LCZ696: The Next Step in Improving RAS Inhibition?

  • Alan H. GradmanEmail author
Therapeutic Trials (M Weir, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Therapeutic Trials


LCZ696 is a single molecule which combines the angiotensin receptor blocker valsartan with the neprilysn inhibitor sacubitril (AHU377). In the recently published PARADIGM-HF trial, LCZ696 proved superior to enalapril in reducing overall mortality, heart failure hospitalizations, and other endpoints in patients with systolic dysfunction heart failure. Increases in counter-regulatory natriuretic peptides which oppose sodium retention, vasoconstriction, and the deleterious structural changes which follow neurohormonal activation are thought to account for these improved outcomes. In two large hypertension studies, LCZ696 has proved to be a potent, effective antihypertensive agent with tolerability similar to valsartan and placebo and potency comparable to amlodipine. Although several have occurred in the heart failure population, there have been no cases of angioedema noted in the hypertension trials, although few black patients—a group at high risk for its occurrence—have been studied. Whether LCZ696 will displace angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) as preferred renin–angiotensin system (RAS) blocking agents in hypertension will require demonstration of improved long-term outcomes compared with currently preferred first-line drugs. In this regard, experience has shown that it is difficult to extrapolate results achieved in heart failure to the treatment of hypertension, a condition in which neurohormonal activation is less critical in determining long-term prognosis. It will be particularly important to demonstrate renal protection with LCZ696 in patients with diabetes, proteinuria, and hypertension—the only therapeutic area other than heart failure in which RAS blockade has proved essential for optimal endpoint reduction. Superiority over available RAS blockers in terms of ‘vascular protection’ in high-risk populations represents another path to acceptance of LCZ696 as a preferred agent in cardiovascular medicine.


Natriuretic peptides Neprilysin LCZ696 Hypertension Heart failure 


Compliance with Ethics Guidelines

Conflict of Interest Alan H Gradman declares research support from Novartis and personal fees from Novartis, Daiichi-Sankyo and Takeda.

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Temple University School of Medicine (Clinical Campus)PittsburghUSA

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