The Cardiovascular Effect of Tirzepatide: A Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide Dual Agonist
0
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Glucagon-like peptide-1 (GLP-1) receptor agonists have been used extensively in the clinic and have an established safety profile in cardiovascular disease settings. For the treatment of peptide-secreting enteroendocrine cells, most research has focused on developing peptide multi-agonists as most of these cells are multihormonal. Among the various peptides secreted by enteroendocrine cells, the combination of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) is an attractive strategy for treating type 2 diabetes mellitus (T2DM) because both of these hormones have glucose-lowering actions. Tirzepatide, a synthetic peptide composed of 39 amino acids, functions as a dual receptor agonist of both the GIP and GLP-1 receptors. This unique mechanism of action has earned tirzepatide the nickname “twincretin.” Tirzepatide’s dual agonist activity may be the mechanism by which tirzepatide significantly reduces glycated hemoglobin levels and body weight in patients with T2DM as observed in phase 3 clinical trials. Besides its glucose-lowering and anti-obesity effects, tirzepatide has been reported to have potential cardiovascular benefits. In this review, we discuss the cardiovascular effects of tirzepatide based on the available preclinical and clinical data.
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists have been used extensively in the clinic and have an established safety profile in cardiovascular disease settings. For the treatment of peptide-secreting enteroendocrine cells, most research has focused on developing peptide multi-agonists as most of these cells are multihormonal. Among the various peptides secreted by enteroendocrine cells, the combination of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) is an attractive strategy for treating type 2 diabetes mellitus (T2DM) because both of these hormones have glucose-lowering actions. Tirzepatide, a synthetic peptide composed of 39 amino acids, functions as a dual receptor agonist of both the GIP and GLP-1 receptors. This unique mechanism of action has earned tirzepatide the nickname “twincretin.” Tirzepatide’s dual agonist activity may be the mechanism by which tirzepatide significantly reduces glycated hemoglobin levels and body weight in patients with T2DM as observed in phase 3 clinical trials. Besides its glucose-lowering and anti-obesity effects, tirzepatide has been reported to have potential cardiovascular benefits. In this review, we discuss the cardiovascular effects of tirzepatide based on the available preclinical and clinical data.
참고문헌 (39)
- Coskun T, "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, 18, pp.3~14 (2018)
- Rosenstock J, "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, 398, pp.143~155 (2021)
- Frías JP, "Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes", N Engl J Med, 385, pp.503~515 (2021)
- Ludvik B, "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, 398, pp.583~598 (2021)
- Del Prato S, "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, 398, pp.1811~1824 (2021)
- Dahl D, "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, 327, pp.534~545 (2022)
- Jastreboff AM, "Tirzepatide once weekly for the treatment of obesity", N Engl J Med, 387, pp.205~216 (2022)
- Baggio LL, "Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease", Mol Metab, 46, pp.101090~ (2021)
- Nauck MA, "GIP and GLP-1 : stepsiblings rather than monozygotic twins within the incretin family", Diabetes, 68, pp.897~900 (2019)
- Bass J, "Dual gut hormone receptor agonists for diabetes and obesity", J Clin Invest, 133, pp.e167952~ (2023)
- Holst JJ, "Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut", FEBS Lett, 211, pp.169~174 (1987)
- Mojsov S, "Insulinotropin : glucagon-like peptide I(7-37)co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas", J Clin Invest, 79, pp.616~619 (1987)
- Kreymann B, "Glucagon-like peptide-1 7-36 : a physiological incretin in man", Lancet, 2, pp.1300~1304 (1987)
- Knudsen LB, "The discovery and development of liraglutide and semaglutide", Front Endocrinol(Lausanne), 10, pp.155~ (2019)
- Brown JC, "Further purification of a polypeptide demonstrating enterogastrone activity", J Physiol, 209, pp.57~64 (1970)
- Dupre J, "Stimulation of insulin secretion by gastric inhibitory polypeptide in man", J Clin Endocrinol Metab, 37, pp.826~828 (1973)
- Rizvi AA, "The emerging role of dual GLP-1 and GIP receptor agonists in glycemic management and cardiovascular risk reduction", Diabetes Metab Syndr Obes, 15, pp.1023~1030 (2022)
- Elahi D, "The insulinotropic actions of glucose-dependent insulinotropic polypeptide(GIP)and glucagon-like peptide-1(7-37)in normal and diabetic subjects", Regul Pept, 51, pp.63~74 (1994)
- Holst JJ, "Recent advances of GIP and future horizons", Peptides, 125, pp.170230~ (2020)
- Yamada Y, "Physiology of GIP--a lesson from GIP receptor knockout mice", Horm Metab Res, 36, pp.771~774 (2004)
- Kim SJ, "GIP-overexpressing mice demonstrate reduced diet-induced obesity and steatosis, and improved glucose homeostasis", PLoS One, 7, pp.e40156~ (2012)
- Holst JJ, "The incretin system in healthy humans : the role of GIP and GLP-1", Metabolism, 96, pp.46~55 (2019)
- Finan B, "Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans", Sci Transl Med, 5, pp.209~ (2013)
- Frias JP, "The sustained effects of a dual GIP", GLP-1 receptor agonist, NNC0090-2746, in patients with type 2 diabetes, 2017, pp.26, 343~352
- Nauck MA, "Incretin hormones: their role in health and disease", Diabetes Obes Metab, 20(Suppl 1), pp.5~21 (2018)
- Nauck MA, "The evolving story of incretins(GIP and GLP-1)in metabolic and cardiovascular disease : a pathophysiological update", Diabetes Obes Metab, 23(Suppl 3), pp.5~29 (2021)
- Inagaki N, "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, 10, pp.623~633 (2022)
- Kadowaki T, "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, 10, pp.634~644 (2022)
- Gastaldelli A, "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, 10, pp.393~406 (2022)
- Heise T, "Tirzepatide reduces appetite, energy intake, and fat mass in people with type 2 diabetes", Diabetes Care, 46, pp.998~1004 (2023)
- Samms RJ, "Tirzepatide induces a thermogenic-like amino acid signature in brown adipose tissue", Mol Metab, 64, pp.101550~ (2022)
- Hoffman S, "GLP-1 attenuates intestinal fat absorption and chylomicron production via vagal afferent nerves originating in the portal vein", Mol Metab, 65, pp.101590~ (2022)
- Guan R, "Efficacy and safety of tirzepatide in patients with type 2 diabetes mellitus : a bayesian network meta-analysis", Front Pharmacol, 13, pp.998816~ (2022)
- Lemos JA, "Abstract 10370 : Effects of tirzepatide on 24-hour ambulatory blood pressure and heart rate in adults with obesity-results from the SURMOUNT-1 ambulatory blood pressure monitoring sub-study", Circulation, 146(Suppl_1), pp.A10370~ (2022)
- Patoulias D, "Meta-analysis assessing the effect of tirzepatide on the risk for atrial fibrillation in patients with type 2 diabetes mellitus", Am J Cardiol, 173, pp.157~158 (2022)
- Sharif S, "Low-grade inflammation as a risk factor for cardiovascular events and all-cause mortality in patients with type 2 diabetes", Cardiovasc Diabetol, 20, pp.220~ (2021)
- Wilson JM, "The dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide improves cardiovascular risk biomarkers in patients with type 2 diabetes : a post hoc analysis", Diabetes Obes Metab, 24, pp.148~153 (2022)
- Mori Y, "GIP as a potential therapeutic target for atherosclerotic cardiovascular disease-a systematic review", Int J Mol Sci, 21, pp.1509~ (2020)
- Sattar N, "Tirzepatide cardiovascular event risk assessment : a pre-specified meta-analysis", Nat Med, 28, pp.591~598 (2022)