Dual Benefits of Tirzepatide: Anti-Obesity and Antidiabetic Efficacy: A Mini review
Abstract
Background: Diabetes mellitus and obesity are two linked conditions that have reached epidemic proportions globally. According to a study published in 2023 by the Indian Council of Medical Research (ICMR) , India has 10.1 crore people with diabetes. The prevalence of obesity, especially abdominal obesity is increasing continuously due to the intake of foods that are high in carbohydrates and processed foods. Obesity can cause inflammation, insulin resistance, and pancreas overload which lead to diabetes mellitus.
Main Body: The present - review focuses on the medicinal chemistry, organic chemistry and pharmacological aspects of trizepatide. Trizepatide is a new chemical moiety that shows dual agonist activity of glucagon-like peptide-1(GLP-1) receptors and glucose-dependent insulinotropic polypeptide(GIP).Trizepatide is a synthetic peptide that constitutes 39 amino acids. Trizepatide has a potent hypoglycemic effect , and it has antiobesity effects because of its adverse effect.
Conclusion : Trizepatide's capacity to lower blood sugar and promote weight loss makes it an effective treatment for these conditions. Further research will confirm its safety and long-term advantages.
Keywords : Trizepatide , Diabetes mellitus , Obesity, Hypoglycaemia
Keywords:
Trizepatide, Diabetes mellitus, Obesity, Hypoglycaemia
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References
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2. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, 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.
3. Sinha DD, Williams RC, Hollar LN, Lucas HR, Johnson-Javois B, Miller HB, et al. Barriers and facilitators to diabetes screening and prevention after a pregnancy complicated by gestational diabetes. PLoS One. 2022;17(11). doi:10.1371/journal.pone.0277330.
4. Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, 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.
5. Two incretin hormones GLP-1 and GIP: Comparison of their actions in insulin secretion and β cell preservation,Progress in Biophysics and Molecular Biology,Volume 107, Issue 2,2011,Pages 248-256,ISSN 0079-6107,https://doi.org/10.1016/j.pbiomolbio.2011.07.010.
6. Müller TD, Finan B, Bloom SR, D'Alessio D, Drucker DJ, Flatt PR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72–130. doi:10.1016/j.molmet.2019.09.010.
7. Irwin S. Primary Prevention and Risk Reduction for Cardiovascular/Pulmonary Disorders—Preferred Practice Pattern 6A. In: Irwin S, Tecklin JS, editors. Cardiopulmonary Physical Therapy. 4th ed. Mosby; 2004. p. 253-269. doi: 10.1016/B978-032301840-1.50014-1.
8. Kim S. H. (2011). Measurement of insulin action: a tribute to Sir Harold Himsworth. Diabetic medicine : a journal of the British Diabetic Association, 28(12), 1487–1493. https://doi.org/10.1111/j.1464-5491.2011.03409.x
9. Ahmed, Awad M. “History of diabetes mellitus.” Saudi medical journal vol. 23,4 (2002): 373-8.
10. Jay S. Skyler, George L. Bakris, Ezio Bonifacio, Tamara Darsow, Robert H. Eckel, Leif Groop, Per-Henrik Groop, Yehuda Handelsman, Richard A. Insel, Chantal Mathieu, Allison T. McElvaine, Jerry P. Palmer, Alberto Pugliese, Desmond A. Schatz, Jay M. Sosenko, John P.H. Wilding, Robert E. Ratner; Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis. Diabetes 1 February 2017; 66 (2): 241–255. https://doi.org/10.2337/db16-0806
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12. Suryawanshi DM, Bachhav D, Suryawanshi K, Sonavane N, Pooja Mairal. THE EMERGING ROLE OF TIRZEPATIDE, DUAL GLP-1 AND GIP RECEPTOR AGONIST IN THE MANAGEMENT OF T2DM AND OBESITY: A REVIEW [Internet]. International Journal of Novel Research and Development. 2022 Nov. Available from: https://www.ijnrd.org/papers/IJNRD2211104.pdf
13.Frederick M.O., Boyse R.A., Braden T.M., Calvin J.R., Campbell B.M., Changi S.M., Coffin S.R., Condon C., Gowran O., McClary J., et al. Kilogram-scale GMP manufacture of tirzepatide using a hybrid SPPS/LPPS approach with continuous manufacturing. Org. Process Res. Dev. 2021;25:1628–1636.
14. Fields GB. Introduction to Peptide Synthesis. Current Protocols in Protein Science [Internet]. 2001 Dec 1;26(1). Available from: https://doi.org/10.1002/0471140864.ps1801s26
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19. Sattar N, McGuire DK, Pavo I, Weerakkody GJ, Nishiyama H, Wiese RJ, Zoungas S. Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat Med. 2022 Mar;28(3):591-598. doi: 10.1038/s41591-022-01707-4. Epub 2022 Feb 24. PMID: 35210595; PMCID: PMC8938269.
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21. Zhang D, Zhang Y, Sun B. The Molecular Mechanisms of Liver Fibrosis and Its Potential Therapy in Application. International Journal of Molecular Sciences [Internet]. 2022 Oct 20;23(20):12572. Available from: https://www.mdpi.com/1422-0067/23/20/12572.
22. Saurabh MK, Ranjan A, All India Institute of Medial Sciences, Dept of Physical and Rehabilitation. Tirzepaptide: A Promising Option for Treating Obesity and Overweight [Internet]. International Journal of Science and Research (IJSR). 2024 Mar. Available from: https://www.ijsr.net/archive/v13i3/SR24305143919.pdf
23. Lin, Fei & Yu, Bin & Ling, Baodong & Lv, Guangyao & Shang, Huijun & Zhao, Xia & Jie, Xiaoling & Chen, Jing & Li, Yan. (2023). Weight loss efficiency and safety of tirzepatide: A Systematic review. PLOS ONE. 18. e0285197. 10.1371/journal.pone.0285197.
24. Ali R, Virendra SA, Chawla PA. Bumps and humps in the success of Tirzepatide as the frst GLP1 and GIP receptor agonist. Health Sci Rev. 2022;4: 100032. https://doi.org/10.1016/j.hsr.2022.100032.
25. Chavda VP, 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. https://doi.org/10.3390/molecules27134315.
26. Ali R, Virendra SA, Chawla PA. Bumps and humps in the success of Tirzepatide as the frst GLP1 and GIP receptor agonist. Health Sci Rev. 2022;4: 100032. https://doi.org/10.1016/j.hsr.2022.100032.
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33.Garvey WT, Frias JP, Jastreboff AM, le Roux CW, Sattar N, Aizenberg D, Mao H, Zhang S, Ahmad NN, Bunck MC, Benabbad I, Zhang XM; SURMOUNT-2 investigators. 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 Aug 19;402(10402):613-626. doi: 10.1016/S0140-6736(23)01200-X. Epub 2023 Jun 26. PMID: 37385275.
34. Rosenstock J, Wysham C, Frías JP, Kaneko S, Lee CJ, Landó LF, Mao H, Cui X, Karanikas CA, Thieu VT. 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. The Lancet. 2021 Jul 10;398(10295):143-55.
35. Ludvik B, Giorgino F, Jódar E, Frias JP, Landó LF, Brown K, Bray R, Rodríguez Á. 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. The Lancet. 2021 Aug 14;398(10300):583-98.
36. 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.
37. Del Prato S, Kahn SE, Pavo I, Weerakkody GJ, Yang Z, Doupis J, Aizenberg D, Wynne AG, Riesmeyer JS, Heine RJ, Wiese RJ. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. The Lancet. 2021 Nov 13;398(10313):1811-24.
38. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, Cabrera O, Roell WC, Kuchibhotla U. 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. Molecular metabolism. 2018 Dec 1;18:3-14.
39. Frias JP, Nauck MA, Van J, Benson C, Bray R, Cui X, Milicevic Z, Urva S, Haupt A, Robins DA. 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, Obesity and Metabolism. 2020 Jun;22(6):938-46.
2. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, 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.
3. Sinha DD, Williams RC, Hollar LN, Lucas HR, Johnson-Javois B, Miller HB, et al. Barriers and facilitators to diabetes screening and prevention after a pregnancy complicated by gestational diabetes. PLoS One. 2022;17(11). doi:10.1371/journal.pone.0277330.
4. Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, 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.
5. Two incretin hormones GLP-1 and GIP: Comparison of their actions in insulin secretion and β cell preservation,Progress in Biophysics and Molecular Biology,Volume 107, Issue 2,2011,Pages 248-256,ISSN 0079-6107,https://doi.org/10.1016/j.pbiomolbio.2011.07.010.
6. Müller TD, Finan B, Bloom SR, D'Alessio D, Drucker DJ, Flatt PR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72–130. doi:10.1016/j.molmet.2019.09.010.
7. Irwin S. Primary Prevention and Risk Reduction for Cardiovascular/Pulmonary Disorders—Preferred Practice Pattern 6A. In: Irwin S, Tecklin JS, editors. Cardiopulmonary Physical Therapy. 4th ed. Mosby; 2004. p. 253-269. doi: 10.1016/B978-032301840-1.50014-1.
8. Kim S. H. (2011). Measurement of insulin action: a tribute to Sir Harold Himsworth. Diabetic medicine : a journal of the British Diabetic Association, 28(12), 1487–1493. https://doi.org/10.1111/j.1464-5491.2011.03409.x
9. Ahmed, Awad M. “History of diabetes mellitus.” Saudi medical journal vol. 23,4 (2002): 373-8.
10. Jay S. Skyler, George L. Bakris, Ezio Bonifacio, Tamara Darsow, Robert H. Eckel, Leif Groop, Per-Henrik Groop, Yehuda Handelsman, Richard A. Insel, Chantal Mathieu, Allison T. McElvaine, Jerry P. Palmer, Alberto Pugliese, Desmond A. Schatz, Jay M. Sosenko, John P.H. Wilding, Robert E. Ratner; Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis. Diabetes 1 February 2017; 66 (2): 241–255. https://doi.org/10.2337/db16-0806
11. Forzano I, Varzideh F, Avvisato R, Jankauskas SS, Mone P, Santulli G. Tirzepatide: A Systematic Update. Int J Mol Sci. 2022;23(23):14631. doi: 10.3390/ijms232314631.
12. Suryawanshi DM, Bachhav D, Suryawanshi K, Sonavane N, Pooja Mairal. THE EMERGING ROLE OF TIRZEPATIDE, DUAL GLP-1 AND GIP RECEPTOR AGONIST IN THE MANAGEMENT OF T2DM AND OBESITY: A REVIEW [Internet]. International Journal of Novel Research and Development. 2022 Nov. Available from: https://www.ijnrd.org/papers/IJNRD2211104.pdf
13.Frederick M.O., Boyse R.A., Braden T.M., Calvin J.R., Campbell B.M., Changi S.M., Coffin S.R., Condon C., Gowran O., McClary J., et al. Kilogram-scale GMP manufacture of tirzepatide using a hybrid SPPS/LPPS approach with continuous manufacturing. Org. Process Res. Dev. 2021;25:1628–1636.
14. Fields GB. Introduction to Peptide Synthesis. Current Protocols in Protein Science [Internet]. 2001 Dec 1;26(1). Available from: https://doi.org/10.1002/0471140864.ps1801s26
15. May S.A., Johnson M.D., Buser J.Y., Campbell A.N., Frank S.A., Haeberle B.D., Hoffman P.C., Lambertus G.R., McFarland A.D., Moher E.D., et al. Development and manufacturing GMP scale-up of a continuous ir-catalyzed homogeneous reductive amination reaction. Org. Process Res. Dev. 2016;20:1870–1898. doi: 10.1021/acs.oprd.6b00148.
16.Wang Z., Wang Z., Lin S., Jin H., Gao S., Zhu Y., Jin J. Nanoparticle-templated nanofiltration membranes for ultrahigh performance desalination. Nat. Commun. 2018;9:2004–2013. doi: 10.1038/s41467-018-04467-3
17. Tirzepatide: Uses, Interactions, Mechanism of Action | DrugBank Online [Internet]. DrugBank. Available from: https://go.drugbank.com/drugs/DB15171
18 National Center for Biotechnology Information. PubChem Compound Summary for CID 163285897. PubChem [Internet]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/163285897. Accessed 2024 Sep 16.
19. Sattar N, McGuire DK, Pavo I, Weerakkody GJ, Nishiyama H, Wiese RJ, Zoungas S. Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat Med. 2022 Mar;28(3):591-598. doi: 10.1038/s41591-022-01707-4. Epub 2022 Feb 24. PMID: 35210595; PMCID: PMC8938269.
20. Roomy MA, Hussain K, Behbehani HM, Abu-Farha J, Al-Harris R, Ambi AM, Abdalla MA, Al-Mulla F, Abu-Farha M, Abubaker J. Therapeutic advances in obesity management: an overview of the therapeutic interventions. Frontiers in Endocrinology [Internet]. 2024 Apr 23;15. Available from: https://doi.org/10.3389/fendo.2024.1364503.
21. Zhang D, Zhang Y, Sun B. The Molecular Mechanisms of Liver Fibrosis and Its Potential Therapy in Application. International Journal of Molecular Sciences [Internet]. 2022 Oct 20;23(20):12572. Available from: https://www.mdpi.com/1422-0067/23/20/12572.
22. Saurabh MK, Ranjan A, All India Institute of Medial Sciences, Dept of Physical and Rehabilitation. Tirzepaptide: A Promising Option for Treating Obesity and Overweight [Internet]. International Journal of Science and Research (IJSR). 2024 Mar. Available from: https://www.ijsr.net/archive/v13i3/SR24305143919.pdf
23. Lin, Fei & Yu, Bin & Ling, Baodong & Lv, Guangyao & Shang, Huijun & Zhao, Xia & Jie, Xiaoling & Chen, Jing & Li, Yan. (2023). Weight loss efficiency and safety of tirzepatide: A Systematic review. PLOS ONE. 18. e0285197. 10.1371/journal.pone.0285197.
24. Ali R, Virendra SA, Chawla PA. Bumps and humps in the success of Tirzepatide as the frst GLP1 and GIP receptor agonist. Health Sci Rev. 2022;4: 100032. https://doi.org/10.1016/j.hsr.2022.100032.
25. Chavda VP, 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. https://doi.org/10.3390/molecules27134315.
26. Ali R, Virendra SA, Chawla PA. Bumps and humps in the success of Tirzepatide as the frst GLP1 and GIP receptor agonist. Health Sci Rev. 2022;4: 100032. https://doi.org/10.1016/j.hsr.2022.100032.
27.EliLillyandCompany2021.ClinicalTrials.gov.https://clinicaltrials.gov/study/NCT03954834?tab=table [Accessed 1 Mar 2024]
28 Eli Lilly and Company 2021. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT03987919?tab=table [Accessed 1 Mar 2024]
29. ELi Lilly and Company 2022. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT03882970 [Accessed 21 Jan 2024]
30 Eli Lilly and Company 2021. — ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT03730662 [Accessed 1 Mar 2024]
31 54. Eli Lilly and Company 2021. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT04039503 [Accessed 1 Mar 2024]
32. Permana H, Yanto TA, Hariyanto TI. Efficacy and safety of tirzepatide as novel treatment for type 2 diabetes: A systematic review and meta-analysis of randomized clinical trials. Diabetes & Metabolic Syndrome Clinical Research & Reviews [Internet]. 2022 Oct 14;16(11):102640. Available from: https://doi.org/10.1016/j.dsx.2022.102640
33.Garvey WT, Frias JP, Jastreboff AM, le Roux CW, Sattar N, Aizenberg D, Mao H, Zhang S, Ahmad NN, Bunck MC, Benabbad I, Zhang XM; SURMOUNT-2 investigators. 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 Aug 19;402(10402):613-626. doi: 10.1016/S0140-6736(23)01200-X. Epub 2023 Jun 26. PMID: 37385275.
34. Rosenstock J, Wysham C, Frías JP, Kaneko S, Lee CJ, Landó LF, Mao H, Cui X, Karanikas CA, Thieu VT. 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. The Lancet. 2021 Jul 10;398(10295):143-55.
35. Ludvik B, Giorgino F, Jódar E, Frias JP, Landó LF, Brown K, Bray R, Rodríguez Á. 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. The Lancet. 2021 Aug 14;398(10300):583-98.
36. 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.
37. Del Prato S, Kahn SE, Pavo I, Weerakkody GJ, Yang Z, Doupis J, Aizenberg D, Wynne AG, Riesmeyer JS, Heine RJ, Wiese RJ. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. The Lancet. 2021 Nov 13;398(10313):1811-24.
38. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, Cabrera O, Roell WC, Kuchibhotla U. 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. Molecular metabolism. 2018 Dec 1;18:3-14.
39. Frias JP, Nauck MA, Van J, Benson C, Bray R, Cui X, Milicevic Z, Urva S, Haupt A, Robins DA. 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, Obesity and Metabolism. 2020 Jun;22(6):938-46.
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Praveen S, sarma A. Dual Benefits of Tirzepatide: Anti-Obesity and Antidiabetic Efficacy: A Mini review . World Journal of Current Med and Pharm Research [Internet]. 2024Nov.12 [cited 2024Dec.6];6(3):15-9. Available from: https://wjcmpr.com/index.php/journal/article/view/342
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