Response by Hubers and Brown to Letter Regarding Article, “Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition”
We thank Rajapakse et al for expanding on our point about the role of neprilysin in amyloid-β degradation from our review article on combined angiotensin receptor antagonism and neprilysin inhibition.1 Rajapakse et al raised the concern that neprilysin inhibition may predispose patients to Alzheimer disease because of decreased degradation of amyloid-β, a key component of the neural plaques and deposits diagnostic of the disease. Therefore, it was suggested that individuals receiving neprilysin inhibition therapy should receive careful attention and may require monitoring of amyloid-β levels.
We agree with Rajapakse et al about the need for further research on the role of neprilysin in amyloid-β degradation and clinical outcomes such as Alzheimer disease. In addition to what was discussed in the review article, LBQ657, the metabolite of sacubitril and the inhibitor of neprilysin, crosses the blood-brain barrier and achieves a mean Cmax of 19.2 ng/mL in the cerebrospinal fluid of healthy volunteers treated with 14 days of valsartan/sacubitril 400 mg daily.2 Whether the finding of increased soluble amyloid-β (1–38) after treatment with valsartan/sacubitril in comparison with placebo was the result of neprilysin inhibition by LBQ657 or of changes in one of the other amyloid-β degradation pathways is not known.
We point out that the US Food and Drug Administration, as part of the approval process for valsartan/sacubitril, has required the sponsor to conduct a multicenter, randomized, active-controlled trial comparing valsartan/sacubitril with valsartan alone on cognitive function, as measured by neurocognitive tests and positron emission tomography imaging.3 Results from this study will likely take several years, because the final report is due to the US Food and Drug Administration in 2022. Given the prolonged time for Alzheimer disease to be clinically recognized, these long-term trials will likely be more informative than shorter trials.
Scott A. Hubers, MD
Nancy J. Brown, MD
Dr Brown served on an adjudication committee for angioedema for valsartan/sacubitril trials and serves as a consultant to Novartis. Dr Hubers reports no conflicts.
Circulation is available at http://circ.ahajournals.org.
- © 2016 American Heart Association, Inc.
- Hubers SA,
- Brown NJ
- Langenickel TH,
- Tsubouchi C,
- Ayalasomayajula S,
- Pal P,
- Valentin MA,
- Hinder M,
- Jhee S,
- Gevorkyan H,
- Rajman I
- 3.↵New Drug Application Approval Letter. US Food and Drug Administration. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/207620Orig1s000ltr.pdf. Accessed May 20, 2016.