A double-blind, placebo-controlled, crossover trial comparing the effects of amiloride and hydrochlorothiazide on glucose tolerance in patients with essential hypertension.

Hypertension guidelines advise limiting the dose of thiazide diuretics and avoiding combination with β-blockade, because of increased risk of diabetes mellitus. We tested whether changes in the 2-hour oral glucose tolerance test could be detected after 4 weeks of treatment with a thiazide and could be avoided by switching to amiloride. Two double-blind, placebo-controlled, crossover studies were performed. In study 1 (41 patients), we found that changes in glucose during a 2-hour oral glucose tolerance test could be detected after 4 weeks of treatment with bendroflumethiazide. In study 2, 37 patients with essential hypertension received, in random order, 4 weeks of once-daily treatment with hydrochlorothiazide (HCTZ) 25 to 50 mg, nebivolol 5 to 10 mg, combination (HCTZ 25-50 mg+nebivolol 5-10 mg), amiloride (10-20 mg), and placebo. Each drug was force titrated at 2 weeks and separated by a 4-week placebo washout. At each visit, we recorded blood pressure and performed a 75-g oral glucose tolerance test. Primary outcome was the difference in glucose (over the 2 hours of the oral glucose tolerance test) between 0 and 4 weeks, when HCTZ and amiloride were compared by repeated-measures analysis. For similar blood pressure reductions, there were opposite changes in glucose between the 2 diuretics (P<0.0001). Nebivolol did not impair glucose tolerance, either alone or in combination. There was a negative correlation between Δpotassium and Δ2-hour glucose (r=-0.28; P<0.0001). In 2 crossover studies, 4 weeks of treatment with a thiazide diuretic impaired glucose tolerance. No impairment was seen with K(+)-sparing diuretic or β(1)-selective blockade. Substitution or addition of amiloride may be the solution to preventing thiazide-induced diabetes mellitus.