The Effects of Tirzepatide in People With Overweight/Obesity and Coronary Artery Disease

Официальное название

The Effects of Tirzepatide on Coronary Plaque Lipid Content and Myocardial Microvascular Function in Overweight and Obese People With Coronary Disease - The IDEAL-COR Study

Обзор

The objective of this study is to investigate, as a proof-of-principle, long-term (52 weeks) effects of tirzepatide once-weekly vs. placebo on changes in coronary plaque composition and progression (assessed by NIRS), plaque burden (assessed by IVUS) and microvascular function (assessed by invasively measured CFR) in overweight and obese individuals with stable coronary artery disease (CAD). In addition, the objective of a baseline cross-sectional sub-study is to explore potential metabolic and cardiovascular (CV) predictors for high arteriosclerotic plaque burden in overweight and obese individuals and to establish a cohort for future research projects.

Подробное описание

The anti-atherogenic effect of tirzepatide has been studied in preclinical studies and seems to involve mechanisms related to a reduction in vascular inflammation and lipid accumulation. Any direct anti-atherogenic effect of tirzepatide may potentially reduce the incidence of major cardiovascular endpoints in individuals with overweight or obesity. As a proof of principle, it would be of scientific and clinical interest to explore the anti-atherogenic effect of tirzepatide in humans. IVUS-NIRS imaging is uniquely suited for this purpose, as it makes it possible to detect changes in not only atheroma burden by IVUS but also to detect progression within the plaques in the lipidic/necrotic core component by NIRS. LCBItotal allows for consecutive detection of small changes in the same individual, which is pivotal to explore the supposed antiatherogenic mechanism of tirzepatide with enough statistical power.

The investigators hypothesize that once-weekly sc. tirzepatide can reduce coronary lipid accumulation in the arterial wall and the progression of atheromatosis in individuals with overweight or obesity and established high-risk atherosclerosis. The investigators aim to investigate this hypothesis in a proof-of-principle study by investigating the change in coronary plaque composition in individuals with overweight or obesity and coronary artery disease (CAD) with high-risk characteristics by NIRS imaging randomised to 52-week treatment with tirzepatide or placebo.

Вмешательства

• Препарат Tirzepatide
  Investigational drug will be administered as a sc. injection once-weekly.
• Препарат Placebo
  Placebo containing the same excipients and volume as the active treatment arm but without tirzepatide will be administered as a sc. injection once-weekly.

Первичные конечные точки

• Lipid core burden index [Срок оценки: Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo:]

Вторичные конечные точки (3)

• Percent atheroma volume (PAV) [Срок оценки: Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo:]
• Number of high-risk coronary lesion [Срок оценки: Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo:]
• Coronary flow reserve [Срок оценки: Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo:]

Критерии участия

Критерии включения

• Informed written consent
• BMI equal to or above 27 kg/m2
• Age 18 years or older
• Referred to coronary angiogram (CAG) due to stable angina
• Coronary atheromatosis by angiography (obstructive or non-obstructive)
• LCBI4mm >200 by NIRS in a vessel not subjected to coronary intervention

Критерии исключения

• History of diabetes or HbA1c ≥48 mmol/mol (6.5%) at baseline
• Treatment with Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RA)
• History of coronary artery bypass surgery (CABG)
• Planned CV intervention (including percutaneous coronary intervention, cardiac surgery or transcatheter valve intervention) at time of randomisation
• History of heart failure New York Heart Association (NYHA) class III or IV
• Left ventricular ejection fraction (LVEF) ≤35%
• eGFR <30 ml/min/1.53 m2
• History of pancreatitis or plasma amylase >2 times upper normal limit
• Impaired hepatic function at baseline (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the upper limit of normal)
• Pregnancy, planned pregnancy or breastfeeding
• Family or history of multiple endocrine neoplasia (MEN) type 2 or familial medullary thyroid carcinoma (FMTC)
• Hypersensitivity to the active substance (Tirzepatide) or to any of the excipients
• Left main stenosis (≥50% diameter or haemodynamically significant)
• Chronic total occlusion of any major coronary vessel
• Multi-vessel disease or complex anatomy potentially requiring coronary bypass surgery
• Coronary anatomy or pathology precluding the safe performance of intravascular imaging in all major coronary arteries not subjected to intervention

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

Дания · 3 центра

• Rigshospitalet — Copenhagen
• Gentofte Hospital — Gentofte Municipality
• Steno Diabetes Center Copenhagen — Herlev

Публикации

• Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A; SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022 Jul 21;387(3):205-216. doi: 10.1056/NEJMoa2206038. Epub 2022 Jun 4. PMID 35658024
• Stoner MCD, Bhushan NL, Maragh-Bass AC, Mitchell JT, Riggins L, Walker M, LeMasters K, Reese B, Dearing A, Debnam S, Golin C, Lightfoot AF, Pettifor A. Using Participatory Methods to Assess PrEP Interest and Uptake Among Young People Living in the Southeastern US: A Mixed Methods Assessment. AIDS Behav. 2022 May;26(5):1672-1683. doi: 10.1007/s10461-021-03519-y. Epub 2021 Nov 1. PMID 34724592
• Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, Cabrera O, Roell WC, Kuchibhotla U, Moyers JS, Benson CT, Gimeno RE, D'Alessio DA, 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 Dec;18:3-14. doi: 10.1016/j.molmet.2018.09.009. Epub 2018 PMID 30473097
• Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, 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 Nov 17;392(10160):2180-2193. doi: 10.1016/S0140-6736(18)32260-8. Epub 2018 Oct 4. PMID 30293770
• Frias JP, Davies MJ, Rosenstock J, Perez Manghi FC, Fernandez Lando L, Bergman BK, Liu B, Cui X, Brown K; SURPASS-2 Investigators. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021 Aug 5;385(6):503-515. doi: 10.1056/NEJMoa2107519. Epub 2021 Jun 25. PMID 34170647
• Kristensen SL, Rorth R, Jhund PS, Docherty KF, Sattar N, Preiss D, Kober L, Petrie MC, McMurray JJV. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019 Oct;7(10):776-785. doi: 10.1016/S2213-8587(19)30249-9. Epub 2019 Aug 14. PMID 31422062
• Caruso I, Cignarelli A, Giorgino F. Heterogeneity and Similarities in GLP-1 Receptor Agonist Cardiovascular Outcomes Trials. Trends Endocrinol Metab. 2019 Sep;30(9):578-589. doi: 10.1016/j.tem.2019.07.004. Epub 2019 Aug 7. PMID 31401015
• ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, Collins BS, Hilliard ME, Isaacs D, Johnson EL, Kahan S, Khunti K, Leon J, Lyons SK, Perry ML, Prahalad P, Pratley RE, Seley JJ, Stanton RC, Gabbay RA, on behalf of the American Diabetes Association. 6. Glycemic Targets: Standards of Care in Diabetes-2023. Diabetes Care. 2023 Jan 1;46(Suppl 1):S97-S110. doi: 10.2337/dc23-S006. PMID 36507646

Идентификаторы

NCT: NCT06606821 · 2023-505270-15-00 · 2023-505270-15-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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