Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Diuretics reduced cardiovascular disease events in diabetic and nondiabetic patients

ACP J Club. 1997 May-Jun;126:57. doi:10.7326/ACPJC-1997-126-3-057


Source Citation

Curb JD, Pressel SL, Cutler JA, et al., for the Systolic Hypertension in the Elderly Program Cooperative Research Group. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA. 1996 Dec 18;276:1886-92.


Abstract

Objective

To determine the efficacy of diuretic-based (chlorthalidone) antihypertensive treatment in patients with non-insulin-dependent diabetes mellitus compared with nondiabetic patients.

Design

Subgroup analysis of a 5-year randomized, double-blind, placebo-controlled trial (Systolic Hypertension in the Elderly Program [SHEP]).

Setting

United States.

Patients

4736 patients (mean age 62 y, 57% women) who were ≥ 60 years of age and had isolated systolic hypertension (average systolic blood pressure [SBP] ≥ 160 mm Hg and diastolic blood pressure < 90 mm Hg during 2 baseline measurements). Exclusion criteria were SBP ≥ 220 mm Hg, major cardiovascular disease (CVD), other major disease, or such medical management problems as depression or diabetes requiring insulin. Of the 4732 patients included in the analysis, 583 patients (12.3%) were considered to have diabetes because of a diagnosis of diabetes, receipt of oral hypoglycemic agents, or a fasting serum glucose level of ≥ 7.8 mmol/L.

Intervention

Patients were allocated to oral chlorthalidone, 12.5 mg/d up to a maximum 25 mg/d (n = 2363 [283 patients with diabetes]) or placebo (n = 2369 [300 patients with diabetes]). Atenolol or reserpine was added if goal SBP was not attained.

Main outcome measures

Combined nonfatal and fatal stroke, nonfatal myocardial infarction (MI) or cardiac death, major coronary heart disease (CHD), and major CVD.

Main results

In diabetic patients, major CVD event rates were lower in patients who received diuretics compared with those who received placebo (20% vs 28% { P = 0.03}*). {This absolute risk reduction (ARR) of 8% means that 12 diabetic patients would need to be treated (NNT) with diuretics to prevent 1 additional CVD event, 95% CI 7 to 169; the relative risk reduction (RRR) was 27%, CI 2% to 46%.}* In nondiabetic patients, CVD event rates were 11% in diuretic recipients compared with 16% in placebo recipients { P < 0.001; ARR 5%; NNT 20, CI 14 to 36; RRR 30%, CI 19% to 40%}*. The rate of nonfatal MI and fatal CHD in diabetic patients was 6% for diuretic recipients compared with 11% for placebo recipients { P = 0.035; ARR 5%; NNT 20, CI 10 to 281; RRR 56%, CI 33% to 96%}*.

Conclusion

In terms of absolute risk reduction, diuretic-based antihypertensive therapy was more efficacious in patients with non-insulin-dependent diabetes mellitus than in nondiabetic patients.

Sources of funding: National Heart, Lung, and Blood Institute, and National Institute on Aging.

For article reprint: Sara L. Pressel, Systolic Hypertension in the Elderly Program Coordinating Center, 1200 Herman Pressler, Room 801, Houston, TX 77030, USA. FAX 713-500-9530.

*Numbers calculated from data in article.


Commentary

The treatment of hypertension in patients with diabetes mellitus should decrease the rate of vascular complications with minimal side effects. In a previous cohort study (1), the use of thiazide diuretics in patients with insulin-dependent diabetes mellitus (IDDM) and hypertension was associated with increased cardiovascular mortality when compared with a group of patients with IDDM and untreated hypertension. This has led to a recommendation for the use of angiotensin-converting enzyme inhibitors and β-blockers as the first line of treatment for hypertension in diabetes and avoidance of thiazide diuretics. The deleterious effect of thiazides was thought to be caused by hypokalemia, worsening dyslipidemia, increased insulin resistance, or unknown mechanisms.

The analysis from the SHEP trial did not find an increased rate of cardiovascular complications; on the contrary, it found a decrease that was more marked in diabetic patients than in nondiabetic, hypertensive patients. The first and most important difference between the 2 studies is that, in the SHEP trial, low-dose chlorthalidone was used. The antihypertensive effect of this agent at lower doses is similar to that at higher doses but the rate of side effects is lower. Other important differences between the previous study and the SHEP study are that the latter included only older patients with isolated systolic hypertension and excluded patients who required insulin.

Although cardiovascular events were decreased in the SHEP study, the diabetic patients treated with chlorthalidone had a higher frequency of sexual dysfunction (in men), hyperglycemia, hypokalemia, hyperuricemia, and hyponatremia than the diabetic patients who received placebo.

This study shows that thiazide diuretics should be considered a viable antihy-pertensive therapy in diabetic patients. They should ideally be used, however, in low doses similar to those used in this study—12.5 to 25 mg/d.

Arturo R. Rolla, MD
Harvard Medical SchoolBoston, Massachusetts, USA


Reference

1. Warram JH, Laffel LM, Valsania P, Christlieb AR, Krolewski AS. Excess mortality associated with diuretic therapy in diabetes mellitus. Arch Intern Med. 1991; 151:1350-6.