TARGETING MULTIPLE PATHWAYS WITH ONE MOLECULE: THE THERAPEUTIC VERSATILITY OF TIRZEPATIDE

Patrycja Jędrzejewska-Rzezak; Adam Żuczek; Kinga Dyndał; Marcelina Broda; Olga Żuczek; Katarzyna Urbańska; Izabela Szczap; Anna Hawryluk; Kamil Marzec; Aleksandra Mokrzycka

doi:10.31435/ijitss.3(47).2025.3902

Patrycja Jędrzejewska-Rzezak The John Paul II Catholic University of Lublin, Lublin, Poland https://orcid.org/0000-0003-2144-5810
Adam Żuczek Gdańsk Medical University, Gdańsk, Poland https://orcid.org/0009-0007-8288-3570
Kinga Dyndał Faculty of Medicine, Rzeszów University, Rzeszów, Poland https://orcid.org/0009-0008-0753-4837
Marcelina Broda Voivodeship Specialist Hospital, Opole, Poland https://orcid.org/0009-0005-0208-6543
Olga Żuczek Voivodeship Specialist Hospital in Słupsk, Słupsk, Poland https://orcid.org/0009-0009-1209-4183
Katarzyna Urbańska Voivodeship Specialist Hospital in Lublin, Lublin, Poland https://orcid.org/0000-0003-3301-0179
Izabela Szczap Roman Ostrzycki Provincial Integrated Hospital in Konin, Konin, Poland https://orcid.org/0009-0006-7814-1198
Anna Hawryluk Independent Public Health Care Facility of the Ministry of Internal Affairs and Administration, Lublin, Poland https://orcid.org/0000-0002-8451-7976
Kamil Marzec Voivodeship Specialist Hospital in Kraków, Kraków, Poland https://orcid.org/0009-0007-5610-9637
Aleksandra Mokrzycka Clinical Voivodeship Hospital No. 2 named after St Jadwiga the Queen in Rzeszów, Rzeszów, Poland https://orcid.org/0009-0004-9168-9479

DOI: https://doi.org/10.31435/ijitss.3(47).2025.3902

Keywords: Tirzepatide, Obesity Treatment, GIP, GLP-1, Glucose-Dependent Insulinotropic Polypeptide, Glucagon-Like Peptide-1

Abstract

Tirzepatide is a novel dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors that offers promising therapeutic potential beyond glycemic control. Originally developed for the treatment of type 2 diabetes mellitus, tirzepatide has demonstrated a wide array of pleiotropic effects in clinical studies. These include significant reductions in body weight, improvements in lipid profiles, decreased blood pressure, and attenuation of hepatic steatosis. Emerging data also support its cardioprotective and nephroprotective roles, as well as efficacy in patients with heart failure with preserved ejection fraction (HFpEF). Furthermore, tirzepatide is currently under investigation for the treatment of obstructive sleep apnea and shows early promise in neuroprotection. This review summarizes the current evidence on the diverse biological actions of tirzepatide and discusses their potential clinical implications in the context of metabolic syndrome and associated comorbidities.

Materials and methods: A review of the literature available in the PubMed database was performed, using the key words: “tirzepatide”, “obesity treatment”, “GIP”, “GLP-1”, “glucose-dependent insulinotropic polypeptide”, “glucagon-like peptide-1”.

Conclusion: The clinical benefits of tirzepatide extend well beyond glucose lowering, encompassing a broad spectrum of metabolic, cardiovascular and renal effects. These pleiotropic actions position tirzepatide as a valuable pharmacological agent in the multifactorial management of type 2 diabetes, obesity and related conditions. Continued investigation into its mechanisms of action and therapeutic scope may further redefine its role in the treatment of complex metabolic disorders. Given the growing body of evidence, tirzepatide represents a paradigm shift toward integrated care for patients with metabolic syndrome and its systemic manifestations.

References

Corrao S, Pollicino C, Maggio D, Torres A, Argano C. Tirzepatide against obesity and insulin-resistance: pathophysiological aspects and clinical evidence. Front Endocrinol (Lausanne) 2024;15. https://doi.org/10.3389/fendo.2024.1402583.

Hamza M, Papamargaritis D, Davies MJ. Tirzepatide for overweight and obesity management. Expert Opin Pharmacother 2024. https://doi.org/10.1080/14656566.2024.2436595.

Sinha R, Papamargaritis D, Sargeant JA, Davies MJ. Efficacy and Safety of Tirzepatide in Type 2 Diabetes and Obesity Management. J Obes Metab Syndr 2023;32:25–45. https://doi.org/10.7570/jomes22067.

Hayes MR, Borner T, De Jonghe BC. The Role of GIP in the Regulation of GLP-1 Satiety and Nausea. Diabetes 2021;70:1956–61. https://doi.org/10.2337/DBI21-0004.

Samms RJ, Coghlan MP, Sloop KW. How May GIP Enhance the Therapeutic Efficacy of GLP-1? Trends in Endocrinology and Metabolism 2020;31:410–21. https://doi.org/10.1016/j.tem.2020.02.006.

Wang L. Designing a Dual GLP-1R/GIPR Agonist from Tirzepatide: Comparing Residues Between Tirzepatide, GLP-1, and GIP. Drug Des Devel Ther 2022;16:1547–59. https://doi.org/10.2147/DDDT.S358989.

Willard FS, Douros JD, Gabe MBN, Showalter AD, Wainscott DB, Suter TM, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight 2020;5. https://doi.org/10.1172/jci.insight.140532.

Killion EA, Wang J, Yie J, Shi SD-H, Bates D, Min X, et al. Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models. Sci Transl Med 2018;10. https://doi.org/10.1126/scitranslmed.aat3392.

Ravussin E, Sanchez-Delgado G, Martin CK, Beyl RA, Greenway FL, O’Farrell LS, et al. Tirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation. Cell Metab 2025. https://doi.org/10.1016/j.cmet.2025.03.011.

Anderson SL, Marrs JC. Tirzepatide for type 2 diabetes. Drugs Context 2023;12. https://doi.org/10.7573/dic.2023-6-1.

Nauck MA, D‘Alessio DA. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. Cardiovasc Diabetol 2022;21. https://doi.org/10.1186/s12933-022-01604-7.

DE BLOCK C, MATHIEU C, SAPIN H, KILJANSKI JI, PELESHOK J. 727-P: Glycemic Effect of Tirzepatide by Duration of Diabetes. Diabetes 2022;71. https://doi.org/10.2337/db22-727-P.

De Block C, Bailey C, Wysham C, Hemmingway A, Allen SE, Peleshok J. Tirzepatide for the treatment of adults with type 2 diabetes: An endocrine perspective. Diabetes Obes Metab 2023;25:3–17. https://doi.org/10.1111/dom.14831.

Lafferty RA, Flatt PR, Irwin N. GLP-1/GIP analogs: potential impact in the landscape of obesity pharmacotherapy. Expert Opin Pharmacother 2023;24:587–97. https://doi.org/10.1080/14656566.2023.2192865.

Rosenstock J, Frías JP, Rodbard HW, Tofé S, Sears E, Huh R, et al. Tirzepatide vs Insulin Lispro Added to Basal Insulin in Type 2 Diabetes: The SURPASS-6 Randomized Clinical Trial. JAMA 2023;330:1631–40. https://doi.org/10.1001/jama.2023.20294.

le Roux CW, Zhang S, Aronne LJ, Kushner RF, Chao AM, Machineni S, et al. Tirzepatide for the treatment of obesity: Rationale and design of the SURMOUNT clinical development program. Obesity 2023;31:96–110. https://doi.org/10.1002/oby.23612.

Gallwitz B. Clinical perspectives on the use of the GIP/GLP-1 receptor agonist tirzepatide for the treatment of type-2 diabetes and obesity. Front Endocrinol (Lausanne) 2022;13. https://doi.org/10.3389/fendo.2022.1004044.

Garvey WT, Frias JP, Jastreboff AM, le Roux CW, Sattar N, Aizenberg D, 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. The Lancet 2023;402:613–26. https://doi.org/10.1016/S0140-6736(23)01200-X.

Wadden TA, Chao AM, Machineni S, Kushner R, Ard J, Srivastava G, et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial. Nat Med 2023;29:2909–18. https://doi.org/10.1038/s41591-023-02597-w.

Aronne LJ, Sattar N, Horn DB, Bays HE, Wharton S, Lin WY, et al. Continued Treatment with Tirzepatide for Maintenance of Weight Reduction in Adults with Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA 2024;331:38–48. https://doi.org/10.1001/jama.2023.24945.

Jastreboff AM, le Roux CW, Stefanski A, Aronne LJ, Halpern B, Wharton S, et al. Tirzepatide for Obesity Treatment and Diabetes Prevention. New England Journal of Medicine 2025;392:958–71. https://doi.org/10.1056/NEJMoa2410819.

Sardar MB, Nadeem ZA, Babar M. Tirzepatide: A novel cardiovascular protective agent in type 2 diabetes mellitus and obesity. Curr Probl Cardiol 2024;49. https://doi.org/10.1016/j.cpcardiol.2024.102489.

De Lemos JA, Linetzky B, Le Roux CW, Laffin LJ, Vongpatanasin W, Fan L, 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;81:E41–3. https://doi.org/10.1161/HYPERTENSIONAHA.123.22022.

Mahar MU, Mahmud O, Ahmed S, Qureshi SA, Kakar WG, Fatima SS. The Effects of Tirzepatide on Lipid Profile: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Obes Metab Syndr 2024;33:348–59. https://doi.org/10.7570/jomes24008.

Das AK, Saboo B, Unnikrishnan AG. Current practices and gaps in management of dyslipidemia in type 2 diabetes mellitus (T2dm) in accordance with american diabetes association (ada) guidelines: A subset analysis from a real-world, cross-sectional observational study (leadd study). Diabetes, Metabolic Syndrome and Obesity 2021;14:2693–700. https://doi.org/10.2147/DMSO.S294842.

Wilson JM, Nikooienejad A, Robins DA, Roell WC, Riesmeyer JS, Haupt A, et al. The dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist, tirzepatide, improves lipoprotein biomarkers associated with insulin resistance and cardiovascular risk in patients with type 2 diabetes. Diabetes Obes Metab 2020;22:2451–9. https://doi.org/10.1111/dom.14174.

Pirro V, Roth KD, Lin Y, Willency JA, Milligan PL, Wilson JM, et al. Effects of Tirzepatide, a Dual GIP and GLP-1 RA, on Lipid and Metabolite Profiles in Subjects with Type 2 Diabetes. Journal of Clinical Endocrinology and Metabolism 2022;107:363–78. https://doi.org/10.1210/clinem/dgab722.

Hankosky ER, Wang H, Neff LM, Kan H, Wang F, Ahmad NN, et al. Tirzepatide reduces the predicted risk of atherosclerotic cardiovascular disease and improves cardiometabolic risk factors in adults with obesity or overweight: SURMOUNT-1 post hoc analysis. Diabetes Obes Metab 2024;26:319–28. https://doi.org/10.1111/dom.15318.

Nicholls SJ, Bhatt DL, Buse JB, Prato S Del, Kahn SE, Lincoff AM, et al. Comparison of tirzepatide and dulaglutide on major adverse cardiovascular events in participants with type 2 diabetes and atherosclerotic cardiovascular disease: SURPASS‐CVOT design and baseline characteristics. Am Heart J 2024;267:1–11. https://doi.org/10.1016/j.ahj.2023.09.007.

Packer M, Zile MR, Kramer CM, Baum SJ, Litwin SE, Menon V, et al. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. New England Journal of Medicine 2025;392:427–37. https://doi.org/10.1056/NEJMoa2410027.

Gastaldelli A, Cusi K, Fernández Landó L, Bray R, Brouwers B, Rodríguez Á. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol 2022;10:393–406. https://doi.org/10.1016/S2213-8587(22)00070-5.

Loomba R, Hartman ML, Lawitz EJ, Vuppalanchi R, Boursier J, Bugianesi E, et al. Tirzepatide for Metabolic Dysfunction–Associated Steatohepatitis with Liver Fibrosis. New England Journal of Medicine 2024;391:299–310. https://doi.org/10.1056/NEJMoa2401943.

Hartman ML, Sanyal AJ, Loomba R, Wilson JM, Nikooienejad A, Bray R, et al. Effects of novel dual GIP and GLP-1 receptor agonist tirzepatide on biomarkers of nonalcoholic steatohepatitis in patients with type 2 diabetes. Diabetes Care, vol. 43, American Diabetes Association Inc.; 2020, p. 1352–5. https://doi.org/10.2337/dc19-1892.

Apperloo EM, Tuttle KR, Pavo I, Haupt A, Taylor R, Wiese RJ, et al. Tirzepatide Associated With Reduced Albuminuria in Participants With Type 2 Diabetes: Pooled Post Hoc Analysis From the Randomized Active- and Placebo-Controlled SURPASS-1-5 Clinical Trials. Diabetes Care 2025;48:430–6. https://doi.org/10.2337/dc24-1773.

Chuang MH, Chen JY, Wang HY, Jiang ZH, Wu VC. Clinical Outcomes of Tirzepatide or GLP-1 Receptor Agonists in Individuals With Type 2 Diabetes. JAMA Netw Open 2024:e2427258. https://doi.org/10.1001/jamanetworkopen.2024.27258.

TREASURE-CKD. https://IchgcpNet/Clinical-Trials-Registry/NCT05536804?Utm_source=chatgptCom n.d. (access available on 07.07.2025)

Malhotra A, Bednarik J, Chakladar S, Dunn JP, Weaver T, Grunstein R, et al. Tirzepatide for the treatment of obstructive sleep apnea: Rationale, design, and sample baseline characteristics of the SURMOUNT -OSA phase 3 trial. Contemp Clin Trials 2024;141. https://doi.org/10.1016/j.cct.2024.107516.

Malhotra A, Heilmann CR, Banerjee KK, Dunn JP, Bunck MC, Bednarik J. Weight reduction and the impact on apnea-hypopnea index: A systematic meta-analysis. Sleep Med 2024;121:26–31. https://doi.org/10.1016/j.sleep.2024.06.014.

Ma J, Liu Y, Hu J, Liu X, Xia Y, Xia W, et al. Tirzepatide administration improves cognitive impairment in HFD mice by regulating the SIRT3-NLRP3 axis. Endocrine 2024. https://doi.org/10.1007/s12020-024-04013-w.

Guo X, Lei M, Zhao J, Wu M, Ren Z, Yang X, et al. Tirzepatide ameliorates spatial learning and memory impairment through modulation of aberrant insulin resistance and inflammation response in diabetic rats. Front Pharmacol 2023;14. https://doi.org/10.3389/fphar.2023.1146960.

Delvadia P, Dhote V, Mandloi AS, Soni R, Shah J. Dual GLP-1 and GIP Agonist Tirzepatide Exerted Neuroprotective Action in a Parkinson’s Disease Rat Model. ACS Chem Neurosci 2025;16:818–25. https://doi.org/10.1021/acschemneuro.4c00729.

TARGETING MULTIPLE PATHWAYS WITH ONE MOLECULE: THE THERAPEUTIC VERSATILITY OF TIRZEPATIDE

Abstract

References

Most read articles by the same author(s)