Alzheimer’s disease and macular degeneration concerns with Entresto

Three academic physicians, writing in an editorial in the Journal of the American Medical Association, raised serious (but theoretical) concerns about the risk of Alzheimer’s disease and macular degeneration with long-term use of the new heart failure drug, valsartan/sacubitril (Entresto, Novartis).

Here is the translation:

Sacubitril is a drug that inhibits neprilysin, which is an enzyme (protein) responsible for breaking down things called natriuretic peptides (other proteins). This is good for heart failure patients because having more natriuretic peptides may prevent worsening heart muscle weakness. The problem is that neprilysin also degrades other proteins, such as angiotensin, endothelin 1, adrenomedullin, opioids, bradykinin, and amyloid-β peptide (Aβ).

The last one there, amyloid-B peptide, has been strongly implicated in Alzheimer’s dementia and macular degeneration. The editorialists cite animal studies showing that neprilysin plays a pivotal role in the development of Alzheimer’s disease in animal models.

They then note the fact that the PARADIGM-HF trial, which was the clinical trial showing modest benefits of valsartan/sacubitril (Entresto, Novartis), was too short to assess for these longer-term concerns. They also write that the trial did not include measures of executive function–a key finding for diagnosing Alzheimer’s.

The FDA is concerned about this. They required a clinical trial, which is being done. But it won’t be available until 2022. That’s a lot of patients who will take the drug before knowing whether it causes dementia or blindness.

The editorialists call for post-market pragmatic trials to look at these concerns.

A few thoughts:

These are theoretical concerns. It’s not proof that the drug will cause brain and eye problems. That’s the problem with new drugs. They are approved after positive findings from trials that carefully select patients and follow them for short periods of time. But then the drugs are used in the  real-world–with less selected patients–for longer periods of time. Real world use often reveals problems not seen in the cocoon of clinical trials.

The second thought here is that drugs don’t do just one thing in the body. Yes, it’s nice that blocking neprilysin promotes higher levels of proteins that may protect the heart; but neprilysin blockade also disrupts biologic process in other parts of the body. All drugs have this problem; think statins and cancer chemotherapy, for instance. The point is that it is not free to chemically block processes in the body.

The third thought is that I don’t think valsartan/sacubitril (Entresto) is a blockbuster. It won against a weak comparator. Yes, it was better than enalapril, but the real trial would have been to compare valsartan alone to valsartan/sacubitril. I wrote an entire post about the slow adoption of valsartan/sacubitril.

JMM

2 comments

  1. I understand your concerns with unintended issues yet to be determined and The possibilities should be explored. I am concerned, although, with the reference of this benefit as “modest” as it seems to understate that benefit. The Ace Inhibitors have realized consensus adoption with less statistical benefit in heart failure and that was comparative to placebo not the gold standard. Modest seems to be an intentional dismissal of the benefit (which was based upon 8,400 patient) to patient and hospital.

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