326
Views
0
CrossRef citations to date
0
Altmetric
Drug Profile

An update on tirzepatide for the management of type 2 diabetes: a focus on the phase 3 clinical development program

Pages 111-130 | Received 19 Dec 2022, Accepted 22 Feb 2023, Published online: 12 Mar 2023

References

  • ElSayed NA, Aleppo G, Aroda VR, et al. Standards of Care in Diabetes-2023. Diabetes Care. 2023;46(Suppl. Supplement_1):S1–S291.
  • Joseph JJ, Deedwania P, Acharya T, et al. Comprehensive management of cardiovascular risk factors for adults with type 2 diabetes: a scientific statement from the American Heart Association. Circulation. 2022;145:e722–e759.
  • Lingvay I, Sumithran P, Cohen RV, et al. Obesity management as a primary treatment goal for type 2 diabetes: time to reframe the conversation. Lancet. 2022;399:394–405. Erratum in: Lancet. 2022;399:358
  • Nauck MA, Quast DR, Wefers J, et al. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab. 2021;46:101102.
  • Wilding JPH, Evans M, Fernando K, et al. The place and value of sodium-glucose cotransporter 2 inhibitors in the evolving treatment paradigm for type 2 diabetes mellitus: a narrative review. Diabetes Ther. 2022;13:847–872.
  • Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022;45:2753–2786.
  • Blonde L, Umpierrez GE, Reddy SS, et al. American association of clinical endocrinology clinical practice guideline: developing a diabetes mellitus comprehensive care plan-2022 update. Endocr Pract. 2022;28:923–1049.
  • Frias JP, Bonora E, Nevarez Ruiz L, et al. Efficacy and safety of dulaglutide 3.0 mg and 4.5 mg versus dulaglutide 1.5 mg in metformin-treated patients with type 2 diabetes in a randomized controlled trial (AWARD-11). Diabetes Care. 2021;44:765–773.
  • Frías JP, Auerbach P, Bajaj HS, et al. Efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial. Lancet Diabetes Endocrinol. 2021;9:563–574.
  • Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol Metab. 2018;18:3–14.
  • Nauck MA, Quast DR, Wefers J, et al. The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: a pathophysiological update. Diabetes Obes Metab. 2021;23(Suppl. 3):5–29.
  • Campbell JE. Targeting the GIPR for obesity: to agonize or antagonize? Potential mechanisms. Mol Metab. 2021;46:101139.
  • Urva S, Quinlan T, Landry J, et al. Effects of renal impairment on the pharmacokinetics of the dual GIP and GLP-1 receptor agonist tirzepatide. Clin Pharmacokinet. 2021;60:1049–1059.
  • Urva S, Quinlan T, Landry J, et al. Effects of hepatic impairment on the pharmacokinetics of the dual GIP and GLP-1 receptor agonist tirzepatide. Clin Pharmacokinet. 2022;61:1057–1067.
  • Heise T, Mari A, DeVries JH, et al. Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial. Lancet Diabetes Endocrinol. 2022;10:418–429.
  • 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;392:2180–2193.
  • 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;22:938–946.
  • Frías JP. Tirzepatide: a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) dual agonist in development for the treatment of type 2 diabetes. Expert Rev Endocrinol Metab. 2020;15:379–394.
  • 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;12:143–157.
  • 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;21:169.
  • fda.gov [internet]. US Food and Drug Administration (FDA). FDA news release. FDA approves novel, dual-targeted treatment for type 2 diabetes. In clinical trials, treatment proved more effective than other therapies evaluated. May 13, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-dual-targeted-treatment-type-2-diabetes. cited 2022 Dec 16
  • ema.europa.eu [internet]. European Medicines Agency (EMA). MOUNJARO (tirzepatide) page. https://www.ema.europa.eu/en/medicines/human/EPAR/mounjaro#overview-section. cited 2022 Dec 16
  • 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;398:143–155.
  • Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385:503–515.
  • 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;398:583–598.
  • Del Prato S, Kahn SE, Pavo I, et al. 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;398:1811–1824.
  • 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;327:534–545.
  • Inagaki N, Takeuchi M, Oura T, et al. Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): a double-blind, multicentre, randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2022;10:623–633.
  • Kadowaki T, Chin R, Ozeki A, et al. Safety and efficacy of tirzepatide as an add-on to single oral antihyperglycaemic medication in patients with type 2 diabetes in Japan (SURPASS J-combo): a multicentre, randomised, open-label, parallel-group, phase 3 trial. Lancet Diabetes Endocrinol. 2022;10:634–644.
  • Sattar N, McGuire DK, Pavo I, et al. Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat Med. 2022;28:591–598.
  • Heerspink HJL, Sattar N, Pavo I, et al. Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: post-hoc analysis of an open-label, randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2022;10:774–785.
  • Battelino T, Bergenstal RM, Rodríguez A, et al. Efficacy of once-weekly tirzepatide versus once-daily insulin degludec on glycaemic control measured by continuous glucose monitoring in adults with type 2 diabetes (SURPASS-3 CGM): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol. 2022;10:407–417. Erratum in: Lancet Diabetes Endocrinol. 2022;10:e8.
  • Gastaldelli A, Cusi K, Fernández Landó L, et al. 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.
  • database.ich.org [internet]. International council for harmonization of technical requirements for pharmaceuticals for human use. addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials E9(R1). November 20, 2019. Available from: https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf. cited 2022 Dec 16
  • Gogtay NJ, Ranganathan P, Aggarwal R. Understanding estimands. Perspect Clin Res. 2021;12:106–112.
  • uspl.lilly.com [internet]. MOUNJARO (tirzepatide) Injection [package insert]. Indianapolis (IN): Eli Lilly and Company. 2022. https://uspl.lilly.com/mounjaro/mounjaro.html. cited 2022 Dec 17
  • ClinicalTrials.gov [internet]. Identifier NCT04093752, A randomized, phase 3, open-label trial comparing the effect of tirzepatide once weekly versus titrated insulin glargine on glycemic control in patients with type 2 diabetes on metformin with or without a sulfonylurea. Bethesda (MD): National Library of Medicine (US). 2019 Sep 18; Last updated 2021 Dec 14. [cited 2022 Dec 16]. [about 7 screens]. Available from: https://clinicaltrials.gov/ct2/show/NCT04093752
  • ClinicalTrials.gov [internet]. Identifier NCT04537923, A randomized, phase 3, open-label trial comparing the effect of the addition of tirzepatide once weekly versus insulin lispro (U100) three times daily in participants with type 2 diabetes inadequately controlled on insulin glargine (U100) with or without metformin (SURPASS-6). Bethesda (MD): National Library of Medicine (US). 2020 Sep 03; Last updated 2022 Nov 23. [cited 2022 Dec 16]. [about 7 screens]. Available from https://clinicaltrials.gov/ct2/show/NCT04537923
  • ClinicalTrials.gov [internet]. Identifier NCT04255433, The effect of tirzepatide versus dulaglutide on major adverse cardiovascular events in patients with type 2 diabetes (SURPASS-CVOT). Bethesda (MD): National Library of Medicine (US). 2020 Feb 05; Last updated 2022 Dec 12. [cited 2022 Dec 16]. [about 7 screens]. Available from https://clinicaltrials.gov/ct2/show/NCT04255433
  • ClinicalTrials.gov [internet]. Identifier NCT05564039, A phase 4, randomized, open-Label, active-controlled study to investigate the efficacy and safety of switching from weekly dulaglutide to weekly tirzepatide in adults with type 2 diabetes. Bethesda (MD): National Library of Medicine (US). 2022 OCT 03; Last updated 2022 Dec 08. [cited 2022 Dec 16]; [about 7 screens]. Available from https://clinicaltrials.gov/ct2/show/NCT05564039
  • ClinicalTrials.gov [internet]. Identifier NCT05433584, A randomized, open-label, parallel-group, two-arm, phase 4 study to evaluate the long-term efficacy and safety of tirzepatide compared with intensified conventional care in adults when initiating treatment early in the course of type 2 diabetes. Bethesda (MD): National Library of Medicine (US). 2012 Jun 27; Last updated 2022 Dec 12 [cited 2022 Dec 16]; [about 7 screens]. Available from https://clinicaltrials.gov/ct2/show/NCT05433584
  • ClinicalTrials.gov [internet]. Identifier NCT05260021, A randomized, double-blind, placebo-controlled, phase 3 study with an open-label extension assessing the efficacy, safety, and pharmacokinetics/pharmacodynamics of tirzepatide in pediatric and adolescent participants with type 2 diabetes mellitus inadequately controlled with metformin, or basal insulin, or both. Bethesda (MD): National Library of Medicine (US). 2022 Mar 02; Last updated 2022 Dec 12. [cited 2022 Dec 16]; [about 7 screens]. Available from https://clinicaltrials.gov/ct2/show/NCT05260021
  • ClinicalTrials.gov [internet]. Identifier NCT04657003, Efficacy and safety of tirzepatide once weekly in participants with type 2 diabetes who have obesity or are overweight: a randomized, double-blind, placebo-controlled trial (SURMOUNT-2). Bethesda (MD): National Library of Medicine (US). 2020 Dec 07; Last updated 2022 Apr 19 [cited 2022 Dec 16]; [about 7 screens]. Available from https://clinicaltrials.gov/ct2/show/NCT04657003
  • ClinicalTrials.gov [internet]. Identifier NCT04847557, A randomized, double-blind, placebo-controlled, phase 3 study comparing the efficacy and safety of tirzepatide versus placebo in patients with heart failure with preserved ejection fraction and obesity (SUMMIT). Bethesda (MD): National Library of Medicine (US). 2021 Apr 19; Last updated 2022 Dec 12 [cited 2022 Dec 16]; [about 7 screens]. Available from https://clinicaltrials.gov/ct2/show/NCT04847557
  • Vadher K, Patel H, Mody R, et al. Efficacy of tirzepatide 5, 10 and 15 mg versus semaglutide 2 mg in patients with type 2 diabetes: an adjusted indirect treatment comparison. Diabetes Obes Metab. 2022;24:1861–1868.
  • Edelman SV, Polonsky WH. Type 2 diabetes in the real world: the elusive nature of glycemic control. Diabetes Care. 2017;40:1425–1432.
  • Strum MW, Hopkins R, West DS, et al. Effects of a medication assistance program on health outcomes in patients with type 2 diabetes mellitus. Am J Health Syst Pharm. 2005 15;62:1048–1052.
  • Wharton S, Davies M, Dicker D, et al. Managing the gastrointestinal side effects of GLP-1 receptor agonists in obesity: recommendations for clinical practice. Postgrad Med. 2022;134:14–19.
  • uspl.lilly.com [internet]. MOUNJARO (tirzepatide) Injection [Instructions for Use]. Indianapolis (IN): Eli Lilly and Company. 2022. https://uspl.lilly.com/mounjaro/mounjaro.html cited 2022 Dec 17
  • Matza LS, Boye KS, Stewart KD, et al. Assessing patient PREFERence between the dulaglutide pen and the semaglutide pen: a crossover study (PREFER). Diabetes Obes Metab. 2020;22:355–364.
  • Wettergreen SA, Stewart MP, Kennedy K, et al. Comparison of the usability, accuracy, preference, and satisfaction of three once-weekly glucagon-Like peptide 1 receptor agonist pen devices in people with type 2 diabetes. Diabetes Spectr. 2022:ds210108. https://doi.org/10.2337/ds21-0108
  • fda.gov [internet]. US Food and Drug Administration (FDA). https://www.accessdata.fda.gov/scripts/drugshortages/dsp_SearchResults.cfm. cited 2022 Dec 17
  • Blonde L, Khunti K, Harris SB, et al. Interpretation and impact of real-world clinical data for the practicing clinician. Adv Ther. 2018 Nov;35(11):1763–1774. Epub 2018 Oct 24. PMID: 30357570; PMCID: PMC6223979
  • Ryan DH, Yockey SR. Weight loss and improvement in comorbidity: differences at 5%, 10%, 15%, and over. Curr Obes Rep. 2017;6:187–194.
  • Zhang J, Van Spall HGC, Wang Y, et al. Twenty-year trends in racial and ethnic enrollment in large diabetes randomized controlled trials. BMC Med. 2022;20:294.
  • FDA.gov [internet]. Food and Drug Administration (FDA). Diversity plans to improve enrollment of participants from underrepresented racial and ethnic populations in clinical trials; draft guidance for industry. April 2022. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/diversity-plans-improve-enrollment-participants-underrepresented-racial-and-ethnic-populations. cited 2022 Dec 17.
  • minorityhealth.hhs.gov [internet]. US department of health and human services office of minority health. https://minorityhealth.hhs.gov. cited 2022 Dec 17
  • Morehouse School of Medicine. Priscilla Pemu, M.D., M.S., F.A.C.P., professor of medicine and vice chair of research. diversity in clinical trials: preparing physicians to make a difference. January 8, 2019. https://www.msm.edu/blog/2019/diversity-clinical-trials.php. cited 2022 Dec 17
  • Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metab. 2022;34:1234–1247.
  • Urva S, Coskun T, Loh MT, et al. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. Lancet. 2022;400:1869–1881.
  • Enebo LB, Berthelsen KK, Kankam M, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial. Lancet. 2021;397:1736–1748.
  • novonordisk.com [internet]. Company announcement. novo nordisk successfully completes phase 2 trial with CagriSema in people with type 2 diabetes. August 22, 2022. https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=131155. cited 2022 Dec 17
  • ClinicalTrials.gov [internet]. Identifier NCT05394519, Efficacy and safety of cagrilintide s.c. 2.4 mg in combination with semaglutide s.c. 2.4 mg (CagriSema s.c. 2.4 mg/2.4 mg) once-weekly in participants with overweight or obesity and type 2 diabetes. Bethesda (MD): National Library of Medicine (US). 2021 May 27; Last updated 2022 Dec 16. [cited 2022 Dec 17]; [about 7 screens]. Available from https://clinicaltrials.gov/ct2/show/NCT05394519
  • ClinicalTrials.gov [internet]. Identifier NCT05567796, Efficacy and safety of cagrilintide s.c. 2.4 Milligram (mg) in combination with semaglutide subcutaneous (s.c). 2.4 mg (CagriSema s.c. 2.4 mg/2.4 mg) once-weekly in participants with overweight or obesity. Bethesda (MD): National Library of Medicine (US). 2021 Oct 05; Last updated 2022 Dec 07 [cited 2022 Dec 17]; [about 7 screens]. Available from https://clinicaltrials.gov/ct2/show/NCT05567796

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.