & Endocrinology. Jan 31, 2018 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/29397376 <Internet> http://www.thelancet.com/journals/landia/article/PIIS2213-8587(18)30024-X/abstract
Tahrani AA, Bellary S, Barnett AH. Once-weekly GLP-1R agonists: moving the goal posts. Lancet Diabetes & Endocrinology. Jan 31, 2018 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/29397375 <Internet> http://www.thelancet.com/journals/landia/article/PIIS2213-8587(18)30049-4/fulltext - ↑ 5.0 5.1 Rosenstock J, Allison D, Birkenfeld AL et al Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With SulfonylureaThe PIONEER 3 Randomized Clinical Trial. JAMA. 2019;321(15):1466-1480. https://jamanetwork.com/journals/jama/fullarticle/2729339
- ↑ 6.0 6.1 Husain M, Birkenfeld AL, Donsmark M et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019 Jun 11 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31185157 https://www.nejm.org/doi/10.1056/NEJMoa1901118
- ↑ 7.0 7.1 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 - ↑ 8.0 8.1 Lingvay I, Catarig AM, Frias JP et al Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial. Lancet Diabetes & Endocrinology. Sept 17, 2019 PMID: https://www.ncbi.nlm.nih.gov/pubmed/3154086 https://www.thelancet.com/journals/landia/article/PIIS2213-8587(19)30311-0/fulltext
Scheen AJ SGLT2 inhibitor or GLP-1 receptor agonist in type 2 diabetes? Lancet Diabetes & Endocrinology. Sept 17, 2019 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31540866 https://www.thelancet.com/journals/landia/article/PIIS2213-8587(19)30310-9/fulltext - ↑ 9.0 9.1 Tucker ME FDA OKs 'Game-Changer' Oral GLP-1 Agonist for Type 2 Diabetes. Medscape - Sep 20, 2019. https://www.medscape.com/viewarticle/918772
- ↑ 10.0 10.1 10.2 Newsome PN, Buchholtz K, Cusi K et al A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med. 2020 Nov 13. PMID: https://www.ncbi.nlm.nih.gov/pubmed/33185364 https://www.nejm.org/doi/full/10.1056/NEJMoa2028395
- ↑ 11.0 11.1 Wilding JPH, Batterham RL, Calanna S et al Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl H Med. 2021. Feb 10 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33567185 https://www.nejm.org/doi/full/10.1056/NEJMoa2032183
Ingelfinger JR, Rosen CJ STEP 1 for Effective Weight Control - Another First Step? N Engl H Med. 2021. Feb 10 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33567184 https://www.nejm.org/doi/full/10.1056/NEJMe2101705 - ↑ 12.0 12.1 Wadden TA, Bailey TS, Billings LK et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: The STEP 3 randomized clinical trial. JAMA 2021 Feb 24:e211831 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33625476 PMCID: PMC7905697 Free PMC article https://jamanetwork.com/journals/jama/fullarticle/2777025
- ↑ 13.0 13.1 Davies M, Faerch L, Jeppesen OK, et al. Semaglutide 2 4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): A randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 2021 Mar 2; [e-pub]. PMID: https://www.ncbi.nlm.nih.gov/pubmed/33667417 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00213-0/fulltext
- ↑ 14.0 14.1 Rubino D, Abrahamsson N, Davies M et al Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity. The STEP 4 Randomized Clinical Trial. JAMA. Published online March 23, 2021 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33755728 https://jamanetwork.com/journals/jama/fullarticle/2777886
- ↑ 15.0 15.1 Busko M FDA Approves 'Gamechanger' Semaglutide for Weight Loss. Medscape - Jun 04, 2021. https://www.medscape.com/viewarticle/952441
- ↑ 16.0 16.1 Ghusn W et al. Weight loss outcomes associated with semaglutide treatment for patients with overweight or obesity. JAMA Netw Open 2022 Sep 19; 5:e2231982. PMID: https://www.ncbi.nlm.nih.gov/pubmed/36121652 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2796491
- ↑ 17.0 17.1 Perreault L et al. Changes in glucose metabolism and glycemic status with once-weekly subcutaneous semaglutide 2.4 mg among participants with prediabetes in the STEP program. Diabetes Care 2022 Oct; 45:2396 PMID: https://www.ncbi.nlm.nih.gov/pubmed/35724304 https://diabetesjournals.org/care/article/45/10/2396/147113/Changes-in-Glucose-Metabolism-and-Glycemic-Status
- ↑ 18.0 18.1 Weghuber D et al. Once-weekly semaglutide in adolescents with obesity. N Engl J Med 2022 Nov 2; [e-pub] PMID: https://www.ncbi.nlm.nih.gov/pubmed/36322838 https://www.nejm.org/doi/10.1056/NEJMoa2208601
- ↑ 19.0 19.1 AMA Morning Rounds. Dec 5, 2022 American Medical Society
- ↑ 20.0 20.1 20.2 Nainggolan L FDA Approves Wegovy (Semaglutide) for Obesity in Teens 12 and Up. Medscape. January 03, 2023 https://www.medscape.com/viewarticle/986403
- ↑ 21.0 21.1 Medical Knowledge Self Assessment Program (MKSAP) 19 American College of Physicians, Philadelphia 2022
- ↑ 22.0 22.1 22.2 Tucker ME Eye check important before starting semaglutide for diabetes. Internal Medicine News. Jan 26, 2023 https://www.mdedge.com/internalmedicine/article/260856/diabetes/eye-check-important-starting-semaglutide-diabetes
Albert SG, Wood ME, Ahir V Glucagon-like peptide 1-receptor agonists and A1c: Good for the heart but less so for the eyes? Diabetes Metab Syndr. 2022. Dec 28;17(1):102696 PMID: https://www.ncbi.nlm.nih.gov/pubmed/36596264 https://www.sciencedirect.com/science/article/abs/pii/S1871402122003137 - ↑ 23.0 23.1 NEJM Knowledge+ Endocrinology
- ↑ 24.0 24.1 Aroda VR et al. Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (PIONEER PLUS): A multicentre, randomised, phase 3b trial. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37385279 Lancet 2023 Jun 25; [e-pub]. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01127-3/fulltext
Knop FK et al. Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2023 Jun 25; [e-pub] PMID: https://www.ncbi.nlm.nih.gov/pubmed/37385278 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01185-6/fulltext - ↑ 25.0 25.1 25.2 Goodman B They took blockbuster drugs for weight loss and diabetes. Now their stomachs are paralyzed. CNN. July 25, 2023 https://www.cnn.com/2023/07/25/health/weight-loss-diabetes-drugs-gastroparesis/index.html
Moniuszko M Ozempic, Mounjaro manufacturers sued over claims of "stomach paralysis" side effects. CBS News. August 3, 2023 https://www.cbsnews.com/news/ozempic-mounjaro-lawsuit-gastroparesis-stomach-paralysis-side-effect/ - ↑ 26.0 26.1 Zoler ML Wegovy Scores HFpEF Benefits in People With Obesity. Medscape. August 25, 2023 https://www.medscape.com/viewarticle/995844
Kosiborod MN, Abildstrom SZ, Borlaug BA et al Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023. August 25. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37622681 https://www.nejm.org/doi/full/10.1056/NEJMoa2306963
Butler J, Abildstrom S, Borlaug B et al. Semaglutide in Patients With Obesity and Heart Failure Across Mildly Reduced or Preserved Ejection Fraction J Am Coll Cardiol. 2023. Nov 28;82(22):2087-2096. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37993201 Free article https://www.jacc.org/doi/abs/10.1016/j.jacc.2023.09.811
Borlaug BA, Kitzman DW, Davies MJ et al Semaglutide in HFpEF across obesity class and by body weight reduction: a prespecified analysis of the STEP-HFpEF trial. Nat Med. 2023 Sep;29(9):2358-2365. Epub 2023 Aug 27. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37635157 PMCID: PMC10504076 Free PMC article. - ↑ 27.0 27.1 27.2 Putka S FDA Adds Intestinal Blockage Reports to Ozempic Labeling. Joins other approved GLP-1 receptor agonists in noting the potential adverse reaction. MedPage Today September 28, 2023 https://www.medpagetoday.com/endocrinology/diabetes/106535
- ↑ 28.0 28.1 Lincoff AM et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med 2023 Nov 11; [e-pub]. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37952131 https://www.nejm.org/doi/10.1056/NEJMoa2307563
- ↑ 29.0 29.1 Butler J, Abildstrom SZ, Borlaug BA et al. Semaglutide in Patients With Obesity and Heart Failure Across Mildly Reduced or Preserved Ejection Fraction. J Am Coll Cardiol. 2023 Nov 28;82(22):2087-2096. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37993201 Free article https://www.sciencedirect.com/science/article/pii/S0735109723075964
- ↑ 30.0 30.1 Wang W et al. Association of semaglutide with risk of suicidal ideation in a real-world cohort. Nat Med 2024 Jan; 30:168 PMID: https://www.ncbi.nlm.nih.gov/pubmed/38182782 https://www.nature.com/articles/s41591-023-02672-2
- ↑ 31.0 31.1 Kosiborod MN, Verma S, Borlaug BA, et al. Effects of Semaglutide on Symptoms, Function, and Quality of Life in Patients With Heart Failure With Preserved Ejection Fraction and Obesity: A Prespecified Analysis of the STEP-HFpEF Trial. Circulation. 2024 Jan 16;149(3):204-216. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37952180 PMCID: PMC10782938 Free PMC article https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.123.067505
- ↑ 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
- ↑ 33.0 33.1 Hansen MK et al Eligibility for and Preventive Potential of Semaglutide in Overweight and Obese Patients With Myocardial Infarction. J Am Coll Cardiol. 2024 2024 Mar 5;83(9):956-958. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38418010 https://www.jacc.org/doi/10.1016/j.jacc.2023.12.029
- ↑ 34.0 34.1 Monaco K Wegovy Approved for Major Heart Disease Prevention. New indication for patients with obesity or overweight and a history of cardiovascular disease. MedPage Today March 8, 2024 https://www.medpagetoday.com/cardiology/prevention/109090
- ↑ 35.0 35.1 Freiden J Medicare to Cover Weight-Loss Drug Wegovy for Certain Patients. News comes in the wake of FDA approval to reduce risk of heart attacks, stroke. MedPage Today March 21, 2024 https://www.medpagetoday.com/publichealthpolicy/medicare/109305
- ↑ 36.0 36.1 Kosiborod MN, Petrie MC, Borlaug BA et al. Semaglutide in patients with obesity-related heart failure and type 2 diabetes. N Engl J Med 2024 Apr 6; [e-pub]. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38587233 https://www.nejm.org/doi/10.1056/NEJMoa2313917
- ↑ 37.0 37.1 Butler J, Shah SJ, Petrie MC et al Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials. Lancet. 2024 Apr 4:S0140-6736(24)00469-0 PMID: https://www.ncbi.nlm.nih.gov/pubmed/38599221
- ↑ 38.0 38.1 Perkovic V et al Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med. 2024. May 23 PMID: https://www.ncbi.nlm.nih.gov/pubmed/38785209 https://www.nejm.org/doi/full/10.1056/NEJMoa2403347
- ↑ Highights of Prescribing Information Ozempic (semaglutide) injection https://www.novo-pi.com/ozempic.pdf
- ↑ Highights of Prescribing Information Rybelsus (semaglutide) tablets for oral use https://www.novo-pi.com/rybelsus.pdf