Do neprilysin inhibitors walk the line? Heart ameliorative but brain threatening

Sacubitril/valsartan (Entresto (TM); LCZ696) is the first angiotensin receptor-neprilysin inhibitor (ARNI) drug approved by the US and EU for heart failure (HF) and especially recommended for hypertensive HF (HHF). Sacubitril inhibits the enzyme neprilysin (NEP) which produces both beneficial and adverse effects in the human body. While LCZ696 causes beneficial cardiovascular effects, it may induce memory and cognitive dysfunction, or even exacerbate Alzheimer's disease (AD). This article reviewed data reported by experimental and clinical studies that examined NEP inhibitors and their dementia-related side effects. Based on the literature, LCZ696 increases the risk of memory and cognitive dysfunctions, and clinical trials failed to show compelling evidence for LCZ696 safety for the brain. Together, it was concluded that more experimental and clinical studies with particular focus on LCZ696 side effects on beta-amyloid (A beta) degradation are needed to assess LCZ696 safety for the cognitive function, especially in case of long-term administration.

Automated summary

Sacubitril/valsartan is the first angiotensin receptor-neprilysin inhibitor drug approved for heart failure by the US and EU, especially recommended for hypertensive heart failure. However, it may cause memory and cognitive dysfunction, and could even exacerbate Alzheimer's disease. More studies are needed to evaluate the safety of Sacubitril/valsartan, particularly its effects on cognitive function long-term.