Tirzepatide: O Início de uma Nova Era na Terapêutica da Diabetes
DOI:
https://doi.org/10.24950/rspmi.1053Palavras-chave:
Diabetes Mellitus Tipo 2, Obesidade, Peptídeo 1 Semelhante ao Glucagon, Polipeptídeo Inibidor Gástrico, Receptor do Peptídeo Semelhante ao Glucagon 1, TirzepatideResumo
A prevalência da obesidade e consequentemente da diabetes tem vindo a aumentar de forma exponencial nas últimas décadas, prevendo-se uma manutenção desta tendência nos próximos anos. Existe por isso, uma necessidade urgente de novas terapêuticas que nos ajudem a modificar esta trajetória.
O tirzepatide, o primeiro de uma nova classe farmacológica
chamada de co-agonistas ou agonistas duplos do glucagon- like peptide-1 (GLP-1) e do glucose-dependent insulinotropic peptide (GIP), demonstrou nos ensaios clínicos publicados nos últimos dois anos, reduzir de forma significativa a glicemia, melhorar a resistência à insulina e reduzir o peso corporal, com benefícios adicionais na hipertensão e no perfil lipídico. Aguardam-se com grande expetativa os resultados sobre o seu impacto nos endpoints cardiovasculares.
Neste artigo apresenta-se uma revisão sobre este fármaco
e as perspetivas que se abrem com o seu aparecimento, no
futuro do tratamento da diabetes e da obesidade.
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Referências
International Diabetes Federation. IDF Diabetes Atlas, 10th edn. Brussels, Belgium: 2021. [accessed Jan 2022] Available from: https://www.diabetesatlas.org
Global report on diabetes. 1. Diabetes Mellitus – epidemiology. 2. Diabetes Mellitus – prevention and control. 3. Diabetes, Gestational. 4. Chronic Disease. 5. Public Health. I. Geneva: World Health Organization; 2016 3. Congdon P. Obesity and Urban Environments. Int J Environ Res Public Health. 2019;16:464. doi: 10.3390/ijerph16030464
Wells JC. The evolution of human adiposity and obesity: where did it all go wrong? Dis Model Mech. 2012;5:595-607. doi: 10.1242/dmm.009613.
Klein S, Gastaldelli A, Yki-Järvinen H, Scherer PE. Why does obesity cause diabetes? Cell Metab. 2022;34:11-20. doi: 10.1016/j.cmet.2021.12.012.
Emerging Risk Factors Collaboration, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215-22. doi: 10.1016/S0140- 6736(10)60484-9. Erratum in: Lancet. 2010;376:958.
Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41:255-323. doi: 10.1093/eurheartj/ehz486. Erratum in: Eur Heart J. 2020;41:4317.
Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Bäck M, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021;42:3227-37. doi: 10.1093/eurheartj/ehab484.
Tancredi M, Rosengren A, Svensson AM, Kosiborod M, Pivodic A, Gudbjörnsdottir S, et al. Excess Mortality among Persons with Type 2 Diabetes. N Engl J Med. 2015;373:1720-32. doi: 10.1056/NEJMoa1504347.
Fahed G, Aoun L, Bou Zerdan M, Allam S, Bou Zerdan M, Bouferraa Y, et al. Metabolic Syndrome: Updates on Pathophysiology and Management in 2021. Int J Mol Sci. 2022;2:786. doi: 10.3390/ijms23020786.
Li M, Chi X, Wang Y, Setrerrahmane S, Xie W, Xu H. Trends in insulin resistance: insights into mechanisms and therapeutic strategy. Signal Transduct Target Ther.2022;7:216. doi: 10.1038/s41392-022-01073-0.
Lingvay I, Sumithran P, Cohen RV, le Roux CW. Obesity management as a primary treatment goal for type 2 diabetes: time to reframe the conversation. Lancet. 2022;399394-405. doi: 10.1016/S0140-6736(21)01919-X. Erratum in: Lancet. 2022;399:358.
Fisman EZ, 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;20:225. doi:10.1186/s12933-021-01412-5
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;27:4315. doi: 10.3390/molecules27134315.
Karagiannis T, Avgerinos I, Liakos A, Del Prato S, Matthews DR, Tsapas 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;65:1251-61. doi: 10.1007/s00125-022-05715-4.
Taylor R, Ramachandran A, Yancy WS Jr, Forouhi NG. Nutritional basis of type 2 diabetes remission. BMJ. 2021;374:n1449. doi: 10.1136/bmj. n1449. Erratum in: BMJ. 2021;374:n1752.
Cinti F, Bouchi R, Kim-Muller JY, et al. Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes. J Clin Endocrinol Metab. 2016;101:1044-54. doi:10.1210/jc.2015-2860
Wijayatunga NN, Dhurandhar EJ. Normal weight obesity and unaddressed cardiometabolic health risk-a narrative review. Int J Obes. 2021;45:2141- 55. doi: 10.1038/s41366-021-00858-7.
Blüher M. Metabolically Healthy Obesity. Endocr Rev. 2020;41:bnaa004. doi: 10.1210/endrev/bnaa004.
American Diabetes Association Professional Practice Committee. 3. Prevention or Delay of Type 2 Diabetes and Associated Comorbidities: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45:S39-S45. doi: 10.2337/dc22-S003.
Riddle MC, Cefalu WT, Evans PH, Gerstein HC, Nauck MA, Oh WK, et al. Consensus Report: Definition and Interpretation of Remission in Type 2 Diabetes. J Clin Endocrinol Metab. 2022;107:1-9. doi: 10.1210/clinem/ dgab585.
Schauer PR, Mingrone G, Ikramuddin S, Wolfe B. Clinical Outcomes of Metabolic Surgery: Efficacy of Glycemic Control, Weight Loss, and Remission of Diabetes. Diabetes Care; 39: 902–11. doi:10.2337/dc16-0382
Yoshino M, Kayser BD, Yoshino J, Stein RI, Reeds D, Eagon JC, et al. Effects of Diet versus Gastric Bypass on Metabolic Function in Diabetes. N Engl J Med. 2020 Aug 20;383:721-32. doi: 10.1056/NEJMoa2003697
Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA. 2014;311:74-86. doi: 10.1001/ jama.2013.281361.
Lean ME, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, et al. Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial. Lancet Diabetes Endocrinol. 2019;7:344-55. doi: 10.1016/S2213-8587(19)30068-3.
Drozdz D, Alvarez-Pitti J, Wójcik M, Borghi C, Gabbianelli R, Mazur A, et al. Obesity and Cardiometabolic Risk Factors: From Childhood to Adulthood. Nutrients. 2021;13:4176. doi: 10.3390/nu13114176.
Busetto L, Bettini S, Makaronidis J, Roberts CA, Halford JC, Batterham RL. Mechanisms of weight regain. Eur J Intern Med. 2021;93:3-7. doi: 10.1016/j.ejim.2021.01.002.
Pearce C, Rychetnik L, Wutzke S, Wilson A. Obesity prevention and the role of hospital and community-based health services: a scoping review. BMC Health Serv Res. 2019;19:453. doi: 10.1186/s12913-019-4262-3.
Elrick H, Stimmler L, Hlad CJ Jr, Arai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964;24:1076-82. doi: 10.1210/jcem-24-10-1076.
Husain M, Bain SC, Holst AG, Mark T, Rasmussen S, Lingvay I. Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials. Cardiovasc Diabetol. 2020;19:156. doi: 10.1186/s12933-020- 01106-4.
Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153-65. doi: 10.1016/j.cmet.2006.01.004.
Nauck MA, Quast DR, Wefers J, Pfeiffer AF. The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update. Diabetes Obes Metab. 2021;23:5-29. doi: 10.1111/ dom.14496.
Lempesis IG, Liu J, Dalamaga M. The catcher in the gut: Tirzepatide, a dual incretin analog for the treatment of type 2 diabetes mellitus and obesity. Metabol Open. 2022;16:100220. doi: 10.1016/j.metop.2022.100220.
Finan B, Ma T, Ottaway N, Müller TD, Habegger KM, Heppner KM, et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci Transl Med. 2013;5:209ra151. doi: 10.1126/ scitranslmed.3007218.
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.
Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, 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;392:2180-93. doi: 10.1016/S0140-6736(18)32260-8.
Frias JP, Nauck MA, Van J, Benson C, Bray R, Cui X, 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;22:938-46. doi: 10.1111/dom.13979.
Rosenstock J, Wysham C, Frías JP, Kaneko S, Lee CJ, Fernández Landó L, 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;398:143-55. doi: 10.1016/S0140- 6736(21)01324-6. Erratum in: Lancet. 2021;398:212.
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;385:503-15. doi: 10.1056/ NEJMoa2107519.
Ludvik B, Giorgino F, Jódar E, Frias JP, Fernández Landó L, Brown K, 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;398:583-98. doi: 10.1016/S0140-6736(21)01443-4.
Del Prato S, Kahn SE, Pavo I, Weerakkody GJ, Yang Z, Doupis J, 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;398:1811-24. 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;327:534–45. doi:10.1001/jama.2022.0078
Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al; SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387:205-16. doi: 10.1056/NEJ Moa2206038.
ClinicalTrials.gov. A Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes Mellitus. ClinicalTrials.gov Identifier: NCT03131687. [accessed Jan 2022] Available from: https://clinicaltrials.gov/ct2/show/ NCT03131687
ClinicalTrials.gov. A Study of Tirzepatide (LY3298176) Versus Insulin Lispro (U100) in Participants With Type 2 Diabetes Inadequately Controlled onInsulin Glargine (U100) With or Without Metformin (SURPASS-6). ClinicalTrials.gov Identifier: NCT04537923. [accessed Jan 2022] Available from: https://clinicaltrials.gov/ct2/show/NCT04537923
ClinicalTrials.gov. A Study of Tirzepatide (LY3298176) Compared to Dulaglutide in Participants With Type 2 Diabetes (SURPASS J-mono). ClinicalTrials.gov Identifier: NCT03861052. [accessed Jan 2022] Available from: https://clinicaltrials.gov/ct2/show/NCT03861052
ClinicalTrials.gov. A Long-term Safety Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes. ClinicalTrials.gov Identifier: NCT03861039. [accessed Jan 2022] Available from: https://clinicaltrials. gov/ct2/show/NCT03861039
ClinicalTrials.gov. A Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes on Metformin With or Without Sulfonylurea (SURPASS-AP- Combo). ClinicalTrials.gov Identifier: NCT04093752. [accessed Jan 2022] Available from: https://clinicaltrials.gov/ct2/show/NCT04093752
ClinicalTrials.gov. A Study of Tirzepatide (LY3298176) Compared With Dulaglutide on Major Cardiovascular Events in Participants With Type 2 Diabetes (SURPASS-CVOT). ClinicalTrials.gov Identifier: NCT04255433. [accessed Jan 2022] Available from: https://clinicaltrials.gov/ct2/show/ NCT04255433
American Diabetes Association Professional Practice Committee; 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2022. Diabetes Care. 2022; 45: S125–S143. doi: 10.2337/ dc22-S009
American Diabetes Association Professional Practice Committee; 10. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes—2022. Diabetes Care.2022; 45: S144–S174. doi: 10.2337/ dc22-S010
Weiss T, Carr RD, Pal S, Yang L, Sawhney B, Boggs R, et al. Real-World Adherence and Discontinuation of Glucagon-Like Peptide-1 Receptor Agonists Therapy in Type 2 Diabetes Mellitus Patients in the United States. Patient Prefer Adherence. 2020;14:2337-45. doi:10.2147/PPA.S277676
Kaneko S. Tirzepatide: a novel, once-weekly dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes. Rev Endocrinol. 2022;18:10-9.
Muzurovic E, Dragnic S, Medenica S, Smolovic B, Bulajic P, Mikhailidis DP. Weight-centric pharmacological management of type 2 diabetes mellitus - An essential component of cardiovascular disease prevention. J Diabetes Complications. 2020;34:107619. doi: 10.1016/j.jdiacomp.2020.107619.
Enebo LB, Berthelsen KK, Kankam M, Lund MT, Rubino DM, Satylganova A, 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;397:1736-48. doi: 10.1016/S0140-6736(21)00845-X.
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