Karalliedde Janaka, Buckingham Robin, Starkie Margaret, Lorand Daniel, Stewart Murray, Viberti Giancarlo
Unit for Metabolic Medicine, Department of Diabetes and Endocrinology, Cardiovascular Division, King's College London School of Medicine, Guy's Hospital, King's College London, London, London SE1 9RT, UK.
J Am Soc Nephrol. 2006 Dec;17(12):3482-90. doi: 10.1681/ASN.2006060606. Epub 2006 Nov 8.
The efficacy of diuretics in the management of rosiglitazone (RSG)-induced fluid retention was evaluated in a multicenter, randomized, open-label, parallel-group, proof-of-concept study. Of 381 patients who had type 2 diabetes and were on treatment with sulfonylurea or sulfonylurea plus metformin, 260 (63% male, 37% female) showed evidence of volume expansion as defined by an absolute reduction in hematocrit (Hct) of > or =0.5% after 12 wk of rosiglitazone 4 mg twice daily. They were randomly assigned to five treatments for 7 d: (1) Continuation of RSG (RSG-C), (2) RSG + furosemide (RSG+FRUS), (3) RSG + hydrochlorothiazide (RSG+HCTZ), (4) RSG + spironolactone (RSG+SPIRO), and (5) discontinuation of RSG. The primary end point was change in Hct at day 7 of diuretic treatment phase, powered to compare each diuretic group and the RSG discontinuation with the control group of RSG-C, with adjustments for multiple testing. After 12 wk on RSG, Hct fell by mean of 2.92% (95% confidence interval [CI] -3.10 to -2.63%; P < 0.001) and extracellular fluid volume increased by 0.62 L/1.73 m(2) (95% CI 0.26 to 0.90 L/1.73 m(2); P < 0.001). After treatment, the RSG+SPIRO group only showed a mean increase in Hct of 0.24%. The estimated mean difference in Hct reduction was significant: 1.14% (95% CI 0.29 to 1.98%) for RSG+SPIRO (P = 0.004) and 0.87% (95% CI 0.03 to 1.71%) for RSG+HCTZ (P = 0.041) only. In additional analyses of between-diuretic treatment effects SPIRO induced a greater Hct rescue at 0.88% (95% CI -0.12 to 1.87%; P = 0.095) and extracellular fluid volume reduction of -0.75 L/1.73 m(2) (95% CI -1.52 to 0.03 L/1.73 m(2); P = 0.06) compared with FRUS, suggesting superiority in the management of RSG-associated fluid retention. There were no significant differences between SPIRO and HCTZ. These findings are consistent with peroxisome proliferator-activated receptor-gamma agonist activation of the epithelial sodium channel in the distal collecting duct, a site of action of SPIRO and a potential target for thiazide diuretics.
在一项多中心、随机、开放标签、平行组概念验证研究中，评估了利尿剂对罗格列酮（RSG）所致液体潴留的治疗效果。381例2型糖尿病患者接受磺脲类药物或磺脲类药物联合二甲双胍治疗，其中260例（63%为男性，37%为女性）在每日两次服用4mg罗格列酮12周后，出现血细胞比容（Hct）绝对值降低≥0.5%，提示存在容量扩张。这些患者被随机分配接受5种治疗，为期7天：（1）继续使用RSG（RSG-C）；（2）RSG + 呋塞米（RSG+FRUS）；（3）RSG + 氢氯噻嗪（RSG+HCTZ）；（4）RSG + 螺内酯（RSG+SPIRO）；（5）停用RSG。主要终点是利尿剂治疗阶段第7天Hct的变化，旨在比较各利尿剂组以及停用RSG组与RSG-C对照组，同时对多重检验进行校正。服用RSG 12周后，Hct平均下降2.92%（95%置信区间[CI] -3.10至-2.63%；P < 0.001），细胞外液量增加0.62 L/1.73 m²（95% CI 0.26至0.90 L/1.73 m²；P < 0.001）。治疗后，RSG+SPIRO组Hct仅平均增加0.24%。Hct降低的估计平均差异具有统计学意义：RSG+SPIRO组为1.14%（95% CI 0.29至1.98%；P = 0.004），RSG+HCTZ组仅为0.87%（95% CI 0.03至1.71%；P = 0.041）。在利尿剂治疗效果的额外分析中，与FRUS相比，SPIRO使Hct回升幅度更大，为0.88%（95% CI -0.12至1.87%；P = 0.095），细胞外液量减少-0.75 L/1.73 m²（95% CI -1.52至0.03 L/1.73 m²；P = 0.06），提示在治疗RSG相关液体潴留方面更具优势。SPIRO与HCTZ之间无显著差异。这些发现与过氧化物酶体增殖物激活受体γ激动剂激活远端集合管上皮钠通道一致，该通道是螺内酯的作用位点，也是噻嗪类利尿剂的潜在靶点。
