Contents

Search

tirzepatide (Mounjaro, Zepbound)

Indications: - treatment of diabetes mellitus type-2 (FDA-approved May 2022) [3] - useful as adjunct to insulin glargine in patients with type 2 diabetes with inadequate glycemic control [2] - reduces progression from prediabetes to type 2 diabetes > 90% at 3 years [21] - weight reduction in obese patients with or without type 2 diabetes* [4,5,8] - regain of weight if tirzepatide discontinued [20] see Clinical trials below - reduces blood pressure & weight within 9 months [13] - obstructive sleep apnea (FDA approval submitted) - reduces apneia-hypopnea index, body weight, hypoxic burden, serum C-reactive protein, systolic blood pressure & improves sleep-related patient-reported outcomes [17] * weight reductions at 15 mg week approach those of bariatric surgery [8] * weight reductions in obese adults > with tirzepatide vs semaglutide (15% vs 8% at 12 months) [18] Contraindications: - gastroparesis [7] - personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type-2 Dosage: - weekly subcutaneous injections - initiate at 2.5 mg SQ, escalate to 5, 7.5, 10, 12.5 or 15 mg SQ weekly every 4 weeks * if 1 or 2 consecutive doses are missed, resume at last administered dose * if >= 3 consecutive doses are missed, restart dose escalation starting at 5 mg Adverse effects: - diarrhea (12-21% vs 10% for placebo), constipation - nausea (13% vs 3% for placebo), vomiting, pancreatitis [16] - abdominal pain, dyspepsia, eructation, gastroesophageal reflux disease - injection site reactions, hypersensitivity reactions, - fatigue, hair loss, Drug interactions: - may interfere with absorption & activity of oral contraceptives [9] Mechanism of action: - dual GLP-1 receptor agonist & GIP receptor agonist [15] - lowers HgbA1c by 2% when added to glargine - promotes weight reduction 7-9 kg (from baseline of 86 kg) [1] - lowers serum triglycerides, LDL cholesterol, & VLDL cholesterol in patients with diabetes mellitus type 2 [6] - weight reduction of 21% at 36 weeks with 10 or 15 mg of tirzepatide [11] - withdrawal of tirzepatide results in regain of lost weight; continued treatment maintains & continues weight reduction [11] Clinical trials: - SURMOUNT-1: effective for weight reduction in obese [4] - SURMOUNT-4:[20] - 36 weeks on tirzepatide, 670 patients had mean weight loss of 21% - those who continued on tirzepatide had mean weight loss of 25% at 88 weeks - those who discontinued tirzepatide had mean weight loss of 10% at 88 weeks. Notes: - likely to be expensive - tirzepatide is most effective GLP-1 agonist for both glycemic control & weight loss [14] - lower risk for all-cause mortality (RR=0.58), major adverse cardiovascular events (RR=0.80), acute kidney injury (RR=0.78),& major adverse kidney events (RR=0.54) than GLP-1 agonists [19] - tirzepatide more effective for weight loss & for lowering HgbA1c levels than GLP-1 agonists [19]

Interactions

drug adverse effects of hypoglycemic agents

General

glucagon-like peptide 1 (GLP-1) receptor agonist; incretin mimetic; GLP-1 mimetic; GLP-1 agonist; glutide; GLP-1RA GIP receptor agonist; gastric inhibitory polypeptide receptor agonist; glucose-dependent insulinotropic polypeptide receptor agonist; GIPR agonist

References

  1. Rosenstock J, Wysham C, Frias JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): A double-blind, randomised, phase 3 trial. Lancet 2021 Jun 25; [e-pub]. PMID: 34186022 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)01324-6/fulltext - Frias JP, Davies MJ, Rosenstock J et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med 2021 Jun 25; [e-pub]. PMID: 34170647 https://www.nejm.org/doi/10.1056/NEJMoa2107519
  2. Dahl D, Onishi Y, Norwood P et al Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes. The SURPASS-5 Randomized Clinical Trial. JAMA. 2022;327(6):534-545 PMID: 35133415 https://jamanetwork.com/journals/jama/fullarticle/2788781
  3. Zoler ML 'Twincretin' Tirzepatide Gets FDA Approval for Type 2 Diabetes. Medscape. May 13, 2022 https://www.medscape.com/viewarticle/974013
  4. Zoler ML Tirzepatide Powers 'Unprecedented' Weight Loss in Obesity Trial. Medcape. June 4, 2022 https://www.medscape.com/viewarticle/975061 - Monaco K Tirzepatide Serves Up Major Weight-Loss Win in Patients With Obesity. SURMOUNT-1 trial tested GIP/GLP-1 receptor agonist in people without diabetes. MedPage Today June 5, 2022 https://www.medpagetoday.com/meetingcoverage/ada/99060 - McCall B 'Staggering' Weight Loss and Benefits in Body Composition With Tirzepatide. Medscape. May 19, 2023 https://www.medscape.com/viewarticle/992211
  5. Busko M Tirzepatide Lowers Weight Across All Groups With Obesity. Medscape. November 07, 2022 https://www.medscape.com/viewarticle/983672
  6. Zoler ML Tirzepatide's Benefits Expand: Lean Mass Up, Serum Lipids Down. Medscape. Oct 14, 2022 https://www.medscape.com/viewarticle/982467
  7. NEJM Knowledge+ Endocrinology
  8. Jastreboff AM et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med 2022 Jul 21; 387:205. PMID: 35658024 https://www.nejm.org/doi/10.1056/NEJMoa2206038 - Garvey WT et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): A double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2023 Jun 26; [e-pub]. PMID: 37385275 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01200-X/fulltext
  9. Scherer L Caution Urged for Obesity Drugs and Birth Control Pills. Medscape. Oct 19, 2023 https://www.medscape.com/s/viewarticle/997498
  10. Abbasi J FDA Green-Lights Tirzepatide, Marketed as Zepbound, for Chronic Weight Management JAMA. Published online November 15, 2023. PMID: 37966831
  11. Aronne LJ, Sattar N, Horn DB et al Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity. The SURMOUNT-4 Randomized Clinical Trial. JAMA. Published online December 11, 2023 PMID: 38078870 https://jamanetwork.com/journals/jama/fullarticle/2812936
  12. Tchang B How to Prescribe Zepbound. Medscape. Dec 12, 2023 https://www.medscape.com/viewarticle/999162
  13. de Lemos JA, Linetzky B, le Roux CW et al Tirzepatide Reduces 24-Hour Ambulatory Blood Pressure in Adults With Body Mass Index >= 27 kg/m2: SURMOUNT-1 Ambulatory Blood Pressure Monitoring Substudy. Hypertension. 2024 Feb 5. PMID: 38314555
  14. 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
  15. Gasbjerg LS, Rosenkilde MM, Meier JJ, Holst JJ, Knop FK. The importance of glucose-dependent insulinotropic polypeptide receptor activation for the effects of tirzepatide. Diabetes Obes Metab. 2023 Nov;25(11):3079-3092. PMID: 37551549 Review.
  16. Grennam K (3.06) A Case of Fatal Fulminant Necrotizing Pancreatitis in a Patient with Recent Tirzepatide Initiation. American Association of Clinical Endocrinology. AACE 2024. May 9-11 https://aace2024.eventscribe.net/fsPopup.asp?efp=RVdOVVZFWFEyMTEyOA&PosterID=662555&rnd=0.9109643&mode=posterInfo
  17. Ault A Tirzepatide Significantly Reduces Sleep Disruptions Medscape. June 22, 2024 https://www.medscape.com/viewarticle/tirzepatide-significantly-reduces-sleep-disruptions-2024a1000bm1 - Malhotra A et al Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity. N Engl J Med. 2024 June 21 PMID: 38912654 https://mediacenteratypon.nejmgroup-production.org/NEJMoa2404881.pdf
  18. Rodriguez PJ, Goodwin Cartwright BM, Gratzl S et al Semaglutide vs Tirzepatide for Weight Loss in Adults With Overweight or Obesity. JAMA Intern Med. Published online July 8, 2024. PMID: 38976257 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2821080
  19. Chuang MH, Chen JY, Wang HY et al. Clinical outcomes of tirzepatide or GLP-1 receptor agonists in individuals with type 2 diabetes. JAMA Netw Open 2024 Aug; 7:e2427258. PMID: 39133485 PMCID: PMC11320168 Free PMC article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2822209
  20. Monaco K Stopping Tirzepatide Led to Weight Gain, Trial Shows. But sustained treatment kept the pounds off MedPage Today December 13, 2023 https://www.medpagetoday.com/endocrinology/obesity/107845 - Aronne LJ, Sattar N, Horn DB et al for the SURMOUNT-4 Investigators. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA. 2024 Jan 2;331(1):38-48. PMID: 38078870 PMCID: PMC10714284 Free PMC article. Clinical Trial. https://jamanetwork.com/journals/jama/fullarticle/2812936 - 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
  21. Tucker ME Tirzepatide Slashes Progression From Prediabetes to T2D. Medscape. Nov 5, 2024 https://www.medscape.com/viewarticle/tirzepatide-slashes-progression-prediabetes-t2d-2024a1000k78
  22. Highlights of Prescribing Information Mounjaro (tirzepatide) injection for subcutaneous use https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215866s000lbl.pdf