Abstract
BACKGROUND AND OBJECTIVES: Thiazolidinediones (pioglitazone and rosiglitazone) induce renal epithelial sodium channel (ENaC)-mediated sodium reabsorption, resulting in plasma volume (PV) expansion. Incidence and long-term management of fluid retention induced by thiazolidinediones remain unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a 4-week run-in period, rosiglitazone, 4 mg twice daily, was added to a background anti-diabetic therapy in 260 South Indian patients with type 2 diabetes mellitus. Patients with PV expansion (absolute reduction in hematocrit in run-in, ≥1.5 percentage points) entered a randomized, placebo-controlled study to evaluate effects of amiloride and spironolactone on attenuating rosiglitazone-induced fluid retention. Primary endpoint was change in hematocrit in each diuretic group versus placebo (control group). RESULTS: Of the 260 patients, 70% (n=180) had PV expansion. These 180 patients (70% male; mean age, 47.8 years [range, 30-80 years]) were randomly assigned to rosiglitazone, 4 mg twice daily, plus spironolactone, 50 mg once daily; rosiglitazone, 4 mg twice daily, plus amiloride, 10 mg once daily; or rosiglitazone, 4 mg twice daily, plus placebo for 24 weeks. Hematocrit continued to decrease significantly in control and spironolactone groups (mean absolute change, -1.2 [P=0.01] and -0.7 [P=0.02] percentage points, respectively), suggesting continued PV expansion. No change occurred with amiloride (mean change, 0.0 percentage points). Amiloride, but not spironolactone, was superior to control (mean hematocrit difference [95% confidence interval] relative to control, 1.27 [0.21-2.55] and 0.49 [-0.79-1.77] percentage points [P=0.04 and P=0.61], respectively). CONCLUSIONS: Prevalence of rosiglitazone-induced fluid retention in South Indian patients with type 2 diabetes is high. Amiloride, a direct ENaC blocker, but not spironolactone, prevented protracted fluid retention in these patients.