Thiazide-induced dysglycemia: call for research from a working group from the national heart, lung, and blood institute.

There are 70-million hypertensive individuals in the United States, and 45-million persons take antihypertensive medications.1,2 Despite the results of the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT), other trials, and the recommendations in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, well under 50% of these regimens include a thiazide-type diuretic.2,3 In the Department of Veterans’ Affairs, which participated in several of the studies supporting the use of thiazide diuretics, 35% of hypertensive patients on pharmacotherapy had a thiazide diuretic included in their hypertension treatment regimens in 2003.4 In private patient encounters, thiazide diuretic use rose from 19% of all of the antihypertensive patient visits in 2002 to 26% in 2004.5 The recommendations for preferred use of thiazide-type diuretics are based on 4 decades of clinical trials, including active-controlled trials, where diuretics were tested against other drugs for their efficacy in preventing hard clinical outcomes, such as myocardial infarction, death, stroke, heart failure, and renal failure. ALLHAT, a randomized, double-blind, activecontrolled antihypertensive treatment trial in 42 418 patients assigned to a thiazide-type diuretic, an angiotensin-converting enzyme (ACE) inhibitor, a calcium channel-blocker, (average follow-up: 4.9 years), or the doxazosin/chlorthalidone comparison (terminated early, average follow-up: 3.2 years) showed that the diuretic was at least as beneficial as the comparator drugs in lowering blood pressure (BP) and preventing cardiovascular (CV) and renal outcomes and was superior for preventing heart failure (versus each comparator arm), combined CV events (versus -blocker and ACE-inhibitor arms), and stroke (versus ACE inhibitor [black subjects only] and -blocker).6 The ongoing success of thiazide-type diuretics in large, adequately powered hypertension outcome trials and new guidelines have created the basis for increased diuretic use.2,6 However, clinical trials have also frequently shown potentially undesirable metabolic biochemical effects during diuretic treatment compared with other drugs, including an increase in serum glucose levels (dysglycemia).6–14 Diureticinduced increases in serum glucose levels are small and appear to attenuate over time (“diuretic-induced” indicates the part of the diuretic-associated increase in serum glucose levels that is above the increase related to aging, weight gain, sedentary lifestyle, and other risk factors). Nevertheless, opinion leaders in the medical community have raised concerns about the potential for long-term adverse CV and renal effects of the observed dysglycemia.15 They argue that the average length of follow-up in clinical trials, 4 to 5 years, is not long enough to recognize the potential long-term adverse effects of the known biochemical changes. In addition, they express a concern that patients who develop thiazideassociated diabetes will require monitoring and treatment for diabetes that they would not have experienced without the thiazide. In contrast to the above concerns, the evidence on whether the development of dysglycemia with any antihypertensive drug treatment produces adverse CV effects is mixed, and there are no direct outcome data for diuretic-induced dysglycemia.16 Among large-sample follow-up studies, the largest (ALLHAT) and the longest (from the Systolic Hypertension in the Elderly Program [SHEP]) show no significant adverse CV events from new diuretic-associated diabetes.17,18 Importantly, 83% of the new-onset diabetes that occurred in the ALLHAT diuretic arm was apparently not because of the diuretic. Although many of these patients had only 3to 4-mg/dL increases in blood sugar over baseline that tipped them over the threshold, the vast majority who developed