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CC BY-NC-ND 4.0 · Journal of Diabetes and Endocrine Practice 2024; 07(01): 15-24
DOI: 10.1055/s-0043-1775966
Review Article

Dual GLP-1/GIP Agonist Tirzepatide for Diabetes and Obesity: A Review of the Evidence

Rahaf Wardeh 
1   Department of Internal Medicine, Rashid Hospital, Dubai Health Authority, Dubai, United Arab Emirates
,
Tabarak Haamid Elbo Iswadi 
1   Department of Internal Medicine, Rashid Hospital, Dubai Health Authority, Dubai, United Arab Emirates
,
Hind Alsharayri
1   Department of Internal Medicine, Rashid Hospital, Dubai Health Authority, Dubai, United Arab Emirates
,
Fauzia Rashid
2   Department of Diabetes & Endocrinology, Dubai Hospital, Dubai Health Authority, Dubai, United Arab Emirates
,
Nada Alhashemi
2   Department of Diabetes & Endocrinology, Dubai Hospital, Dubai Health Authority, Dubai, United Arab Emirates
,
Alaaeldin Bashier 
2   Department of Diabetes & Endocrinology, Dubai Hospital, Dubai Health Authority, Dubai, United Arab Emirates
› Author Affiliations Funding and Sponsorship None.
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Abstract

Background Tirzepatide is a novel dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptors agonist in management of type 2 diabetes mellitus. The aim of this literature review is to comprehensively assess its clinical, biochemical, and safety profiles.

Materials and Methods Search was conducted in several databases including PubMed from drug inception through end of 2022. Publications relevant to tirzepatide including randomized controlled trials, meta-analysis studies, post-hoc analyses, and conference proceedings were identified to examine its profile. Additional necessary references were explored and included as needed.

Results Tirzepatide is a twincretin, acting on both GLP-1 and GIP receptors. Its performance in glycemic control and weight loss was greater than that of GLP-1 receptor agonist or insulin, comparatively. It demonstrated promising positive renal outcomes and was not associated with a higher cardiovascular risk, in addition to favorable effects on lipid, hepatic and blood pressure profiles. Most common adverse events were gastrointestinal side effects and hypoglycemia.

Conclusion Novel dual GLP-1/GIP agonist Tirzepatide shows superior efficacy in glycemic control and weight loss in T2 diabetes mellitus patients. More evidence is needed to explore and compare long-term cardiovascular and renal outcomes reflecting real-world clinical practice.

Keywords

tirzepatide - GIP/GLP-1 agonist - type 2 diabetes - weight loss - glycemic control - incretin

Compliance with Ethical Principles

This review falls in compliance with research ethical standards and principles. There has been no human subjects or participants involved.


Authors' Contributions

A.B. conceived the concept of the study and coordinated its design. R.W., T.E., and H.A. performed the literature search, selection of studies and review of the data, drafting the manuscript and editing it. F.R., N.A., and A.B. critically reviewed the manuscript and edited it. R.W. and A.B. supervised the article. All authors read and approved the final manuscript.




Publication History

Article published online:
13 October 2023

© 2023. Gulf Association of Endocrinology and Diabetes (GAED). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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  • References

  • 1 International Diabetes Federation. 2021 , December 9). Diabetes facts & figures. International Diabetes Federation - Home. Accessed September 19, 2023 at: https://idf.org/aboutdiabetes/what-is-diabetes/facts-figures.html
    PubMedGoogle Scholar
  • 2 World Health Organization. 2022 , September 16). Diabetes Key Facts. World Health Organization. Accessed September 19, 2023 at: https://www.who.int/news-room/fact-sheets/detail/diabetes
    PubMedGoogle Scholar
  • 3 Al Awadi F, Hassanein M, Hussain HY. et al. Prevalence of diabetes and associated health risk factors among adults in Dubai, United Arab Emirates: results from Dubai Household Survey 2019. Dubai Diabetes Endocrinol J 2021; 26 (04) 164-173
    CrossrefGoogle Scholar
  • 4 Rosenstock J, Wysham C, Frías 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; 398 (10295): 143-155
    CrossrefPubMedGoogle Scholar
  • 5 Min T, Bain SC. The role of tirzepatide, dual GIP and GLP-1 receptor agonist, in the management of type 2 diabetes: the surpass clinical trials. Diabetes Ther 2021; 12 (01) 143-157
    CrossrefPubMedGoogle Scholar
  • 6 Dutta D, Surana V, Singla R, Aggarwal S, Sharma M. Efficacy and safety of novel twincretin tirzepatide a dual GIP and GLP-1 receptor agonist in the management of type-2 diabetes: a Cochrane meta-analysis. Indian J Endocrinol Metab 2021; 25 (06) 475-489
    CrossrefPubMedGoogle Scholar
  • 7 Mahapatra MK, Karuppasamy M, Sahoo BM. Therapeutic potential of semaglutide, a newer GLP-1 receptor agonist, in abating obesity, non-alcoholic steatohepatitis and neurodegenerative diseases: a narrative review. Pharm Res 2022; 39 (06) 1233-1248
    CrossrefPubMedGoogle Scholar
  • 8 Frías JP, Davies MJ, Rosenstock J. et al; SURPASS-2 Investigators. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med 2021; 385 (06) 503-515
    CrossrefPubMedGoogle Scholar
  • 9 Ludvik B, Giorgino F, Jódar E. et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet 2021; 398 (10300): 583-598
    CrossrefPubMedGoogle Scholar
  • 10 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. JAMA 2022; 327 (06) 534-545
    CrossrefPubMedGoogle Scholar
  • 11 Del Prato S, Kahn SE, Pavo I. et al; SURPASS-4 Investigators. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet 2021; 398 (10313): 1811-1824
    CrossrefPubMedGoogle Scholar
  • 12 Ryan DH, Yockey SR. Weight loss and improvement in comorbidity: differences at 5%, 10%, 15%, and over. Curr Obes Rep 2017; 6 (02) 187-194
    CrossrefPubMedGoogle Scholar
  • 13 Jung HN, Jung CH. The upcoming weekly tides (Semaglutide vs. Tirzepatide) against obesity: step or surpass?. J Obes Metab Syndr 2022; 31 (01) 28-36
    CrossrefPubMedGoogle Scholar
  • 14 Pedersen S, Umpierrez GE, Giorgino F. et al. 729-P: Relationship between body weight change and glycemic control with Tirzepatide treatment in people with type 2 diabetes. Diabetes 2022; 71 (supplement_1): 729-p
    CrossrefGoogle Scholar
  • 15 Davies M, Færch L, Jeppesen OK. et al; STEP 2 Study Group. 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; 397 (10278): 971-984
    CrossrefPubMedGoogle Scholar
  • 16 Rawshani A, Rawshani A, Franzén S. et al. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2018; 379 (07) 633-644
    CrossrefPubMedGoogle Scholar
  • 17 Sattar N, McGuire DK, Pavo I. et al. Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat Med 2022; 28 (03) 591-598
    CrossrefPubMedGoogle Scholar
  • 18 A Study of Tirzepatide (LY3298176) Compared With Dulaglutide on Major Cardiovascular Events in Participants With Type 2 Diabetes (SURPASS-CVOT). Accessed September 19, 2023 at: https://clinicaltrials.gov/ct2/show/NCT04255433
    Google Scholar
  • 19 Marso SP, Bain SC, Consoli A. et al; SUSTAIN-6 Investigators. SEMAGLUTIDE and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016; 375 (19) 1834-1844
    CrossrefPubMedGoogle Scholar
  • 20 Husain M, Birkenfeld AL, Donsmark M. et al; PIONEER 6 Investigators. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019; 381 (09) 841-851
    CrossrefPubMedGoogle Scholar
  • 21 Marso SP, Daniels GH, Brown-Frandsen K. et al; LEADER Steering Committee, LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375 (04) 311-322
    CrossrefPubMedGoogle Scholar
  • 22 Sattar N, Lee MMY, Kristensen SL. et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol 2021; 9 (10) 653-662
    CrossrefPubMedGoogle Scholar
  • 23 de Jong M, van der Worp HB, van der Graaf Y, Visseren FLJ, Westerink J. Pioglitazone and the secondary prevention of cardiovascular disease. A meta-analysis of randomized-controlled trials. Cardiovasc Diabetol 2017; 16 (01) 134
    CrossrefPubMedGoogle Scholar
  • 24 Thomas MK, Nikooienejad A, Bray R. et al. Dual GIP and GLP-1 receptor agonist tirzepatide improves beta-cell function and insulin sensitivity in type 2 diabetes. J Clin Endocrinol Metab 2021; 106 (02) 388-396
    CrossrefPubMedGoogle Scholar
  • 25 Taskinen M-R, Borén J. New insights into the pathophysiology of dyslipidemia in type 2 diabetes. Atherosclerosis 2015; 239 (02) 483-495
    CrossrefPubMedGoogle Scholar
  • 26 Ramms B, Gordts PLSM. Apolipoprotein C-III in triglyceride-rich lipoprotein metabolism. Curr Opin Lipidol 2018; 29 (03) 171-179
    CrossrefPubMedGoogle Scholar
  • 27 Wilson JM, Nikooienejad A, Robins DA. 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 (12) 2451-2459
    CrossrefPubMedGoogle Scholar
  • 28 Asmar M, Asmar A, Simonsen L. et al. The gluco- and liporegulatory and vasodilatory effects of glucose-dependent insulinotropic polypeptide (GIP) are abolished by an antagonist of the human GIP receptor. Diabetes 2017; 66 (09) 2363-2371
    CrossrefPubMedGoogle Scholar
  • 29 Ginsberg HN, Elam MB, Lovato LC. et al; ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010; 362 (17) 1563-1574
    CrossrefPubMedGoogle Scholar
  • 30 Dulai PS, Singh S, Patel J. et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology 2017; 65 (05) 1557-1565
    CrossrefPubMedGoogle Scholar
  • 31 Loomba R, Abraham M, Unalp A. et al; Nonalcoholic Steatohepatitis Clinical Research Network. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology 2012; 56 (03) 943-951
    CrossrefPubMedGoogle Scholar
  • 32 Romero-Gómez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol 2017; 67 (04) 829-846
    CrossrefPubMedGoogle Scholar
  • 33 Hartman ML, Sanyal AJ, Loomba 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 2020; 43 (06) 1352-1355
    CrossrefPubMedGoogle Scholar
  • 34 Vuppalanchi R, Jain AK, Deppe R. et al. Relationship between changes in serum levels of keratin 18 and changes in liver histology in children and adults with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2014; 12 (12) 2121-30.e1 , 2
    CrossrefPubMedGoogle Scholar
  • 35 Luo Y, Oseini A, Gagnon R. et al. An evaluation of the collagen fragments related to fibrogenesis and fibrolysis in nonalcoholic steatohepatitis. Sci Rep 2018; 8 (01) 12414
    CrossrefPubMedGoogle Scholar
  • 36 Bril F, Leeming DJ, Karsdal MA. et al. Use of plasma fragments of propeptides of type III, V, and VI Procollagen for the detection of liver fibrosis in type 2 diabetes. Diabetes Care 2019; 42 (07) 1348-1351
    CrossrefPubMedGoogle Scholar
  • 37 Dutta D, Kumar M, Shivaprasad KS, Kumar A, Sharma M. Impact of semaglutide on biochemical and radiologic measures of metabolic-dysfunction associated fatty liver disease across the spectrum of glycaemia: a meta-analysis. Diabetes Metab Syndr 2022; 16 (06) 102539
    CrossrefPubMedGoogle Scholar
  • 38 Carretero-Gómez J, Carrasco-Sánchez FJ, Fernández-Rodríguez JM. et al. Effect of semaglutide on fatty liver disease biomarkers in patients with diabetes and obesity. Rev Clin Esp 2023; 223 (03) 134-143
    Google Scholar
  • 39 Lingvay I, Mosenzon O, Brown K, Cui X, Lando LF, Patel H. 716-P: Systolic blood pressure reduction with tirzepatide across SURPASS program: a mediation analysis using weight loss as a factor. Diabetes 2022; 71 (supplement_1): 716–P
    CrossrefGoogle Scholar
  • 40 Aviles Bueno B, Soler MJ, Perez-Belmonte L, Jimenez Millan A, Rivas Ruiz F, Garcia de Lucas MD. Semaglutide in type 2 diabetes with chronic kidney disease at high risk progression-real-world clinical practice. Clin Kidney J 2022; 15 (08) 1593-1600
    CrossrefPubMedGoogle Scholar
  • 41 Heerspink HL, Ssattar N, Pavo I. et al. 17-OR: ADA Presidents' Select Abstract: effects of tirzepatide vs. insulin glargine 100 U/mL on kidney outcomes in participants with type 2 diabetes in SURPASS-4. Diabetes 2022; 71 (supplement_1): 17–OR
    CrossrefGoogle Scholar
  • 42 Neuen BL, Young T, Heerspink HJL. et al. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2019; 7 (11) 845-854
    CrossrefPubMedGoogle Scholar
  • 43 Frias JP, Nauck MA, Van J. et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet 2018; 392 (10160): 2180-2193
    CrossrefPubMedGoogle Scholar
  • 44 Frias JP, Nauck MA, Van J. et al. Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens. Diabetes Obes Metab 2020; 22 (06) 938-946
    CrossrefPubMedGoogle Scholar