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(Hypertension. 2008;52:1022.)
© 2008 American Heart Association, Inc.

Original Articles

Changes in Serum Potassium Mediate Thiazide-Induced Diabetes

Tariq Shafi; Lawrence J. Appel; Edgar R. Miller, III; Michael J. Klag; Rulan S. Parekh

From the Department of Medicine, Division of Nephrology (T.S., R.S.P.), and General Internal Medicine (L.J.A., E.R.M., M.J.K.), Department of Pediatrics, Division of Nephrology (R.S.P.), Johns Hopkins University School of Medicine; Department of Epidemiology (L.J.A., E.R.M., M.J.K., R.S.P.), Johns Hopkins Bloomberg School of Public Health; and the Welch Center for Prevention, Epidemiology and Clinical Research (L.J.A., E.R.M., M.J.K., R.S.P.), Baltimore, Md.

Correspondence to Tariq Shafi, Division of Nephrology, Johns Hopkins University School of Medicine, 4940 Eastern Ave, B2/Room 209, Baltimore, MD 21224-2780. E-mail tshafi{at}jhmi.edu

Thiazides, recommended as first-line antihypertensive therapy, are associated with an increased risk of diabetes. Thiazides also lower serum potassium. To determine whether thiazide-induced diabetes is mediated by changes in potassium, we analyzed data from 3790 nondiabetic participants in the Systolic Hypertension in Elderly Program, a randomized clinical trial of isolated systolic hypertension in individuals aged 60 years treated with chlorthalidone or placebo. Incident diabetes was defined by self-report, antidiabetic medication use, fasting glucose 126 mg/dL, or random glucose 200 mg/dL. The mediating variable was change in serum potassium during year 1. Of the 459 incident cases of diabetes during follow-up, 42% occurred during year 1. In year 1, the unadjusted incidence rates of diabetes per 100 person-years were 6.1 and 3.0 in the chlorthalidone and placebo groups, respectively. In year 1, the adjusted diabetes risk (hazard ratio) with chlorthalidone was 2.07 (95% CI: 1.51 to 2.83; P<0.001). After adjustment for change in serum potassium, the risk was significantly reduced (hazard ratio: 1.54; 95% CI: 1.09 to 2.17; P=0.01); the extent of risk attenuation (41%; 95% CI: 34% to 49%) was consistent with a mediating effect. Each 0.5-mEq/L decrease in serum potassium was independently associated with a 45% higher adjusted diabetes risk (95% CI: 24% to 70%; P<0.001). After year 1, chlorthalidone use was not associated with increased diabetes risk. In conclusion, thiazide-induced diabetes occurs early after initiating treatment and appears to be mediated by changes in serum potassium. Potassium supplementation might prevent thiazide-induced diabetes. This hypothesis can and should be tested in a randomized trial.

Key Words: hypertension • diabetes mellitus • thiazide diuretics • chlorthalidone • hypokalemia • potassium

Related Article:

Hypertension, Hypokalemia, and Thiazide-Induced Diabetes: A 3-Way Connection

Rajiv Agarwal
Hypertension 2008 52: 1012-1013. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				M. Moser and P. U. Feig Fifty Years of Thiazide Diuretic Therapy for Hypertension Arch Intern Med, November 9, 2009; 169(20): 1851 - 1856. [Abstract] [Full Text] [PDF]

				R. Agarwal Hypertension, Hypokalemia, and Thiazide-Induced Diabetes: A 3-Way Connection Hypertension, December 1, 2008; 52(6): 1012 - 1013. [Full Text] [PDF]