Effect of Various Diuretic Treatments on Rosiglitazone-Induced Fluid Retention

Abstract

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 ≥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 m² (95% CI 0.26 to 0.90 L/1.73 m²; 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 m² (95% CI −1.52 to 0.03 L/1.73 m²; 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-γ 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.