Thiazide-Associated Glucose Abnormalities: Prognosis, Etiology, and Prevention

Abstract

Thiazide diuretics have been recommended as the preferred class of antihypertensive (AHT) drugs for initial therapy and for inclusion in a regimen of multiple drugs.1 This recommendation is based on 4 decades of randomized clinical events trials with placebo (or usual care) comparators, meta-analyses of such trials, and active-controlled trials, including the very large Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial (ALLHAT).2,3 In the latter, treatment beginning with the thiazide-like diuretic chlorthalidone reduced the risk for major coronary events (the primary outcome) similar to treatment based on representatives of newer drug classes (amlodipine, doxazosin, and lisinopril); diuretic-based treatment was more effective at preventing heart failure, and in some comparisons, other cardiovascular disease (CVD) events. However, in ALLHAT mean fasting blood glucose (FBG) and incident diabetes mellitus (IDM) were slightly but significantly increased in the chlorthalidone compared with the other arms.3 Although the design precluded distinguishing between a benefit of the alternate drugs (especially lisinopril) and an adverse effect of the diuretic, previous evidence suggested that thiazides can cause dysglycemia (impaired glucose tolerance, impaired fasting glucose, or diabetes).4 One point about the ALLHAT results that has not received enough emphasis is that if the calcium channel blocker is taken as metabolically neutral, the 4-year IDM rates in the diuretic and calcium channel blocker arms (11.6% and 9.8%, respectively) imply that 83% of IDM occurring in association with thiazide use is not because of the diuretic. Nevertheless, based on the assumption that there is a direct relationship between thiazide exposure and dysglycemia, several key questions need to be addressed: (1) What are the long-term morbidity/mortality consequences, if any? (2) What are the mechanisms? and (3) Are the changes preventable and/or reversible? The role of potassium may be important to addressing each of these issues. Evidence …