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Heart Drug Entresto May Pose Risk to Brain and Eye, Researchers Warn
Patients with mild heart failure stand to benefit from a new drug that can halt the progression of their disease and reduce their risk of cardiovascular-related death. But the drug — Entresto (valsartan/sacubitril, Novartis) — may be too good to be true, according to researchers at Temple University’s Lewis Katz School of Medicine in Philadelphia, Pennsylvania.
In an article published online in JAMA, Arthur M. Feldman, MD, PhD, and his colleagues warn that valsartan/sacubitril could theoretically increase patients’ risk of Alzheimer’s disease (AD) and macular degeneration. The drug was approved by the FDA in July 2015.
Valsartan/sacubitril works by inhibiting the enzyme neprilysin, which normally plays a critical role in breaking down an array of peptides in cells. Among those substances are natriuretic peptides, which function in regulating scarring and cell growth in the heart when neprilysin is blocked. Because of those activities, valsartan/sacubitril may delay the progression of heart failure in some patients.
Neprilysin, however, also degrades amyloid beta, a peptide that can accumulate in the brain, where it contributes to AD, as well as in the eye, where it is implicated in macular degeneration. The balance between the production and clearance of amyloid beta is crucial to the pathogenesis of AD and is suspected to influence the development of macular degeneration. In animal models, blocking neprilysin disturbs that balance and exacerbates the development of AD pathology.
Valsartan/sacubitril was approved for heart failure via the FDA’s fast track program, in which drugs that promise to fulfill unmet medical needs undergo an accelerated review process. In the studies that led to the drug’s approval, no adverse events related to dementia were reported. However, according to Feldman and his colleagues, patients were followed for too short a period to confidently rule out potential adverse effects on cognitive function or vision, and specific tests were not performed to assess whether early changes in either AD-specific cognitive function or macular degeneration had occurred.
Moreover, preclinical studies of valsartan/sacubitril involved young monkeys and healthy human volunteers. In both groups, the blood–brain barrier functions as it should. In heart failure patients, however, the blood–brain barrier often is compromised by hypertension and other vascular conditions, allowing drugs to enter the central nervous system, Feldman said.
The FDA has required Novartis to conduct a thorough assessment of the cognitive risks associated with valsartan/sacubitril in a clinical trial in patients with heart failure and a preserved ejection fraction. However, the data from that study will not be available until 2022.
“My hope is that physicians will be prudent with the use of this new drug,” Feldman said. “The risks are theoretical, but every precaution should be taken to avoid them. The outcomes could be devastating for patients.”
Source: Medical Xpress; December 9, 2015.