title: Effect of various diuretic treatments on rosiglitazone-induced fluid retention.
abstract: 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 > or =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 m(2) (95% CI 0.26 to 0.90 L/1.73 m(2); 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 m(2) (95% CI -1.52 to 0.03 L/1.73 m(2); 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-gamma 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.
authors.affiliation: 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, London SE1 9RT, UK.
authors.forename: Janaka
authors.initials: J
authors.lastname: Karalliedde
authors.forename: Robin
authors.initials: R
authors.lastname: Buckingham
authors.forename: Margaret
authors.initials: M
authors.lastname: Starkie
authors.forename: Daniel
authors.initials: D
authors.lastname: Lorand
authors.forename: Murray
authors.initials: M
authors.lastname: Stewart
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Viberti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004232:Diuretics / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D045604:Extracellular Fluid / Q000187:drug effects; D005260:Female; D005665:Furosemide / Q000627:therapeutic use; D006400:Hematocrit; D006801:Humans; D006852:Hydrochlorothiazide / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010953:Plasma Volume / Q000187:drug effects*; D000077154:Rosiglitazone; D013148:Spironolactone / Q000627:therapeutic use; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D004232:Diuretics; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D006852:Hydrochlorothiazide; D013148:Spironolactone; D005665:Furosemide