A Double-Blind, Placebo-Controlled, Crossover Trial Comparing the Effects of Amiloride and Hydrochlorothiazide on Glucose Tolerance in Patients With Essential Hypertension

Hypertension, 04/10/2012

Stears AJ et al. – No impairment was seen with K+–sparing diuretic or β1–selective blockade. Substitution or addition of amiloride may be the solution to preventing thiazide–induced diabetes mellitus.


  • Two double–blind, placebo–controlled, crossover studies were performed.
  • In study 1 (41 patients), the authors 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, the authors 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.

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