Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications
Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications
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DOI：
10.1161/circulationaha.116.021887
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发表时间：
2016-09-06
期刊：
影响因子：
37.8
通讯作者：
Cherney, David Z. I.
中科院分区：
文献类型：
--
作者：
Heerspink, Hiddo J. L.;Perkins, Bruce A.;Cherney, David Z. I.
钠-葡萄糖协同转运蛋白-2（SGLT 2）抑制剂，包括恩格列净、达格列净和卡格列净，目前已被广泛批准用于抗高血糖治疗。由于其独特的糖尿机制，SGLT 2抑制剂也可以减轻体重。也许更重要的是渗透性利尿和利钠作用，有助于血浆容量收缩，收缩压和舒张压分别降低4 - 6和1 - 2 mm Hg，这可能是心血管和肾脏获益的基础。SGLT 2抑制还与估计的肾小球滤过率急性剂量依赖性降低约5 mL.min（-1 1. 73 m（-2））和白蛋白尿减少约30%至40%相关。这些效应反映了临床前观察结果，表明近端肾小管钠尿排泄通过增加致密斑钠和氯化物递送激活肾小管肾小球反馈，导致传入血管收缩。在肾小球滤过率降低的基础上，慢性肾脏疾病患者的糖尿和体重减轻效应减弱（估计肾小球滤过率降低30%，与恩格列净相关的心血管死亡率、总死亡率和心力衰竭住院率降低，尽管根据设计，随机化组之间的血红蛋白A1 c差异很小。除了肌肉生殖器感染的风险增加外，恩格列净治疗的患者严重不良事件较少，包括急性肾损伤的风险较低。根据EMPA-REG OUTCOME结果，一些糖尿病临床实践指南现在建议，在未达到血糖目标和患有普遍动脉粥样硬化性心血管疾病的2型糖尿病患者中，优先使用已证实心血管获益的SGLT 2抑制剂。随着其他心肾保护试验的进行，SGLT 2抑制剂的钠相关生理效应和尿钠排泄的临床相关性，如对血压、心力衰竭、肾脏保护和死亡率的影响，将成为主要的管理重点。
Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits. SGLT2 inhibition also is associated with an acute, dose-dependent reduction in estimated glomerular filtration rate by approximate to 5 mL.min(-1).1.73 m(-2) and approximate to 30% to 40% reduction in albuminuria. These effects mirror preclinical observations suggesting that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (estimated glomerular filtration rate 30% reductions in cardiovascular mortality, overall mortality, and heart failure hospitalizations associated with empagliflozin, even though, by design, the hemoglobin A1c difference between the randomized groups was marginal. Aside from an increased risk of mycotic genital infections, empagliflozin-treated patients had fewer serious adverse events, including a lower risk of acute kidney injury. In light of the EMPA-REG OUTCOME results, some diabetes clinical practice guidelines now recommend that SGLT2 inhibitors with proven cardiovascular benefit be prioritized in patients with type 2 diabetes mellitus who have not achieved glycemic targets and who have prevalent atherosclerotic cardiovascular disease. With additional cardiorenal protection trials underway, sodium-related physiological effects of SGLT2 inhibitors and clinical correlates of natriuresis, such as the impact on blood pressure, heart failure, kidney protection, and mortality, will be a major management focus.