Tirzepatide: A First-in-class Twincretin for the Management of Type 2
Diabetes

Shalini      Jaswal; Priya      Bisht; Rajiv      Patel; Darakhshan      Parveen; Ghanshyam   Das   Gupta; Sant   Kumar   Verma

doi:10.2174/1570180820666230130153219

Abstract

Background: Tirzepatide (LY3298176) was approved by U.S. Food and Drug Administration (FDA) on May 13th, 2022. The drug was developed by Eli Lilly and Co. and marketed under the trade name of ‘Mounjaro’, a first-in-class ‘Twincretin’, which is a dual activator of GIP and GLP-1 receptors, resulting in improved blood sugar control in type 2 diabetics The review covered the comprehensive insight on the drug discovery journey of tirzepatide.

Methods: Using the keywords "Tirzepatide", "Twincretin", "Type 2 Diabetes", "GLP-1", and "GIP," data were gathered from Medline, PubMed, Google Scholar, and Science Direct.

Results: The review covers comprehensive insight into the drug discovery journey of tirzepatide. The drug-target structural specialty has been discussed to establish the dual inhibition mechanism of action of tirzepatide. The results of in vitro studies, preclinical and clinical trial data, pharmacokinetic profile, dosing regimen, side effects, and toxicities of tirzepatide are reviewed to account for the potency, efficacy, and safety of the newly approved drug. The drug molecule may attain a privileged status in the antidiabetic market as the clinical data showed that it effectively reduces HbA1c level in monotherapy as well as in add-on therapy, compared to placebo, semaglutide, insulin degludec, and insulin glargine, and found effective in type 2 diabetes associated conditions like atherogenic dyslipidemia and non-alcoholic steatohepatitis.

Conclusion: Tirzepatide is a clinically efficient drug, exhibiting a good safety profile as evident from the existing clinical data, and could be a new alternative to the currently available antidiabetics for the treatment of T2D.

Keywords: Tirzepatide, type 2 diabetes, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), atherosclerosis, amino acids.

« Previous

Graphical Abstract

[1]
FDA approves tirzepatide: A potent new drug for type 2 diabetes.   Available from:
          https://www.medicalnewstoday.com/articles/fda-approves-tirzepatide-a-potent-new-drug-for-type-2-diabetes#How-effective-is-it

[2]
FDA approves novel, dual-targeted treatment for type 2 diabetes.    Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-novel-dual-targeted-treatment-type-2-diabetes? utm_medium=email&utm_source=govdelivery

[3]
Chavda, V.P.; Ajabiya, J.; Teli, D.; Bojarska, J.; Apostolopoulos, V. Tirzepatide, a new era of dual-targeted treatment for diabetes and obesity: A mini-review. Molecules,  2022, 27(13), 4315.
 [http://dx.doi.org/10.3390/molecules27134315] [PMID:  35807558]

[4]
Janssen, P.; Rotondo, A.; Mulé, F.; Tack, J. Review article: a comparison of glucagon-like peptides 1 and 2. Aliment. Pharmacol. Ther.,  2013, 37(1), 18-36.
 [http://dx.doi.org/10.1111/apt.12092] [PMID:  23121085]

[5]
Verspohl, E.J. Novel therapeutics for type 2 diabetes: Incretin hormone mimetics (glucagon-like peptide-1 receptor agonists) and dipeptidyl peptidase-4 inhibitors. Pharmacol. Ther.,  2009, 124(1), 113-138.
 [http://dx.doi.org/10.1016/j.pharmthera.2009.06.002] [PMID:  19545590]

[6]
Lovshin, J.A. Glucagon-like peptide-1 receptor agonists: a class update for treating type 2 diabetes. Can. J. Diabetes,  2017, 41(5), 524-535.
 [http://dx.doi.org/10.1016/j.jcjd.2017.08.242] [PMID:  28942790]

[7]
Kalra, S.; Bhattacharya, S.; Kapoor, N. Contemporary classification of glucagon-like peptide 1 receptor agonists (GLP1RAs). Diabetes Ther.,  2021, 12(8), 2133-2147.
 [http://dx.doi.org/10.1007/s13300-021-01113-y] [PMID:  34268675]

[8]
Li, J.; Albajrami, O.; Zhuo, M.; Hawley, C.E.; Paik, J.M. Decision algorithm for prescribing SGLT2 inhibitors and GLP-1 receptor agonists for diabetic kidney disease. Clin. J. Am. Soc. Nephrol.,  2020, 15(11), 1678-1688.
 [http://dx.doi.org/10.2215/CJN.02690320] [PMID:  32518100]

[9]
Nathan, D.M.; Buse, J.B.; Davidson, M.B.; Heine, R.J.; Holman, R.R.; Sherwin, R.; Zinman, B. Management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care,  2006, 29(8), 1963-1972.
 [http://dx.doi.org/10.2337/dc06-9912] [PMID:  16873813]

[10]
Thondam, S.K. The role of Glucose dependent Insulinotropic Polypeptide (GIP) and other gut hormones in glucose regulation and adipose tissue metabolism in obesity and type 2 diabetes. Doctor of Medicine. The University of Liverpool: United Kingdom, May, 2017.

[11]
Heimbürger, S.M.; Bergmann, N.C.; Augustin, R.; Gasbjerg, L.S.; Christensen, M.B.; Knop, F.K. Glucose-dependent insulinotropic polypeptide (GIP) and cardiovascular disease. Peptides,  2020, 125, 170174.
 [http://dx.doi.org/10.1016/j.peptides.2019.170174] [PMID:  31689454]

[12]
Brown, E.; Wilding, J.P.H.; Barber, T.M.; Alam, U.; Cuthbertson, D.J. Weight loss variability with SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes mellitus and obesity: Mechanistic possibilities. Obes. Rev.,  2019, 20(6), 816-828.
 [http://dx.doi.org/10.1111/obr.12841] [PMID:  30972878]

[13]
Seino, Y.; Fukushima, M.; Yabe, D. GIP and GLP-1, the two incretin hormones: Similarities and differences. J. Diabetes Investig.,  2010, 1(1-2), 8-23.
 [http://dx.doi.org/10.1111/j.2040-1124.2010.00022.x] [PMID:  24843404]

[14]
Cho, Y.M.; Kieffer, T.J. K-cells and glucose-dependent insulinotropic polypeptide in health and disease. Vitam. Horm.,  2010, 84, 111-150.
 [http://dx.doi.org/10.1016/B978-0-12-381517-0.00004-7] [PMID:  21094898]

[15]
McIntosh, C.H.S.; Widenmaier, S.; Kim, S.J. Glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide; GIP). Vitam. Horm.,  2009, 80, 409-471.
 [http://dx.doi.org/10.1016/S0083-6729(08)00615-8] [PMID:  19251046]

[16]
Seino, Y.; Kuwata, H.; Yabe, D. Incretin-based drugs for type 2 diabetes: Focus on East Asian perspectives. J. Diabetes Investig.,  2016, 7(S1)(Suppl. 1), 102-109.
 [http://dx.doi.org/10.1111/jdi.12490] [PMID:  27186364]

[17]
Sun, B.; Willard, F.S.; Feng, D.; Alsina-Fernandez, J.; Chen, Q.; Vieth, M.; Ho, J.D.; Showalter, A.D.; Stutsman, C.; Ding, L.; Suter, T.M.; Dunbar, J.D.; Carpenter, J.W.; Mohammed, F.A.; Aihara, E.; Brown, R.A.; Bueno, A.B.; Emmerson, P.J.; Moyers, J.S.; Kobilka, T.S.; Coghlan, M.P.; Kobilka, B.K.; Sloop, K.W. Structural determinants of dual incretin receptor agonism by tirzepatide. Proc. Natl. Acad. Sci. USA,  2022, 119(13), e2116506119.
 [http://dx.doi.org/10.1073/pnas.2116506119] [PMID:  35333651]

[18]
Willard, F.S.; Douros, J.D.; Gabe, M.B.N.; Showalter, A.D.; Wainscott, D.B.; Suter, T.M.; Capozzi, M.E.; van der Velden, W.J.C.; Stutsman, C.; Cardona, G.R.; Urva, S.; Emmerson, P.J.; Holst, J.J.; D’Alessio, D.A.; Coghlan, M.P.; Rosenkilde, M.M.; Campbell, J.E.; Sloop, K.W. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight,  2020, 5(17), e140532.
 [http://dx.doi.org/10.1172/jci.insight.140532] [PMID:  32730231]

[19]
Liu, C.; Zou, Y.; Qian, H. GLP-1R agonists for the treatment of obesity: a patent review (2015-present). Expert Opin. Ther. Pat.,  2020, 30(10), 781-794.
 [http://dx.doi.org/10.1080/13543776.2020.1811851] [PMID:  32799587]

[20]
Zhao, F.; Zhou, Q.; Cong, Z.; Hang, K.; Zou, X.; Zhang, C.; Chen, Y.; Dai, A.; Liang, A.; Ming, Q.; Wang, M.; Chen, L.N.; Xu, P.; Chang, R.; Feng, W.; Xia, T.; Zhang, Y.; Wu, B.; Yang, D.; Zhao, L.; Xu, H.E.; Wang, M.W. Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors. Nat. Commun.,  2022, 13(1), 1057.
 [http://dx.doi.org/10.1038/s41467-022-28683-0] [PMID:  35217653]

[21]
Zhao, F.; Zhou, Q.; Cong, Z.; Hang, K.; Zou, X.; Zhang, C.; Chen, Y.; Dai, A.; Liang, A.; Ming, Q.; Wang, M. Structural basis for the therapeutic advantage of dual and triple agonists at the human GIP, GLP-1 or GCG receptors. BioRxiv, 2021.
 [http://dx.doi.org/10.1101/2021.07.29.454286]

[22]
Chen, Y.; Xu, Y.; Ye, C.; Feng, W.; Zhou, Q.; Yang, D.; Wang, M. GLP-1 mimetics as a potential therapy for nonalcoholic steatohepatitis. Acta Pharmacol. Sin.,  2022, 43(5), 1156-1166.
 [http://dx.doi.org/10.1038/s41401-021-00836-9] [PMID:  34934197]

[23]
Mitra, P.; Bauri, R.; Bele, S.; Edelli, J.; Dasadhikari, S.; Reddy, NC.; Kurukuti, S.; Garai, K.; Devasia, T.; Ibrahim, A.; Rai, V. IM-150847, a novel GLP-1 and GIP receptor dual agonist, reduces body weight gain and improves glycemic control in the rodent model of type 2 diabetes and obesity. BioRxiv, 2021.

[24]
González-Mariscal, I.; Krzysik-Walker, S.M.; Kim, W.; Rouse, M.; Egan, J.M. Blockade of cannabinoid 1 receptor improves GLP-1R mediated insulin secretion in mice. Mol. Cell. Endocrinol.,  2016, 423, 1-10.
 [http://dx.doi.org/10.1016/j.mce.2015.12.015] [PMID:  26724516]

[25]
Johnson, R.M.; Zhang, X.; Piper, S.J.; Nettleton, T.J.; Vandekolk, T.H.; Langmead, C.J.; Danev, R.; Sexton, P.M.; Wootten, D. Cryo-EM structure of the dual incretin receptor agonist, peptide-19, in complex with the glucagon-like peptide-1 receptor. Biochem. Biophys. Res. Commun.,  2021, 578, 84-90.
 [http://dx.doi.org/10.1016/j.bbrc.2021.09.016] [PMID:  34547628]

[26]
Samms, R.J.; Coghlan, M.P.; Sloop, K.W. How may GIP enhance the therapeutic efficacy of GLP-1? Trends Endocrinol. Metab.,  2020, 31(6), 410-421.
 [http://dx.doi.org/10.1016/j.tem.2020.02.006] [PMID:  32396843]

[27]
Bergmann, N.C.; Lund, A.; Gasbjerg, L.S.; Jørgensen, N.R.; Jessen, L.; Hartmann, B.; Holst, J.J.; Christensen, M.B.; Vilsbøll, T.; Knop, F.K. Separate and combined effects of GIP and GLP-1 infusions on bone metabolism in overweight men without diabetes. J. Clin. Endocrinol. Metab.,  2019, 104(7), 2953-2960.
 [http://dx.doi.org/10.1210/jc.2019-00008] [PMID:  30848791]

[28]
Lund, A.; Vilsbøll, T.; Bagger, J.I.; Holst, J.J.; Knop, F.K. The separate and combined impact of the intestinal hormones, GIP, GLP-1, and GLP-2, on glucagon secretion in type 2 diabetes. Am. J. Physiol. Endocrinol. Metab.,  2011, 300(6), E1038-E1046.
 [http://dx.doi.org/10.1152/ajpendo.00665.2010] [PMID:  21386059]

[29]
Drugs at FDA, U.S. Food and Drug Administration, Full prescribing information and Medication Guide MOUNJAROTM, Reference ID: 4983783.  Available from:
          https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215866s000lbl.pdf(accessed 2022-06-20).

[30]
Nowak, M.; Nowak, W.; Grzeszczak, W. Tirzepatide-A dual GIP/GLP-1 receptor agonist -A new antidiabetic drug with potential metabolic activity in the treatment of type 2 diabetes. Endokrynol. Pol.,  2022, 73(4), 745-755.
 [http://dx.doi.org/10.5603/EP.a2022.0029]

[31]
Min, T.; Bain, S.C. 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(1), 143-157.
 [http://dx.doi.org/10.1007/s13300-020-00981-0] [PMID:  33325008]

[32]
Coskun, T.; Sloop, K.W.; Loghin, C.; Alsina-Fernandez, J.; Urva, S.; Bokvist, K.B.; Cui, X.; Briere, D.A.; Cabrera, O.; Roell, W.C.; Kuchibhotla, U.; Moyers, J.S.; Benson, C.T.; Gimeno, R.E.; D’Alessio, D.A.; Haupt, A. 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.
 [http://dx.doi.org/10.1016/j.molmet.2018.09.009] [PMID:  30473097]

[33]
Baggio, L.L.; Drucker, D.J. Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease. Mol. Metab.,  2021, 46, 101090.
 [http://dx.doi.org/10.1016/j.molmet.2020.101090] [PMID:  32987188]

[34]
Frias, J.P.; Nauck, M.A.; Van, J.; Benson, C.; Bray, R.; Cui, X.; Milicevic, Z.; Urva, S.; Haupt, A.; Robins, D.A. 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(6), 938-946.
 [http://dx.doi.org/10.1111/dom.13979] [PMID:  31984598]

[35]
Thomas, M.K.; Nikooienejad, A.; Bray, R.; Cui, X.; Wilson, J.; Duffin, K.; Milicevic, Z.; Haupt, A.; Robins, D.A. 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(2), 388-396.
 [http://dx.doi.org/10.1210/clinem/dgaa863] [PMID:  33236115]

[36]
Frías, J.P.; Davies, M.J.; Rosenstock, J.; Pérez Manghi, F.C.; Fernández Landó, L.; Bergman, B.K.; Liu, B.; Cui, X.; Brown, K. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N. Engl. J. Med.,  2021, 385(6), 503-515.
 [http://dx.doi.org/10.1056/NEJMoa2107519] [PMID:  34170647]

[37]
Fonseca, L.; Paredes, S.; Ramos, H.; Oliveira, J.C.; Palma, I. Apolipoprotein B and non-high-density lipoprotein cholesterol reveal a high atherogenicity in individuals with type 2 diabetes and controlled low-density lipoprotein-cholesterol. Lipids Health Dis.,  2020, 19(1), 127.
 [http://dx.doi.org/10.1186/s12944-020-01292-w] [PMID:  32505210]

[38]
Taskinen, M.R.; Borén, J. New insights into the pathophysiology of dyslipidemia in type 2 diabetes. Atherosclerosis,  2015, 239(2), 483-495.
 [http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.039] [PMID:  25706066]

[39]
Fisman, E.Z.; Tenenbaum, A. The dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide: a novel cardiometabolic therapeutic prospect. Cardiovasc. Diabetol.,  2021, 20(1), 225.
 [http://dx.doi.org/10.1186/s12933-021-01412-5] [PMID:  34819089]

[40]
Dewidar, B.; Kahl, S.; Pafili, K.; Roden, M. Metabolic liver disease in diabetes - From mechanisms to clinical trials. Metabolism,  2020, 111, 154299.
 [http://dx.doi.org/10.1016/j.metabol.2020.154299] [PMID:  32569680]

[41]
Hartman, M.L.; Sanyal, A.J.; Loomba, R.; Wilson, J.M.; Nikooienejad, A.; Bray, R.; Karanikas, C.A.; Duffin, K.L.; Robins, D.A.; Haupt, A. 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(6), 1352-1355.
 [http://dx.doi.org/10.2337/dc19-1892] [PMID:  32291277]

[42]
Dahl, D.; Onishi, Y.; Norwood, P.; Huh, R.; Bray, R.; Patel, H.; Rodríguez, A. 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. J. Am. Med. Assoc.,  2022, 327(6), 534-545.
 [http://dx.doi.org/10.1001/jama.2022.0078] [PMID:  35133415]

[43]
Chipkin, S.R. Tirzepatide for patients with type 2 diabetes. JAMA,  2022, 327(6), 529-530.
 [http://dx.doi.org/10.1001/jama.2021.25016] [PMID:  35133426]

[44]
Farzam, K.; Jan, A. Beta Blockers. In: StatPearls; StatPearls Publishing: Treasure Island, FL, 2022. 

[45]
Trujillo, J. Safety and tolerability of once-weekly GLP-1 receptor agonists in type 2 diabetes. J. Clin. Pharm. Ther.,  2020, 45(S1)(Suppl. 1), 43-60.
 [http://dx.doi.org/10.1111/jcpt.13225] [PMID:  32910487]

[46]
LiverTox. Clinical and Research Information on Drug-Induced Liver Injury; National Institute of Diabetes and Digestive and Kidney Diseases: Bethesda, MD, 2022. 

[47]
Frias, J.P.; Nauck, M.A.; Van, J.; Kutner, M.E.; Cui, X.; Benson, C.; Urva, S.; Gimeno, R.E.; Milicevic, Z.; Robins, D.; Haupt, A. 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.
 [http://dx.doi.org/10.1016/S0140-6736(18)32260-8] [PMID:  30293770]

[48]
Ali, R.; Virendra, S.A.; Chawla, P.A. Bumps and humps in the success of Tirzepatide as the first GLP1 and GIP receptor agonist;. HSR,  2022, 4,  p. 100032.

Rights & Permissions Print Cite

Article Metrics

22

2

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1570180820666230130153219	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X

Letters in Drug Design & Discovery

Tirzepatide: A First-in-class Twincretin for the Management of Type 2 Diabetes

Abstract

Graphical Abstract

Related Journals

Related Books

Related Articles