150
Views
0
CrossRef citations to date
0
Altmetric
Drug Discovery Case History

The preclinical discovery and clinical evaluation of tirzepatide for the treatment of type 2 diabetes

, , , & ORCID Icon
Pages 511-522 | Received 11 Dec 2023, Accepted 26 Feb 2024, Published online: 05 Mar 2024

References

  • Cho NH, Shaw JE, Karuranga S, et al. IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabet Res Clin Pract. 2018;138:271–281. doi: 10.1016/j.diabres.2018.02.023
  • Defronzo RBL. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773–795. doi: 10.2337/db09-9028
  • Rawshani A, Rawshani A, Franzén S, et al. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med. 2017;376(15):1407–1418. doi: 10.1056/NEJMoa1608664
  • Rao Kondapally Seshasai S, Kaptoge S, Thompson A, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011;364:829–841.
  • Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000;106(4):473. doi: 10.1172/JCI10842
  • American Diabetes Association Professional Practice Committee. 9. Pharmacologic approaches to glycemic treatment: standards of care in diabetes—2024. Diabetes Care. 2024;47(Supplement_1):S158–S178. doi: 10.2337/dc24-S009
  • Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American diabetes Association (ADA) and the European Association for the Study of diabetes (EASD). Diabetologia. 2022;65(12):1925–1966. doi: 10.1007/s00125-022-05787-2
  • Diabetes medications for adults with type 2 diabetes: an update [internet] – PubMed [Internet]. [cited 2023 Sep 29]. Available from: https://pubmed.ncbi.nlm.nih.gov/27227214/
  • Karagiannis T, Paschos P, Paletas K, et al. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ. 2012;344(1):e1369. doi: 10.1136/bmj.e1369
  • Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159:262–274. doi: 10.7326/0003-4819-159-4-201308200-00007
  • Tsapas A, Karagiannis T, Kakotrichi P, et al. Comparative efficacy of glucose‐lowering medications on body weight and blood pressure in patients with type 2 diabetes: a systematic review and network meta‐analysis. Diab Obes Metab. 2021 Sep;23(9):2116–2124.
  • Tsapas A, Avgerinos I, Karagiannis T, et al. Comparative effectiveness of glucose-lowering drugs for type 2 diabetes: a systematic review and network meta-analysis. Ann Intern Med. 2020;173:278–287. doi: 10.7326/M20-0864
  • Mcintyre N, Holdsworth CD, Turner DS. New interpretation of oral glucose tolerance. Lancet. 1964;2(7349):20–21. doi: 10.1016/S0140-6736(64)90011-X
  • Elrick H, Stimmler L, Hlad CJ, et al. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964;24(10):1076–1082. doi: 10.1210/jcem-24-10-1076
  • Brown JC, Dryburgh JR. A gastric inhibitory polypeptide. II. The complete amino acid sequence. Can J Biochem. 1971;49(8):867–872. doi: 10.1139/o71-122
  • Nauck M, Schmidt WE, Ebert R, et al. Insulinotropic properties of synthetic human gastric inhibitory polypeptide in man: interactions with glucose, phenylalanine, and cholecystokinin-8. J Clin Endocrinol Metab. 1989;69(3):654–662. doi: 10.1210/jcem-69-3-654
  • Holst JJ, Ørskov C, Vagn Nielsen O, et al. Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut. FEBS Lett. 1987;211(2):169–174. doi: 10.1016/0014-5793(87)81430-8
  • Vilsbøll T, Krarup T, Madsbad S, et al. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept. 2003;114(2–3):115–121. doi: 10.1016/S0167-0115(03)00111-3
  • Drucker DJ, Holst JJ. The expanding incretin universe: from basic biology to clinical translation. Diabetologia. 2023;66(10):1765–1779. doi: 10.1007/s00125-023-05906-7
  • Nauck MA, Meier JJ. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol. 2016;4(6):525–536. doi: 10.1016/S2213-8587(15)00482-9
  • Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696–1705. doi: 10.1016/S0140-6736(06)69705-5
  • Turton MD, O’Shea D, Gunn I, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature. 1996;379(6560):69–72. doi: 10.1038/379069a0
  • Nagell CF, Wettergren A, Pedersen JF, et al. Glucagon-like peptide-2 inhibits antral emptying in man, but is not as potent as glucagon-like peptide-1. Scand J Gastroenterol. 2004;39(4):353–358. doi: 10.1080/00365520410004424
  • Drucker DJ. The cardiovascular biology of glucagon-like peptide-1. Cell Metab. 2016;24(1):15–30. doi: 10.1016/j.cmet.2016.06.009
  • Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27(4):740–756. doi: 10.1016/j.cmet.2018.03.001
  • Yabut JM, Drucker DJ. Glucagon-like peptide-1 receptor-based therapeutics for metabolic liver disease. Endocr Rev. 2023;44(1):14–32. doi: 10.1210/endrev/bnac018
  • Kim SJ, Nian C, Karunakaran S, et al. GIP-overexpressing mice demonstrate reduced diet-induced obesity and steatosis, and improved glucose homeostasis. PloS One. 2012;7(7):e40156. doi: 10.1371/journal.pone.0040156
  • Christensen M, Vedtofte L, Holst JJ, et al. Glucose-dependent insulinotropic polypeptide: a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans. Diabetes. 2011;60(12):3103–3109. doi: 10.2337/db11-0979
  • Finan B, Ma T, Ottaway N, et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci Transl Med. 2013;5(209). doi: 10.1126/scitranslmed.3007218
  • NamKoong C, Kim MS, Jang BT, et al. Central administration of GLP-1 and GIP decreases feeding in mice. Biochem Biophys Res Commun. 2017;490(2):247–252. doi: 10.1016/j.bbrc.2017.06.031
  • Getty-Kaushik L, Song DH, Boylan MO, et al. Glucose-dependent insulinotropic polypeptide modulates adipocyte lipolysis and reesterification. Obesity. 2006;14(7):1124–1131. doi: 10.1038/oby.2006.129
  • Vilsbøll T, Krarup T, Madsbad S, et al. Defective amplification of the late phase insulin response to glucose by GIP in obese type II diabetic patients. Diabetologia. 2002;45(8):1111–1119. doi: 10.1007/s00125-002-0878-6
  • Højberg PV, Vilsbøll T, Rabøl R, et al. Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia. 2009;52:199–207. doi: 10.1007/s00125-008-1195-5
  • Christensen MB, Calanna S, Holst JJ, et al. Glucose-dependent insulinotropic polypeptide: blood glucose stabilizing effects in patients with type 2 diabetes. J Clin Endocrinol Metab. 2014;99(3):E418–E426. doi: 10.1210/jc.2013-3644
  • Deacon CF. Circulation and degradation of GIP and GLP-1. Horm Metab Res. 2004;36(11/12):761–765. doi: 10.1055/s-2004-826160
  • 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. Diab Obes Metab. 2021;Suppl 23(S3):5–29. doi: 10.1111/dom.14496
  • 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. doi: 10.1016/j.molmet.2018.09.009
  • Benson CT, Ohwaki K, Furihata K, et al. Effect of tirzepatide, a dual GIP and GLP-1 receptor agonist, on glycaemic control and body weight in Japanese patients with type 2 diabetes. Diabetes. 2019;68(Suppl 1):S353. doi: 10.2337/db19-1024-P
  • 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. doi: 10.1016/S0140-6736(18)32260-8
  • 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. Diab Obes Metab. 2020;22(6):938–946. doi: 10.1111/dom.13979
  • 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. doi: 10.1016/S0140-6736(21)01324-6
  • 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(6):503–515. doi: 10.1056/NEJMoa2107519
  • 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. doi: 10.1016/S0140-6736(21)01443-4
  • 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(10313):1811–1824. doi: 10.1016/S0140-6736(21)02188-7
  • 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. doi: 10.1001/jama.2022.0078
  • Rosenstock J, Frías JP, Rodbard HW, et al. Tirzepatide vs Insulin Lispro Added to Basal Insulin in Type 2 Diabetes: The SURPASS-6 Randomized Clinical Trial. JAMA. 2023;330(17):1631–1640. doi: 10.1001/jama.2023.20294
  • Nicholls SJ, Bhatt DL, Buse JB, 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. doi: 10.1016/j.ahj.2023.09.007
  • Gao L, Lee BW, Chawla M, et al. Tirzepatide versus insulin glargine as second-line or third-line therapy in type 2 diabetes in the Asia-Pacific region: the SURPASS-AP-Combo trial. Nat Med. 2023;29(6):1500–1510. doi: 10.1038/s41591-023-02344-1
  • 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(9):634–644. doi: 10.1016/S2213-8587(22)00187-5
  • 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(9):623–633. doi: 10.1016/S2213-8587(22)00188-7
  • Karagiannis T, Avgerinos I, Liakos A, et al. Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis. Diabetologia. 2022;65(8):1251–1261. doi: 10.1007/s00125-022-05715-4
  • Shi Q, Wang Y, Hao Q, et al. Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of randomised controlled trials. Lancet. 2022;399(10321):259–269. doi: 10.1016/S0140-6736(21)01640-8
  • Idrees Z, Cancarevic I, Huang L. FDA-Approved pharmacotherapy for weight loss over the Last Decade. Cureus. 2022;14(9):e29262. doi: 10.7759/cureus.29262
  • le Roux CW, Zhang S, Aronne LJ, et al. Tirzepatide for the treatment of obesity: rationale and design of the SURMOUNT clinical development program. Obesity. 2023;31:96–110. doi: 10.1002/oby.23612
  • Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205–216. doi: 10.1056/NEJMoa2206038
  • Garvey WT, Frias JP, Jastreboff AM, 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;402(10402):613–626. doi: 10.1016/S0140-6736(23)01200-X
  • Wadden TA, Chao AM, Machineni S, et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial. Nat Med. 2023;29(11):2909–2918. doi: 10.1038/s41591-023-02597-w
  • 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. 2024;331(1):38–48. doi: 10.1001/jama.2023.24945
  • Karagiannis T, Avgerinos I, Malandris K, et al. Tirzepatide compared to subcutaneous semaglutide for type 2 diabetes: a network meta-analysis. Diabetologia. 2023;66(Suppl 1):S5. doi: 10.1007/s00125-023-05962-z
  • Investor.lilly.org. [Internet]. Indianapolis (IN): Eli Lilly and Company. FDA approves Lilly’s Mounjaro™ (tirzepatide) injection, the first and only GIP and GLP-1 receptor agonist for the treatment of adults with type 2 diabetes; 2022 May 13 [cited 2024 Feb 25]. Available from: https://investor.lilly.com/news-releases/news-release-details/fda-approves-lillys-mounjarotm-tirzepatide-injection-first-and
  • EMA.europe.eu [Internet]. Amsterdam (NL): European Medicines Agency. Mounjaro; 2024 Feb 02 [cited 2024 Feb 25]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/mounjaro
  • He L, Wang J, Ping F, et al. Association of glucagon-like peptide-1 receptor agonist use with risk of gallbladder and biliary diseases: a systematic review and meta-analysis of randomized clinical trials. JAMA Intern Med. 2022;182(5):513–519. doi: 10.1001/jamainternmed.2022.0338
  • Rehfeld JF, Knop FK, Asmar A, et al. Cholecystokinin secretion is suppressed by glucagon-like peptide-1: clue to the mechanism of the adverse gallbladder events of GLP-1-derived drugs. Scand J Gastroenterol. 2018;53(12):1429–1432. doi: 10.1080/00365521.2018.1530297
  • Faillie JL, Yu OH, Yin H, et al. Association of Bile Duct and gallbladder diseases with the use of incretin-based drugs in patients with type 2 diabetes mellitus. JAMA Intern Med. 2016;176(10):1474–1481. doi: 10.1001/jamainternmed.2016.1531
  • Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–1844. doi: 10.1056/NEJMoa1607141
  • Vilsbøll T, Bain SC, Leiter LA, et al. Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy. Diab Obes Metab. 2018;20(4):889–897. doi: 10.1111/dom.13172
  • Lorenz M, Lawson F, Owens D, et al. Differential effects of glucagon-like peptide-1 receptor agonists on heart rate. Cardiovasc Diabetol. 2017;16(1):6. doi: 10.1186/s12933-016-0490-6
  • FDA.org. [Internet]. Silver Spring (MD): U.S. Food and Drug Administration. FDA Approves New Medication for Chronic Weight Management; 2023 Nov 08 [cited 2023 Nov 15]. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-new-medication-chronic-weight-management
  • Gov.uk [Internet]. United Kingdom: the medicines and healthcare products regulatory agency. MHRA authorises diabetes drug Mounjaro (tirzepatide) for weight management and weight loss; 2023 Nov 08 [cited 2023 Nov 22]. Available from: https://www.gov.uk/government/news/mhra-authorises-diabetes-drug-mounjaro-tirzepatide-for-weight-management-and-weight-loss
  • EMA.europe.eu [Internet]. Amsterdam (NL): European Medicines Agency. Mounjaro: Pending EC decision | European Medicines Agency; 2023 Nov 10 [cited 2023 Nov 22]. Available from: https://www.ema.europa.eu/en/medicines/human/summaries-opinion/mounjaro
  • Karagiannis T, Bekiari E, Tsapas A. Socioeconomic aspects of incretin-based therapy. Diabetologia. 2023;66(10):1859–1868. doi: 10.1007/s00125-023-05962-z
  • Eli Lilly and Company. A study to evaluate tirzepatide (LY3298176) in pediatric and adolescent participants with type 2 diabetes mellitus inadequately controlled with metformin or basal insulin or both. In ClinicalTrials.Gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2023 Sep 30]. Available from: https://clinicaltrials.gov/study/NCT05260021NLM.Identifier:NCT05260021
  • Eli Lilly and Company. A study of tirzepatide compared with intensified conventional care in adult participants with type 2 diabetes. In ClinicalTrials.Gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2023 Sep 30]. Available from: https://clinicaltrials.gov/study/NCT05433584NLMIdentifier:NCT05433584
  • Eli Lilly and Company. A study of tirzepatide (LY3298176) in Chinese participants with type 2 diabetes (SURPASS-CN-MONO). In ClinicalTrials.Gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2023 Sep 30]. Available from: https://clinicaltrials.gov/study/NCT05963022NLMIdentifier:NCT05963022
  • Eli Lilly and Company. A study of tirzepatide (LY3298176) in Chinese participants with type 2 diabetes. In ClinicalTrials.Gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2023 Sep 30]. Available from: https://clinicaltrials.gov/study/NCT05691712NLMIdentifier:NCT05691712
  • Eli Lilly and Company. A study of tirzepatide (LY3298176) in adult participants with type 2 diabetes switching from dulaglutide (SURPASS-SWITCH). In ClinicalTrials.Gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2023 Sep 30]. Available from: https://clinicaltrials.gov/study/NCT05564039NLMIdentifier:NCT05564039
  • Eli Lilly and Company. A study of tirzepatide (LY3298176) in Chinese participants without type 2 diabetes who have obesity or overweight (SURMOUNT-CN). In ClinicalTrials.Gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2023 Sep 30]. Available from: https://clinicaltrials.gov/study/NCT05024032NLMIdentifier:NCT05024032
  • Eli Lilly and Company. A study of tirzepatide (LY3298176) in participants with obesity disease. In ClinicalTrials.Gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2023 Sep 30]. Available from: https://clinicaltrials.gov/study/NCT04844918NLMIdentifier:NCT04844918
  • Eli Lilly and Company. Obstructive Sleep Apnea Master Protocol GPIF: A Study of Tirzepatide (LY3298176) in Participants With Obstructive Sleep Apnea. In ClinicalTrials.Gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2023 Sep 30]. Available from: https://clinicaltrials.gov/study/NCT05412004NLMIdentifier:NCT05412004
  • Eli Lilly and Company. A study of tirzepatide (LY3298176) on the reduction on morbidity and mortality in adults with obesity. In ClinicalTrials.Gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2023 Sep 30]. Available from: https://clinicaltrials.gov/study/NCT05556512NLMIdentifier:NCT05556512

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.