Thiazide-associated glucose abnormalities: prognosis, etiology, and prevention: is potassium balance the key?

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); diureticbased 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 is conflicting on the relationship between dysglycemia and CVD risk in the context of AHT treatment. Perhaps relevant are the clear findings that the relative CVD benefits of thiazide-based treatment are equally apparent in patients with normal FBG, impaired fasting glucose, and diabetes.5 More directly, 3 clinical epidemiologic studies have compared the risk conferred by DM6–8 observed in subjects before they were placed on AHT drugs to that while taking such medications (a thiazide alone or with other drugs). In these 3 studies, the relative risk (RR) conferred by DM at baseline was greater than that of DM occurring during treatment, and in 2 of them,6,7 the risk of IDM during treatment was not statistically significant, whereas that of baseline DM was significant. Although this difference could have been influenced by differential diabetes duration, these 2 studies did have very long total follow-up (22 and 14 years, respectively). The analyses from the Systolic Hypertension in the Elderly Program Extension (SHEP-X) were the most robust by far, because of the large sample size and hard end points (especially, CVD mortality); IDM in the group randomized to chlorthalidone during the 5-year trial had no effect on subsequent risk, in contrast to the effect of IDM occurring on placebo.7 Also, SHEP-X had the least contamination with other drugs in the regimen, whereas in the other studies, most patients were on multidrug regimens, and the percentage on thiazide alone was small. Another study found the effect of FBG change on risk of myocardial infarction to be higher in treated hypertensive patients compared with nonhypertensive persons, but it has been criticized for this design and because it adjusted differentially for blood pressure in the 2 groups.9 So what might be different about FBG changes and IDM because of thiazide use versus “naturally occurring” diabetes? In the latter situation, the major causes are established to be adiposity, a sedentary lifestyle, and genetics, but no role of potassium balance has been generally cited. However, the article by Zillich et al10 in this issue of Hypertension points out that a direct relationship between hypokalemia and glucose intolerance has been observed in experimental and clinical studies for 40 years, a relationship that seems to be of some importance in the setting of diuretic treatment. In the diuretic-treated patient, hypokalemia is likely to be intermittent because of dietary and drug adherence variation and potassium-sparing therapeutic intervention. This may also translate to dysglycemia that is intermittent (as argued below) and, thus, confers little risk of diabetic complications. Studies that have measured hemoglobin A1c would be useful in examining this hypothesis. In the newly reported analyses, a close statistical association between serum potassium decrease and blood glucose increase has now been well demonstrated in this quantitative review of 59 The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. The views are those of the author and do not necessarily represent positions of the U.S. Department of Health and Human Services. From the Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Md. Correspondence to Jeffrey A. Cutler, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, 6701 Rockledge Dr, MSC 7938, Bethesda, MD 20892. E-mail CutlerJ@nhlbi. nih.gov (Hypertension. 2006;48:198-200.) © 2006 American Heart Association, Inc.