Changes in serum potassium mediate thiazide-induced diabetes

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 >or=60 years treated with chlorthalidone or placebo. Incident diabetes was defined by self-report, antidiabetic medication use, fasting glucose >or=126 mg/dL, or random glucose >or=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.

Figure 1

Unadjusted Cumulative Incidence of Diabetes in the 3,790 Non-Diabetic Participants from the SHEP Trial.

Figure 2

Unadjusted Incidence Rates of Diabetes in Year 1 by Change in Serum Potassium in the 3,790 Non-Diabetic Participants from the SHEP Trial.

Figure 3

Predicted Probability of Developing Diabetes in Year 1 by Chlorthalidone Use and Change in Serum Potassium in the 3,790 Non-Diabetic Participants from the SHEP Trial. Predicted from Cox proportional hazards regression adjusted for age, gender, race, baseline systolic and diastolic BP, baseline body mass index, baseline creatinine, baseline fasting glucose and change in serum potassium. Change is serum potassium = baseline serum potassium – mean serum potassium in year 1. * Each dot near the abscissa indicates a data point