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Effect of Various Diuretic Treatments on Rosiglitazone-Induced Fluid Retention

Janaka Karalliedde^*, Robin Buckingham^*, Margaret Starkie, Daniel Lorand, Murray Stewart, Giancarlo Viberti^* for the Rosiglitazone Fluid Retention Study Group

^* Unit for Metabolic Medicine, Department of Diabetes and Endocrinology, Cardiovascular Division, King’s College London School of Medicine, Guy’s Hospital, King’s College London, London, and Clinical Development and Medical Affairs and Biomedical Data Sciences–Statistics & Programming, GlaxoSmithKline Pharmaceuticals, Harlow and Greenford, Essex, United Kingdom

Address correspondence to: Prof. Giancarlo Viberti, Unit for Metabolic Medicine, 5th Floor, Thomas Guy House, Guy’s Hospital, St. Thomas Street, London SE1 9RT, UK. Phone: +44-2071881910; Fax: +44-2071880146; E-mail: giancarlo.viberti{at}kcl.ac.uk

Received for publication June 13, 2006. Accepted for publication September 26, 2006.

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- 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.

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