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Am Fam Physician. 2004;70(9):1646-1648

to the editor: I read with great interest the article, “New Developments in the Management of Hypertension,”1 in American Family Physician, which provides an excellent introduction to the management of this condition.

I am aware of the guidelines on offering diuretics as first-line therapy. However, I must take issue with the authors’ assertion that diuretics should be the first or second drug administered for the control of hypertension in patients who have diabetes. It has been long established that diuretics, especially thiazide diuretics, adversely affect glucose metabolism. Although lower doses of these medications have less of an adverse effect, many of these patients have more severe hypertension that requires maximal dosing of treatment strategies.2 The use of this class of medications can worsen glucose control unnecessarily because other treatment options exist.

in reply: Dr. Hood raises an excellent point regarding thiazide diuretics and blood glucose control. This is an area of much controversy. The recommendations of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)1 and the American Diabetes Association (ADA)2 advocate the use of thiazide diuretics (usually in addition to an angiotensin-converting enzyme [ACE] inhibitor) in patients who have hypertension and diabetes. The highest dosages of thiazide diuretics used in the 16 major clinical trials published since 1990 (on which these recommendations are based) were 25 mg of chlorthalidone or hydrochlorothiazide.3 In a meta-analysis,4 an average 1 percent elevation in blood glucose levels was seen in patients taking thiazide diuretics at these dosages; this does not represent a clinically significant increase in most patients with diabetes.4 Dosages above 25 mg appear to contribute only to increases in adverse effects such as hypokalemia, and not to further improvements in blood pressure control.4 The JNC and the ADA also advise that most patients with diabetes will need three or four medications to bring blood pressures to the goal of less than 130/80 mm Hg, with thiazide diuretics providing complementary reductions in blood pressure when combined with ACE inhibitors, angiotensin-receptor blockers, and/or beta blockers.1,2 These statements do not support the use of the high or “maximal” dosages (50 mg or greater) of thiazide diuretics that have been associated with elevations in blood glucose, but do support the use of lower doses in combination with other agents to reach blood pressure goals.3

In terms of efficacy, thiazide diuretics have demonstrated the same or greater benefits on long-term outcomes of cardiovascular and cerebrovascular disease in patients with diabetes as in those who do not have diabetes, reflecting the higher cardiovascular risk seen in patients with diabetes.2,5 In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), patients who had diabetes had fewer cardiovascular events with diuretic treatment than with ACE inhibitor treatment.5 The mean increase in fasting glucose levels in all patients over the four years of ALLHAT was 3 mg per dL (0.17 mmol per L) in those receiving chlorthalidone compared with a 0.6 mg per dL (0.03 mmol per L) increase in those receiving amlodipine, and a 1.4 mg per dL (0.08 mmol per L) decrease in those receiving lisinopril. Interestingly, among patients without diabetes at the beginning of the trial, the average fasting glucose level in all treatment groups was greater than 100 (104.4 mg per dL [5.80 mmol per L], 103.1 mg per dL [5.72 mmol per L], and 100.5 mg per dL [5.58 mmol per L], respectively). These numbers meet the ADA criteria for the diagnosis of pre-diabetes, which is associated with adverse cardiovascular outcomes.

With the current dosages of thiazide diuretics being used in practice, the negative effect of the small increases in blood glucose levels is overshadowed by the beneficial effects seen in clinical trials using thiazides as part of the multidrug regimen that is required to achieve blood pressure control in most patients with diabetes.

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This series is coordinated by Kenny Lin, MD, MPH, deputy editor.

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