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 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.

Figure 1.

Flow chart of patients' disposition.

Figure 2.

Mean difference in hematocrit, relative to values in control (placebo) group, in the amiloride and spironolactone treatment groups after 24 weeks of treatment with spironolactone, amiloride, or placebo. Values obtained in 180 patients receiving rosiglitazone, 4 mg twice daily, in addition to background antidiabetic therapy.