title: 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.
authors.affiliation: Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD 21224-2780, USA. tshafi@jhmi.edu
authors.forename: Tariq
authors.initials: T
authors.lastname: Shafi
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Appel
authors.forename: Edgar R
authors.initials: ER
authors.lastname: Miller
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Klag
authors.forename: Rulan S
authors.initials: RS
authors.lastname: Parekh
mesh_terms: D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001262:Atenolol / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects; D002752:Chlorthalidone / Q000008:administration & dosage / Q000009:adverse effects*; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced* / Q000453:epidemiology; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000453:epidemiology; D007008:Hypokalemia / Q000139:chemically induced* / Q000453:epidemiology; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011188:Potassium / Q000097:blood; D016016:Proportional Hazards Models; D012110:Reserpine / Q000008:administration & dosage; D012307:Risk Factors
chemical_list: D000959:Antihypertensive Agents; D001262:Atenolol; D012110:Reserpine; D002752:Chlorthalidone; D011188:Potassium