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BackgroundIt is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance. MethodsIn this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization. ResultsThe cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P = 0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P = 0.85). ConclusionsAmong patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)Copyright © 2010 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org by JEAN-CHRISTOPHE PHILIPS on May 3, 2010 .T h e ne w e ngl a nd jou r na l o f m e dic i ne n engl j med 362;16 nejm.org april 22, 2010 1478 P atients with impaired glucose tolerance have an increased risk of type 2 diabetes mellitus and cardiovascular disease. [1][2][3] Interventions that might reduce the incidence of diabetes and associated rates of death and complications from cardiovascular causes in such patients are therefore of importance. 3 Several trials have shown that lifestyle modification, including increased physical activity and weight loss, reduces the risk of diabetes, although these trials did not evaluate cardiovascular outcomes. [3][4][5][6][7][8] Certain drugs, including metformin, acarbose, and rosiglitazone, also reduce the incidence of diabetes, although their effect on cardiovascular events is uncertain. 6,9,10 Another pharmacologic approach to reducing the risk of diabetes and cardiovascular disease is inhibition of the renin-angiotensin system. Some studies have shown that angiotensin-convertingenzyme (ACE) inhibitors and ang...

SUMMARY (De)acetylation of histone and non-histone proteins is an important post-translational modification affecting many cellular processes. Here we report that NuA4 acetylation of Sip2, one of three regulatory β subunits of Snf1 complex (yeast AMP-activated protein kinase), decreases as cells age. We used mutations at four acetylation sites, K12, 16, 17 and 256, to study acetyl-Sip2 function. Sip2 acetylation, controlled by antagonizing NuA4 acetyltransferase and Rpd3 deacetylase, enhances interaction with Snf1, the catalytic subunit of Snf1 complex. Sip2-Snf1 interaction inhibits Snf1 activity, thus decreasing phosphorylation of a downstream target, Sch9 (homolog of Akt/S6K), ultimately leads to slower growth but extends replicative lifespan. Sip2 acetylation mimetics are more resistant to oxidative stress. We further demonstrate that the anti-aging effect of Sip2 acetylation is independent of extrinsic nutrient availability and TORC1 activity. We propose a novel protein acetylation- phosphorylation cascade that regulates Sch9 activity, controls intrinsic aging and extends replicative lifespan in yeast.

Natriuretic peptides (NPs) have multiple biological effects, including natriuresis, vasodilatation, inhibition of the renin-angiotensin system (RAS) and the sympathetic nervous system, positive lusitropism, and inhibition of fibrosis. Levels of NPs may be decreased in some hypertensive states. 4 Neprilysin degrades NPs, and inhibition of neprilysin increases NP levels.5 However, the BP reductions observed with neprilysin inhibition alone are modest.6,7 Concomitant neprilysin inhibition and RAS suppression have effects on sodium and volume excretion and BP reductions to a greater extent compared with RAS inhibitors alone. 5,8Omapatrilat, a neprilysin and angiotensin-converting enzyme inhibitor, has been shown to have significantly better systolic Abstract-LCZ696 (Japanese adopted name: sucabitril valsartan sodium hydrate), a first-in-class angiotensin receptor neprilysin inhibitor, concomitantly inhibits neprilysin and blocks angiotensin type 1 receptor. This randomized, doubleblind, placebo-controlled study, the first in Asia for this drug, evaluated the dose-related efficacy and safety of LCZ696 in patients with hypertension using 24-hour ambulatory blood pressure (BP) monitoring. Asian patients aged ≥18 years (n=389) with hypertension were randomized to receive LCZ696 100 mg (n=100), 200 mg (n=101), 400 mg (n=96), or placebo (n=92) for 8 weeks. The primary end point was mean difference across the 3 single-dose pairwise comparisons of LCZ696 versus placebo in clinic diastolic BP after 8-week treatment. Key secondary efficacy variables included changes in clinic systolic BP and pulse pressure and changes in 24-hour, daytime, and nighttime ambulatory BPs and pulse pressure. Safety assessments included recording all adverse events and serious adverse events. A total of 362 patients completed the study. Reductions in clinic systolic BP, diastolic BP (P<0.0001), and pulse pressure (P<0.001) were significantly greater with all doses of LCZ696 than with placebo. There were also significant reductions in 24-hour, daytime, and nighttime ambulatory systolic BP, diastolic BP, and pulse pressure for all doses of LCZ696 compared with placebo (P<0.0001). LCZ696 was well tolerated, and no cases of angioedema were reported. In conclusion, LCZ696 is effective for the treatment of hypertension in Asian population and, in general, is safe and well tolerated. Clinical Trial Information-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01193101.