Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada
Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Diabetes Care. 2017 Aug;40(8):1073-1081. doi: 10.2337/dc17-0061. Epub 2017 May 26.
Antihyperglycemic agents, such as empagliflozin, stimulate proximal tubular natriuresis and improve cardiovascular and renal outcomes in patients with type 2 diabetes. Because dipeptidyl peptidase 4 (DPP-4) inhibitors are used in combination with sodium-glucose cotransporter 2 (SGLT2) inhibitors, we examined whether and how sitagliptin modulates fractional sodium excretion and renal and systemic hemodynamic function.
We studied 32 patients with type 2 diabetes in a prospective, double-blind, randomized, placebo-controlled trial. Measurements of renal tubular function and renal and systemic hemodynamics were obtained at baseline, then hourly after one dose of sitagliptin or placebo, and repeated at 1 month. Fractional excretion of sodium and lithium and renal hemodynamic function were measured during clamped euglycemia. Systemic hemodynamics were measured using noninvasive cardiac output monitoring, and plasma levels of intact versus cleaved stromal cell-derived factor (SDF)-1α were quantified using immunoaffinity and tandem mass spectrometry.
Sitagliptin did not change fractional lithium excretion but significantly increased total fractional sodium excretion (1.32 ± 0.5 to 1.80 ± 0.01% vs. 2.15 ± 0.6 vs. 2.02 ± 1.0%, = 0.012) compared with placebo after 1 month of treatment. Moreover, sitagliptin robustly increased intact plasma SDF-1α and decreased truncated plasma SDF-1α. Renal hemodynamic function, systemic blood pressure, cardiac output, stroke volume, and total peripheral resistance were not adversely affected by sitagliptin.
DPP-4 inhibition promotes a distal tubular natriuresis in conjunction with increased levels of intact SDF-1α. Because of the distal location of the natriuretic effect, DPP-4 inhibition does not affect tubuloglomerular feedback or impair renal hemodynamic function, findings relevant to using DPP-4 inhibitors for treating type 2 diabetes.
恩格列净等抗高血糖药物可刺激近端肾小管钠排泄，改善 2 型糖尿病患者的心血管和肾脏结局。由于二肽基肽酶 4（DPP-4）抑制剂与钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂联合使用，我们研究了西他列汀是否以及如何调节钠排泄分数和肾脏及全身血液动力学功能。
我们在一项前瞻性、双盲、随机、安慰剂对照试验中研究了 32 例 2 型糖尿病患者。在基线时、服用西他列汀或安慰剂后 1 小时每小时测量肾小管功能和肾脏及全身血液动力学，并在 1 个月时重复测量。在夹闭性血糖正常时测量钠和锂的排泄分数和肾脏血液动力学功能。使用非侵入性心输出量监测测量全身血液动力学，使用免疫亲和和串联质谱法定量测定完整与切割基质细胞衍生因子（SDF-1α）的血浆水平。
与安慰剂相比，西他列汀治疗 1 个月后，锂排泄分数没有变化，但总钠排泄分数明显增加（1.32±0.5%至 1.80±0.01% vs. 2.15±0.6%至 2.02±1.0%，P=0.012）。此外，西他列汀显著增加了完整的 SDF-1α 血浆水平，并降低了截断的 SDF-1α 血浆水平。西他列汀并未对肾脏血液动力学功能、全身血压、心输出量、每搏输出量和总外周阻力产生不利影响。
DPP-4 抑制作用促进了与 SDF-1α 水平升高相关的远端肾小管钠排泄。由于利尿作用的位置在远端，DPP-4 抑制不会影响管球反馈或损害肾脏血液动力学功能，这对于使用 DPP-4 抑制剂治疗 2 型糖尿病具有重要意义。
