tirzepatide (Mounjaro, Zepbound)
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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 apnea-hypopnea index, body weight, hypoxic burden, serum C-reactive protein, systolic blood pressure & improves sleep-related patient-reported outcomes[17]
- decreases risk of worsening heart failure or cardiovascular death in obese with HFpEF[22]
* 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]
- drug interaction(s) of antidepressant in combination with GLP1-agonist
- drug interaction(s) of SGLT-2 inhititor (flozin) in combination with GLP1-agonist
- drug interaction(s) of acetaminophen in combination with GLP1-agonist
- drug interaction(s) of fluoroquinolones with hypoglycemic agents
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.
- 36 weeks on tirzepatide, 670 patients had mean weight loss of 21%
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]
More general terms
References
- ↑ 1.0 1.1 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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/34170647 https://www.nejm.org/doi/10.1056/NEJMoa2107519 - ↑ 2.0 2.1 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: https://www.ncbi.nlm.nih.gov/pubmed/35133415 https://jamanetwork.com/journals/jama/fullarticle/2788781
- ↑ 3.0 3.1 Zoler ML 'Twincretin' Tirzepatide Gets FDA Approval for Type 2 Diabetes. Medscape. May 13, 2022 https://www.medscape.com/viewarticle/974013
- ↑ 4.0 4.1 4.2 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 - ↑ 5.0 5.1 Busko M Tirzepatide Lowers Weight Across All Groups With Obesity. Medscape. November 07, 2022 https://www.medscape.com/viewarticle/983672
- ↑ 6.0 6.1 Zoler ML Tirzepatide's Benefits Expand: Lean Mass Up, Serum Lipids Down. Medscape. Oct 14, 2022 https://www.medscape.com/viewarticle/982467
- ↑ 7.0 7.1 NEJM Knowledge+ Endocrinology
- ↑ 8.0 8.1 8.2 Jastreboff AM et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med 2022 Jul 21; 387:205. PMID: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/37385275 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01200-X/fulltext - ↑ 9.0 9.1 Scherer L Caution Urged for Obesity Drugs and Birth Control Pills. Medscape. Oct 19, 2023 https://www.medscape.com/s/viewarticle/997498
- ↑ Abbasi J FDA Green-Lights Tirzepatide, Marketed as Zepbound, for Chronic Weight Management JAMA. Published online November 15, 2023. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37966831
- ↑ 11.0 11.1 11.2 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: https://www.ncbi.nlm.nih.gov/pubmed/38078870 https://jamanetwork.com/journals/jama/fullarticle/2812936
- ↑ Tchang B How to Prescribe Zepbound. Medscape. Dec 12, 2023 https://www.medscape.com/viewarticle/999162
- ↑ 13.0 13.1 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: https://www.ncbi.nlm.nih.gov/pubmed/38314555
- ↑ 14.0 14.1 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
- ↑ 15.0 15.1 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: https://www.ncbi.nlm.nih.gov/pubmed/37551549 Review.
- ↑ 16.0 16.1 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
- ↑ 17.0 17.1 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: https://www.ncbi.nlm.nih.gov/pubmed/38912654 https://mediacenteratypon.nejmgroup-production.org/NEJMoa2404881.pdf - ↑ 18.0 18.1 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: https://www.ncbi.nlm.nih.gov/pubmed/38976257 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2821080
- ↑ 19.0 19.1 19.2 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: https://www.ncbi.nlm.nih.gov/pubmed/39133485 PMCID: PMC11320168 Free PMC article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2822209
- ↑ 20.0 20.1 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: https://www.ncbi.nlm.nih.gov/pubmed/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 - ↑ 21.0 21.1 Tucker ME Tirzepatide Slashes Progression From Prediabetes to T2D. Medscape. Nov 5, 2024 https://www.medscape.com/viewarticle/tirzepatide-slashes-progression-prediabetes-t2d-2024a1000k78
- ↑ 22.0 22.1 Packer M, Zile MR, Kramer CM et l Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2024 Nov 16. PMID: https://www.ncbi.nlm.nih.gov/pubmed/39555826 https://www.nejm.org/doi/10.1056/NEJMoa2410027
- ↑ Highlights of Prescribing Information Mounjaro (tirzepatide) injection for subcutaneous use https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215866s000lbl.pdf