Effect of Spironolactone and Amiloride on Thiazolidinedione-Induced Fluid Retention in South Indian Patients with Type 2 Diabetes

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 rosiglitazoneinduced 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, 4mg twice daily, plus spironolactone, 50mg once daily; rosiglitazone, 4 mg twice daily, plus amiloride, 10 mg once daily; or rosiglitazone, 4 mg twice daily, plus placebo for 24weeks. Hematocrit continued to decrease significantly in control and spironolactone groups (mean absolute change, 21.2 [P=0.01] and 20.7 [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 [20.79–1.77] 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.