Petrykiv Sergei, Sjöström C David, Greasley Peter J, Xu John, Persson Frederik, Heerspink Hiddo J L
Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
AstraZeneca Gothenburg, Mölndal, Sweden.
Clin J Am Soc Nephrol. 2017 May 8;12(5):751-759. doi: 10.2215/CJN.10180916. Epub 2017 Mar 16.
Sodium glucose cotransporter 2 inhibition with dapagliflozin decreases hemoglobin A1c (HbA1c), body weight, BP, and albuminuria (urinary albumin-to-creatinine ratio). Dapagliflozin also modestly increases hematocrit, likely related to osmotic diuresis/natriuresis. Prior studies suggest that the HbA1c-lowering effects of dapagliflozin attenuate at lower eGFR. However, effects on other cardiovascular risk factors at different eGFR levels are incompletely understood.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This pooled analysis of 11 phase 3 clinical trials assessed changes in HbA1c, body weight, BP, hematocrit, and urinary albumin-to-creatinine ratio with placebo (=2178) or dapagliflozin 10 mg (=2226) over 24 weeks in patients with type 2 diabetes according to baseline eGFR (eGFR≥45 to <60 ml/min per 1.73 m, eGFR≥60 to <90 ml/min per 1.73 m, and eGFR≥90 ml/min per 1.73 m).
Compared with placebo, reductions in HbA1c with dapagliflozin were 0.6%, 0.5%, and 0.3%, respectively, for each consecutive lower eGFR subgroup ( value interaction <0.001). Effects of dapagliflozin on hematocrit, body weight, and BP were similar regardless of baseline eGFR, suggesting that effects potentially related to volume and natriuresis are eGFR independent. Moreover, among individuals with baseline urinary albumin-to-creatinine ratio ≥30 mg/g, placebo-adjusted reductions in urinary albumin-to-creatinine ratio were larger in the lowest eGFR subgroup ( value interaction <0.001). Adverse events occurred more frequently in the lowest eGFR subgroup; this was true for both dapagliflozin- and placebotreated patients.
The HbA1c-lowering effects of dapagliflozin decrease as renal function declines. However, dapagliflozin consistently decreases body weight, BP, and urinary albumin-to-creatinine ratio regardless of eGFR. These effects in conjunction with the finding of similar effects on hematocrit, a proxy for volume contraction, suggest that the effects of dapagliflozin are partly mediated nonglucosuric-dependent mechanisms.
达格列净抑制钠-葡萄糖协同转运蛋白2可降低糖化血红蛋白（HbA1c）、体重、血压及蛋白尿（尿白蛋白与肌酐比值）。达格列净还可适度提高血细胞比容，这可能与渗透性利尿/利钠有关。既往研究表明，达格列净降低HbA1c的作用在估算肾小球滤过率（eGFR）较低时会减弱。然而，对于不同eGFR水平下对其他心血管危险因素的影响，目前尚不完全清楚。
设计、地点、参与者及测量：这项对11项3期临床试验的汇总分析，评估了2型糖尿病患者在24周内，根据基线eGFR（每1.73平方米eGFR≥45至<60毫升/分钟、每1.73平方米eGFR≥60至<90毫升/分钟、每1.73平方米eGFR≥90毫升/分钟），使用安慰剂（n = 2178）或达格列净10毫克（n = 2226）时，HbA1c、体重、血压、血细胞比容及尿白蛋白与肌酐比值的变化。
与安慰剂相比，达格列净使HbA1c降低的幅度在eGFR依次降低的亚组中分别为0.6%、0.5%和0.3%（P值交互作用<0.001）。无论基线eGFR如何，达格列净对血细胞比容、体重和血压的影响相似，这表明可能与血容量和利钠相关的作用不依赖于eGFR。此外，在基线尿白蛋白与肌酐比值≥30毫克/克的个体中，最低eGFR亚组经安慰剂校正后的尿白蛋白与肌酐比值降低幅度更大（P值交互作用<0.001）。不良事件在最低eGFR亚组中更频繁发生；达格列净治疗组和安慰剂治疗组均如此。
随着肾功能下降，达格列净降低HbA1c的作用减弱。然而，无论eGFR如何，达格列净均可持续降低体重、血压及尿白蛋白与肌酐比值。这些作用以及对血细胞比容（血容量收缩的替代指标）有相似影响的发现，提示达格列净的作用部分是由非葡萄糖依赖机制介导的。
