Sorice Gian Pio, Cinti Francesca, Leccisotti Lucia, D'Amario Domenico, Lorusso Margherita, Guzzardi Maria Angela, Mezza Teresa, Cocchi Camilla, Capece Umberto, Ferraro Pietro Manuel, Crea Filippo, Giordano Alessandro, Iozzo Patricia, Giaccari Andrea
Dipartimento di Scienze Mediche e Chirurgiche, Centro Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, Rome, Italy.
Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
Diabetes Ther. 2021 Jul;12(7):2101-2113. doi: 10.1007/s13300-021-01083-1. Epub 2021 May 26.
Sodium-glucose co-transporter-2 (SGLT-2) inhibitors have been shown to have beneficial effects on various cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) in primary prevention and in those with a high CV risk profile. However, the mechanism(s) responsible for these CV benefits remain elusive and unexplained. The aim of the DAPAHEART study will be to demonstrate that treatment with SGLT-2 inhibitors is associated with greater myocardial insulin sensitivity in patients with T2D, and to determine whether this improvement can be attributed to a decrease in whole-body (and tissue-specific) insulin resistance and to increased myocardial perfusion and/or glucose uptake. We will also determine whether there is an appreciable degree of improvement in myocardial-wall conditions subtended by affected and non-affected coronary vessels, and if this relates to changes in left ventricular function.
The DAPAHEART trial will be a phase III, single-center, randomized, two-arm, parallel-group, double-blind, placebo-controlled study. A cohort of 52 T2D patients with stable coronary artery disease (without any previous history of myocardial infarction, with or without previous percutaneous coronary intervention), with suboptimal glycemic control (glycated hemoglobin [HbA1c] 7-8.5%) on their current standard of care anti-hyperglycemic regimen, will be randomized in a 1:1 ratio to dapagliflozin or placebo. The primary outcome is to detect changes in myocardial glucose uptake from baseline to 4 weeks after treatment initiation. The main secondary outcome will be changes in myocardial blood flow, as measured by N-ammonia positron emission tomography/computed tomography (PET/CT). Other outcomes include cardiac function, glucose uptake in skeletal muscle, adipose tissue, liver, brain and kidney, as assessed by fluorodeoxyglucose (FDG) PET-CT imaging during hyperinsulinemic-euglycemic clamp; pericardial, subcutaneous and visceral fat, and browning as observed on CT images during FDG PET-CT studies; systemic insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp, glycemic control, urinary glucose output; and microbiota modification.
SGLT-2 inhibitors, in addition to their insulin-independent plasma glucose-lowering effect, are able to directly (substrate availability, fuel utilization, insulin sensitivity) as well as indirectly (cardiac after-load reduction, decreased risk factors for heart failure) affect myocardial functions. Our study will provide novel insights into how these drugs exert CV protection in a diabetic population.
EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752.
钠-葡萄糖协同转运蛋白2（SGLT-2）抑制剂已被证明对2型糖尿病（T2D）患者的一级预防以及心血管（CV）高风险患者的各种心血管结局具有有益影响。然而，这些心血管益处的作用机制仍不清楚且无法解释。DAPAHEART研究的目的是证明SGLT-2抑制剂治疗与T2D患者更高的心肌胰岛素敏感性相关，并确定这种改善是否可归因于全身（和组织特异性）胰岛素抵抗的降低以及心肌灌注和/或葡萄糖摄取的增加。我们还将确定受影响和未受影响的冠状动脉所支撑的心肌壁状况是否有明显改善，以及这是否与左心室功能的变化有关。
DAPAHEART试验将是一项III期、单中心、随机、双臂、平行组、双盲、安慰剂对照研究。一组52例患有稳定冠状动脉疾病（无心肌梗死病史，有或无经皮冠状动脉介入治疗史）、当前标准降糖治疗方案血糖控制不佳（糖化血红蛋白[HbA1c] 7-8.5%）的T2D患者，将按1:1比例随机分为达格列净组或安慰剂组。主要结局是检测治疗开始后4周心肌葡萄糖摄取相对于基线的变化。主要次要结局将是通过N-氨正电子发射断层扫描/计算机断层扫描（PET/CT）测量的心肌血流变化。其他结局包括心脏功能、通过高胰岛素-正常血糖钳夹期间的氟脱氧葡萄糖（FDG）PET-CT成像评估的骨骼肌、脂肪组织、肝脏、大脑和肾脏中的葡萄糖摄取；FDG PET-CT研究期间CT图像上观察到的心包、皮下和内脏脂肪以及褐变；通过高胰岛素-正常血糖钳夹评估的全身胰岛素敏感性、血糖控制、尿糖输出；以及微生物群改变。
SGLT-2抑制剂除了具有不依赖胰岛素的降血糖作用外，还能够直接（底物可用性、燃料利用、胰岛素敏感性）以及间接（降低心脏后负荷、降低心力衰竭风险因素）影响心肌功能。我们的研究将为这些药物如何在糖尿病患者中发挥心血管保护作用提供新的见解。
EudraCT编号：2016-003614-27；ClinicalTrials.gov标识符：NCT03313752。
