Effect of Neprilysin Inhibition on Alzheimer Disease

- Posted by

It's been known for more than 20 years that neprilysin inhibitors such as sacubitril could foster Alzheimer's disease. Yet in 2015, Novartis decided to ask the FDA to authorize Entresto (sacubitril/valsartan) for heart failure. A clinical trial was set up and failed to meet the primary objective (heart failure), nevertheless (usual story) the drug was authorized by FDA.

At that time it was well known that this drug could foster Alzheimer's disease, so the FDA mandated that another clinical trial was also designed (PERSPECTIVE; NCT02884206) to test if there was a risk to cognitive functions. There were also other clinical trials with the same goal, for example in Korea. These clinical trials didn't show any aggravation of cognitive functions.

More recent studies have suggested that this class of drugs (neprilysin inhibitors) could have both positive and negative effects on the development of Alzheimer's disease. enter image description here. (source: Naif H. Ali and Hayder M. Al-Kuraishy)

A re-analysis of the results of another clinical trial by scientists from the University of Gothenburg, in collaboration with colleagues from the University of Glasgow, is less optimistic about the effects of sacubitril on cognitive functions.

There are many other drugs to manage heart failure and it is not even clear if Entresto brings substantial benefits to the patients. Why was Entresto authorized in the first place in 2015, and why is it still prescribed given the abundant literature about the effects of sacubitril on Alzheimer's disease?

Please, help us continue to provide valuable information: