UOC Di Medicina Nucleare, Dipartimento Di Diagnostica Per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore, Rome, Italia.
Centro Malattie Endocrine E Metaboliche, Dipartimento Di Scienze Mediche E Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore, Rome, Italia.
Cardiovasc Diabetol. 2022 Sep 3;21(1):173. doi: 10.1186/s12933-022-01607-4.
Cardiovascular (CV) outcome trials have shown that in patients with type 2 diabetes (T2D), treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) reduces CV mortality and hospital admission rates for heart failure (HF). However, the mechanisms behind these benefits are not fully understood. This study was performed to investigate the effects of the SGLT-2i dapagliflozin on myocardial perfusion and glucose metabolism in patients with T2D and stable coronary artery disease (coronary stenosis ≥ 30% and < 80%), with or without previous percutaneous coronary intervention (> 6 months) but no HF.
This was a single-center, prospective, randomized, double-blind, controlled clinical trial including 16 patients with T2D randomized to SGLT-2i dapagliflozin (10 mg daily) or placebo. The primary outcome was to detect changes in myocardial glucose uptake (MGU) from baseline to 4 weeks after treatment initiation by [(18)F]2-deoxy-2-fluoro-D-glucose (FDG) PET/CT during hyperinsulinemic euglycemic clamp. The main secondary outcome was to assess whether the hypothetical changes in MGU were associated with changes in myocardial blood flow (MBF) and myocardial flow reserve (MFR) measured by N-ammonia PET/CT. The study was registered at eudract.ema.europa.eu (EudraCT No. 2016-003614-27) and ClinicalTrials.gov (NCT03313752).
16 patients were randomized to dapagliflozin (n = 8) or placebo (n = 8). The groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, renal and heart function). There was no significant change in MGU during euglycemic hyperinsulinemic clamp in the dapagliflozin group (2.22 ± 0.59 vs 1.92 ± 0.42 μmol/100 g/min, p = 0.41) compared with the placebo group (2.00 ± 0.55 vs 1.60 ± 0.45 μmol/100 g/min, p = 0.5). Dapagliflozin significantly improved MFR (2.56 ± 0.26 vs 3.59 ± 0.35 p = 0.006 compared with the placebo group 2.34 ± 0.21 vs 2.38 ± 0.24 p = 0.81; p = 0.001) associated with a reduction in resting MBF corrected for cardiac workload (p = 0.005; p = 0.045). A trend toward an increase in stress MBF was also detected (p = 0.054).
SGLT-2 inhibition increases MFR in T2D patients. We provide new insight into SGLT-2i CV benefits, as our data show that patients on SGLT-2i are more resistant to the detrimental effects of obstructive coronary atherosclerosis due to increased MFR, probably caused by an improvement in coronary microvascular dysfunction. Trial registration EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752.
心血管（CV）结局试验表明，在 2 型糖尿病（T2D）患者中，钠-葡萄糖共转运蛋白-2 抑制剂（SGLT-2i）的治疗可降低 CV 死亡率和心力衰竭（HF）的住院率。然而，这些益处背后的机制尚不完全清楚。本研究旨在探讨 SGLT-2i 达格列净对 T2D 合并稳定型冠状动脉疾病（冠状动脉狭窄≥30%且<80%）患者的心肌灌注和葡萄糖代谢的影响，这些患者之前有或没有经皮冠状动脉介入治疗（>6 个月）但没有 HF。
这是一项单中心、前瞻性、随机、双盲、对照临床试验，纳入了 16 例 T2D 患者，随机分为 SGLT-2i 达格列净（每日 10mg）或安慰剂组。主要结局是通过高胰岛素正常血糖钳夹术在治疗开始后 4 周时检测 [(18)F]2-脱氧-2-氟-D-葡萄糖（FDG）PET/CT 检测到的心肌葡萄糖摄取（MGU）的变化。主要次要结局是评估假设的 MGU 变化是否与通过 N-氨 PET/CT 测量的心肌血流（MBF）和心肌血流储备（MFR）的变化相关。该研究在 EudraCT.ema.europa.eu（EudraCT No.2016-003614-27）和 ClinicalTrials.gov（NCT03313752）注册。
16 例患者随机分为达格列净（n=8）或安慰剂（n=8）组。两组在基线特征（年龄、糖尿病病程、HbA1c、肾功能和心功能）方面匹配良好。在达格列净组，高胰岛素正常血糖钳夹期间 MGU 无明显变化（2.22±0.59 与 1.92±0.42 μmol/100g/min，p=0.41）与安慰剂组（2.00±0.55 与 1.60±0.45 μmol/100g/min，p=0.5）。与安慰剂组相比，达格列净显著改善 MFR（2.56±0.26 与 3.59±0.35 p=0.006 与安慰剂组 2.34±0.21 与 2.38±0.24 p=0.81；p=0.001），并伴有校正心脏工作量的静息 MBF 降低（p=0.005；p=0.045）。还检测到应激 MBF 增加的趋势（p=0.054）。
SGLT-2 抑制增加了 T2D 患者的 MFR。我们提供了 SGLT-2i 对心血管获益的新见解，因为我们的数据表明，接受 SGLT-2i 治疗的患者由于 MFR 增加而对阻塞性动脉粥样硬化的有害影响更具抵抗力，这可能是由于冠状动脉微血管功能障碍的改善所致。试验注册 EudraCT No.2016-003614-27；ClinicalTrials.gov 标识符：NCT03313752。
