Elsevier

The Lancet

Volume 359, Issue 9311, 23 March 2002, Pages 1004-1010
The Lancet

Articles
Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol

https://doi.org/10.1016/S0140-6736(02)08090-XGet rights and content

Summary

Background

The most suitable antihypertensive drug to reduce the risk of cardiovascular disease in patients with hypertension and diabetes is unclear. In prespecified analyses, we compared the effects of losartan and atenolol on cardiovascular morbidity and mortality in diabetic patients.

Methods

As part of the LIFE study, in a double-masked, randomised, parallel-group trial, we assigned a group of 1195 patients with diabetes, hypertension, and signs of left-ventricular hypertrophy (LVH) on electrocardiograms losartan-based or atenolol-based treatment. Mean age of patients was 67 years (SD 7) and mean blood pressure 177/96 mm Hg (14/10) after placebo run-in. We followed up patients for at least 4 years (mean 4·7 years [1·1]). We used Cox regression analysis with baseline Framingham risk score and electrocardiogram-LVH as covariates to compare the effects of the drugs on the primary composite endpoint of cardiovascular morbidity and mortality (cardiovascular death, stroke, or myocardial infarction).

Findings

Mean blood pressure fell to 146/79 mm Hg (17/11) in losartan patients and 148/79 mm Hg (19/11) in atenolol patients. The primary endpoint occurred in 103 patients assigned losartan (n=586) and 139 assigned atenolol (n=609); relative risk 0·76 (95% CI 0·58–0·98), p=0·031. 38 and 61 patients in the losartan and atenolol groups, respectively, died from cardiovascular disease; 0·63 (0·42–0·95), p=0·028. Mortality from all causes was 63 and 104 in losartan and atenolol groups, respectively; 0·61 (0·45–0·84), p=0·002.

Interpretation

Losartan was more effective than atenolol in reducing cardiovascular morbidity and mortality as well as mortality from all causes in patients with hypertension, diabetes, and LVH. Losartan seems to have benefits beyond blood pressure reduction.

Introduction

The Losartan Intervention For Endpoint reduction (LIFE) study was designed in the early 1990s1, 2, 3, 4 when no drug class for the treatment of essential hypertension had been shown to be more effective in prevention of cardiovascular morbidity and mortality than β-blockers and diuretics. The main hypothesis of LIFE was that selective angiotensin-II type-1-receptor antagonism with losartan would be more effective than β-blockade with atenolol in reducing cardiovascular morbidity and mortality in patients with essential hypertension and signs of left ventricular hypertrophy (LVH) on electrocardiograms.

Diabetes mellitus doubles the risk of cardiovascular disease,5 even in patients with hypertension who are already at high risk because of their high blood pressure.6 Since many patients with hypertension develop diabetes, this combination of risk factors will account for a large proportion of cardiovascular morbidity and mortality. The frequency of diabetes mellitus is increasing rapidly worldwide.7 In the LIFE study,1 we compared the long-term effects of once-daily losartan-based with atenolol-based antihypertensive treatment in patients with hypertension and LVH on the frequency of cardiovascular morbidity and mortality (a composite of cardiovascular mortality, stroke and myocardial infarction). The most suitable drug to prevent premature cardiovascular disease in diabetic patients with high blood pressure is unclear. Therefore, we analysed the outcome in the prespecified subgroup of patients who had diabetes mellitus at the start of the LIFE study.

Section snippets

Patients and procedures

The LIFE study1 was a double-masked, randomised, parallel-group study with double dummy drugs. The main outcome1 and the complete study protocol with study design, organisation, clinical measures, endpoint definitions, exclusion criteria, reasons for choice of comparative agents, statistical power calculations, and baseline characteristics have been published.2, 3, 4

We included patients aged 55–80 years with hypertension (either treated or untreated) and signs of LVH on electrocardiograms. We

Results

Groups were closely matched in demographic characteristics, severity of hypertension, prevalence of coexisting cardiovascular conditions, Framingham risk score, and electrocardiogram-based LVH criteria (table 1). Compared with the remaining LIFE participants without diabetes,1 patients with the disease had higher body-mass index, higher Framingham risk score, a higher prevalence of cardiovascular disease at baseline (table 1), higher systolic blood pressure (difference 3 mm Hg), lower diastolic

Discussion

Our results show that losartan was better than atenolol in reducing the risk of cardiovascular morbidity and mortality in patients with diabetes and hypertension. Results were especially marked in the small group (20%) of patients who had not been treated for hypertension before the study. We emphasise that we decided before the start of the study to adjust results for the Framingham risk score and degree of LVH to account for any difference in key risk predictors at baseline and thus accounted

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