This posthoc analysis of the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study compared the cardiovascular effects of losartan- and atenolol-based therapy over 4.8 years in a subgroup of patients with hyper-tension and left ventricular hypertrophy, who were clinically free of vascular disease. Of the 9,193 participants in the LIFE study, nearly 75% (6,886) of subjects were free of clinically evident coronary, cerebral, or peripheral vascular diseases at the time of enrollment.
Despite equivalent reductions in systolic and diastolic blood pressures, there were significant differences in end point reduction. Using a losartan-based antihypertensive regimen with concurrent thiazide diuretics in more than 50% of subjects, there was a 20% lower cardiovascular death rate, 34% fewer strokes, and a 31% lower incidence of new-onset diabetes than in the atenolol group. The ability of losartan to reduce the cardiovascular end points and new-onset diabetes beyond that of atenolol is remarkable. There is ample evidence that treatment of hypertension is effective in reducing strokes and that hypertension was traditionally regarded as the single important factor in the prevention of strokes.1 The present studies suggest that factors other than reductions in blood pressure contribute to the favorable outcomes noted with losartan.
As discussed by Devereux and Lyle (page 29), the beneficial effect of losartan might be related to the inhibition of angiotensin at the tissue level. This might result in an alteration of endothelial dysfunction, vascular remodeling, and other possible mechanisms that are the subject of interest in many basic science and clinical investigations. Moreover, the beneficial effects of losartan, compared with atenolol on cardiovascular morbidity and mortality in the LIFE study, might result from an attenuated increase in serum uric acid, which is now considered an independent cardiovascular risk factor.2,3 This attenuated increase in serum uric acid is unique to losartan among all angiotensin receptor blockers (ARBs), partly by competing with uric acid for the anion exchanger in the proximal tubule to increase urinary uric acid excretion.4 This unique feature of losartan might mitigate the conclusion that the results of the LIFE study are applicable to all ARBs. Future studies should address this unique feature of losartan.
The 31% reduction in new-onset diabetes with losartan has great potential implications. This finding is comparable to the benefits derived from the use of ramipril in the Heart Outcomes Prevention Evaluation trial, but the mechanisms have not been elucidated. Several mechanisms have been proposed, including bradykinin-induced insulin sensitization by angiotensin-converting enzyme (ACE) inhibition.5,6 While the data on the effects of ARBs on insulin sensitization have been inconsistent in animal studies, the profound reduction in new-onset diabetes observed with the ARB losartan suggests that an increase in insulin sensitization might also exist in humans.5
The cardiovascular benefits afforded by losartan in the LIFE study do not appear to apply to the black