Author + information
- Scott D. Solomon, MD∗ (, )
- John J.V. McMurray, MD,
- on behalf of the PARAGON-HF Steering Committee
- ↵∗Noninvasive Cardiology, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115
As neprilysin is 1 of several proteases that plays a role in the degradation of amyloid β proteins, concern has been raised about the theoretical possibility that long-term neprilysin inhibition could influence the development of Alzheimer’s disease (AD); yet the specific role of neprilysin in the pathogenesis of AD remains unclear. In addition to the likely redundancy in the enzymes that break down amyloid β, individuals with truncating mutations in the gene encoding for neprilysin, who have total neprilysin deficiency, appear to lack any phenotypic consequence (1). Moreover, in individuals with amyloid precursor protein or presenilin mutations, lifelong increase in cellular production of pathogenic amyloid β1-42 by 40% to 50% or more do not result in clinically noticeable cognitive symptoms until the fifth or six decades. Human experiments with sacubitril/valsartan in volunteers did not show selective elevation of the toxic form of amyloid β1-42 (2); and in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor with Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial (N = 8,399 participants with follow-up of up to 4.25 years) there were no observed increases in adverse events secondary to dementia (3), although comprehensive cognitive function testing was not performed.
Nevertheless, these theoretical concerns have prompted several specific proactive approaches on the part of the manufacturer of sacubitril/valsartan and sponsor of the PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor with Angiotensin Receptor Blocker Global Outcomes in HF With Preserved Ejection Fraction) trial to assess the potential role of neprilysin inhibition in AD. In addition to the large cognitive function study embedded in PARAGON-HF (4), which will use the Mini Mental State Examination (MMSE) at baseline and 2 years, the PERSPECTIVE (Prospective Evaluation of Cognitive Function in Heart Failure: A Randomized double-blind Study in Patients with Preserved Ejection Fraction Cardiac Failure Treated with Valsartan or Entresto) trial (NCT02884206), which was designed in close collaboration with major health authorities, will assess the overall impact of long-term LCZ696 therapy on cognitive function through a much more comprehensive battery of neuropsychological tests in approximately 500 patients with heart failure with preserved ejection fraction and will assess amyloid β deposition in the brain by using positron emission tomography amyloid imaging. These data will further help inform clinicians regarding the benefit/risk ratio of a therapy that has already been proven to reduce morbidity and mortality in heart failure with reduced ejection fraction and which is currently undergoing testing in heart failure with preserved ejection fraction and in the post-myocardial infarction setting.
Please note: Dr. Solomon has received grant support from and is a consultant for Novartis. Dr. McMurray has received compensation through his institution for clinical trials, advisory board membership, and speakers fees from Novartis.
- Cannon J.A.,
- Shen L.,
- Jhund P.S.,
- et al.,
- for the PARADIGM-HF Investigators and Committees
- Solomon S.D.,
- Rizkala A.R.,
- Gong J.,
- et al.