Chlorthalidone: mechanisms of action and effect on cardiovascular events

How chlorthalidone (CTDN) reduces risk for cardiovascular events (CVEs) can be considered in light of its ability to lower blood pressure (BP) and its non-BP related, pleiotropic effects. The mechanism by which CTDN lowers BP is unclear but may include alterations in whole body regulation and vasodilatory actions on vasculature, possibly mediated via its inhibitory effects on carbonic anhydrase. Additionally, CTDN has potentially beneficial, non-BP related, pleiotropic effects that include improvements in endothelial function, anti-platelet activity, and oxidative status. CTDN reduces pulse wave velocity, predictor of CVEs and a measure of central aortic stiffness associated with endothelial dysfunction. On the other hand, CTDN fosters hypokalemia, hyperglycemia, sympathetic discharge, and the renin-angiotensin-aldosterone system, but these potentially harmful effects do not appear to materially reduce CTDN's ability to prevent CVEs. Further, CTDN reduces and regresses left ventricular hypertrophy (LVH), an important BP-dependent predictor of CVEs. Consistent with this finding, CTDN was more effective than amlodipine in reducing congestive heart failure (CHF) in the Anti-hypertensive and Lipid-lowering Treatment to Prevent Heart Attach Trial (ALLHAT). In reducing CVEs, CTDN was superior to lisinopril in ALLHAT and superior to hydrochlorthiazide in observational cohort analyses and in network analyses of randomized trials. A statistical synthesis of randomized trials suggests that the reduction in cardiovascular risk from CTDN can be explained primarily on the basis of its ability to lower blood pressure rather than its influence upon non-BP related, pleiotropic effects.