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

Abstract

SummaryBackground 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, 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, 21. 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.

PPARγ Agonist-Induced Fluid Retention Depends on αENaC Expression in Connecting Tubules

“…A role for ENaC in CNT in TZD-induced fluid retention dovetails with the physiological relevance of ENaC in this segment for Na + reabsorption [17-20]. The findings are also in agreement with studies that found that the ENaC blocker, amiloride, and the aldosterone-antagonist, spironolactone, attenuated TZD-induced fluid retention in diabetic patients [16;23]. …”

“…The epithelial sodium channel ENaC is expressed in the apical membrane of the CNT and CD and serves as a primary effector of regulated sodium reabsorption. Studies in mice [15] and in patients with type 2 diabetes [16] found that TZD-induced weight gain and fluid retention were attenuated by the ENaC inhibitor, amiloride, indicating a potential role of ENaC in this process.…”

Spironolactone and glucose metabolism, a systematic review and meta-analysis of randomized controlled trials

“…Table 1 shows the characteristics of the 18 selected trials; 13 were in both men and women, showing no effect or a potential benefit. Eight trials were in people with diabetes, of these 8 trials, 6 were conducted in people with type 2 diabetes (212 in the treatment arms and 207 in the placebo arms) [11,[26][27][28][29][30]. One cross-over trial was conducted in 21 people with type 1 diabetes [31].…”

Increased susceptibility of db/db mice to rosiglitazone-induced plasma volume expansion: role of dysregulation of renal water transporters

“…The changes in Hct have been used as a surrogate marker for TZD-induced plasma volume expansion. Viswanathan et al (27) recently showed that of 260 patients on RGZ, 70% had plasma volume expansion as reflected by a drop of Hct. The severity of the side effect increases in patients treated with TZD in combination with insulin therapy (15).…”