Fears of neprilysin inhibition effects on cognition removed

Trial results show no evidence that neprilysin inhibition raised cognitive impairment risk due to brain amyloid-β accumulation, for HFmrEF/HFpEF patients.

A first trial evaluating long-term treatment with sacubitril/valsartan

Sacubitril/valsartan is the first of the class of dual neprilysin and angiotensin receptor inhibitors (ARNI). "Neprilysin is one of the many enzymes involved in the proteolytic breakdown of amyloid-β peptides, one of which (amyloid-β1–42) may be neurotoxic and is associated with Alzheimer's disease, for example, and concern was raised that their accumulation in the brain during sustained inhibition of neprilysin could cause or worsen cognitive impairment,” Prof. John McMurray (University of Glasgow, UK) explained as rationale for the presented trial1.

PERSPECTIVE (NCT02884206) was the first randomised-controlled trial to prospectively evaluate the effect of long-term treatment with sacubitril/valsartan, compared with valsartan alone, on cognitive function in patients with HFmrEF or HFpEF (EF >40%). A total of 592 patients were randomised 1:1 to receive sacubitril/valsartan (target dose 97/103 mg twice daily) or valsartan alone (target dose 160 mg twice daily). The primary endpoint was the change in cognitive function from baseline to 3-year follow-up. Cognitive function was assessed using the CogState global cognition composite score (GCCS), which includes 7 tests for assessing attention, episodic memory, and executive function.

No difference across the 2 trial arms

Roughly 60% of patients had some extent of cognitive impairment at baseline, but at the 3-year follow-up primary endpoint, there was no difference between the 2 arms (least squares mean change in GCCS -0.0180; 95% CI -0.1230 to 0.0870; P=0.74). Non-inferiority was established statistically (Cohen effect d size - 0.0277; 95% CI -0.1101 to 0.0778). The data was confirmed in all subgroups.

A key secondary outcome was the change from baseline at 18 months and 3 years in the deposition of amyloid-β in the brain measured using 18F-florbetaben PET and MRI (n=491 patients), and, again, no difference was observed (difference in least squares mean change -0.0292; 95% CI -0.0593 to 0.0010; P=0.058), “indicating that amyloid-β deposition in the brain tended to be unexpectedly lower in patients treated with sacubitril/valsartan compared with valsartan,” Prof. McMurray said. “The trend towards decreased amyloid deposition on the PET scan is surprising and may only reflect a factor of chance,” he added.

Closing remarks

Overall, Prof. McMurray said, “there was no evidence that inhibition of neprilysin increased the risk of cognitive impairment due to the accumulation of amyloid-β in the brain in patients with HFmrEF and HFpEF.” In any case, he said, “the absence of any negative effect on cognitive function is very important to remove a concern some doctors had about long-term treatment with sacubitril/valsartan.”

At the end of the presentation, it was asked whether valsartan itself might have similar effects that could mask any differences within a drug combination.

“No,” Prof. McMurray replied. “If anything, the evidence could be that angiotensin receptor blockers are able to protect cognitive function, and this goes back a long time with the SCOPE study conducted with candesartan in a hypertensive population2.”

  1. McMurray JJV, et al. PERSPECTIVE - Sacubitril/valsartan and cognitive function in HFmrEF and HFpEF. Hot Line Session 1, ESC Congress 2022, Barcelona, Spain, 26–29 August.
  2. Lithell H, et al. J Hypertens. 2003;21(5):875–86.