title: A double-blind, placebo-controlled, crossover trial comparing the effects of amiloride and hydrochlorothiazide on glucose tolerance in patients with essential hypertension.
abstract: 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.
authors.affiliation: Clinical Pharmacology Unit, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Stears
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Woods
authors.forename: Michaela M
authors.initials: MM
authors.lastname: Watts
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Burton
authors.forename: Johann
authors.initials: J
authors.lastname: Graggaber
authors.forename: Fraz A
authors.initials: FA
authors.lastname: Mir
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Brown
mesh_terms: D000328:Adult; D000368:Aged; D000584:Amiloride / Q000008:administration & dosage* / Q000009:adverse effects; D001262:Atenolol / Q000008:administration & dosage* / Q000009:adverse effects; D001786:Blood Glucose / Q000187:drug effects*; D001795:Blood Pressure Determination; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005951:Glucose Tolerance Test; D006801:Humans; D006852:Hydrochlorothiazide / Q000008:administration & dosage* / Q000009:adverse effects; D006973:Hypertension / Q000175:diagnosis* / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D018570:Risk Assessment; D012720:Severity of Illness Index; D016896:Treatment Outcome; D006113:United Kingdom
chemical_list: D001786:Blood Glucose; D006852:Hydrochlorothiazide; D001262:Atenolol; D000584:Amiloride