Changes in Serum Potassium Mediate Thiazide-Induced Diabetes

Author:

Shafi Tariq1,Appel Lawrence J.1,Miller Edgar R.1,Klag Michael J.1,Parekh Rulan S.1

Affiliation:

1. 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.

Abstract

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Internal Medicine

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