SAN DIEGO — Spironolactone appears to be the most effective antidiuretic for the management of rosiglitazone-associated fluid retention, Janaka Karalliedde, M.D., reported at the annual scientific sessions of the American Diabetes Association.
Edema is a common side effect of the insulin sensitizer rosiglitazone, occurring in approximately 5% of patients with type 2 diabetes when used as monotherapy or in combination with other glucose-lowering agents, and in about 15% of patients who use it in combination with insulin.
The precise mechanism is unclear, although the phenomenon is reflected in a reduction in both hematocrit and hemoglobin, which is indicative of plasma volume expansion, said Dr. Karalliedde of the department of endocrinology and internal medicine, Kings College and Guys Hospital, London.
In a study sponsored by GlaxoSmithKline, 4 mg of rosiglitazone was given twice daily for 12 weeks to 381 patients with type 2 diabetes (67% male, mean age 60 years). One-fourth of the patients were already being treated with sulfonylurea alone, and the rest with sulfonylurea plus metformin. Their mean baseline hemoglobin A1c was 7.5%, and mean body mass index was 30 kg/m
A total of 68% showed evidence of volume expansion, defined as a reduction in hematocrit of at least 0.5%. Those 260 patients were then randomized to one of five 1-week treatment arms: continuation of rosiglitazone, continuation of rosiglitazone with the addition of either 40 mg/day of furosemide, 25 mg/day of hydrochlorothiazide, 50 mg/day of spironolactone, or discontinuation of rosiglitazone (with placebo).
Among the three diuretic groups, the dose of diuretic was doubled to 100 mg/day in the 33% whose urine output did not increase by at least 30% in the first 24 hours.
After the initial 12 weeks on rosiglitazone, those who were subsequently randomized had a mean reduction in hematocrit level of 2.9%, with a mean weight gain of 1.8 kg.
Plasma sodium levels rose significantly, while plasma aldosterone fell significantly. Both systolic and diastolic blood pressures dropped slightly, Dr. Karalliedde reported.
After randomization, hematocrit continued to fall in the group that continued taking rosiglitazone without a diuretic, with a total drop of 0.89% by day 7.
This reduction was attenuated to 0.7% in the furosemide group, to 0.12% in those who were withdrawn from rosiglitazone, and 0.02% with hydrochlorothiazide.
With spironolactone, however, hematocrit actually increased by 0.24% despite continuation of rosiglitazone. These results were statistically significant for both spironolactone and hydrochlorothiazide, he noted.
Total body weight fell in all diuretic groups, but the 1.2-kg loss with spironolactone was the greatest.
Only that and the 1-kg loss with hydrochlorothiazide reached statistical significance, compared with the group that continued taking rosiglitazone without a diuretic, Dr. Karalliedde said.