Neprilysin inhibition appears beneficial in diabetic kidney disease
medwireNews: Secondary analysis of the PARADIGM-HF trial shows that the adverse effects of diabetes on kidney function can be ameliorated by a neprilysin inhibitor.
PARADIGM-HF assessed a medication combining the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan, comparing it with the angiotensin-converting enzyme inhibitor enalapril in patients with mild-to-moderate chronic heart failure.
Of the 8399 patients in the trial, 3784 had diabetes and their kidney function declined significantly faster than that of patients without diabetes, by an average of 2.0 versus 1.1 mL/min per 1.73 m2 each year.
In the overall trial population, the annual rate of decline was significantly lower among patients given sacubitril/valsartan than those given enalapril, at 1.3 versus 1.8 mL/min per 1.73 m2, the researchers report in The Lancet Diabetes & Endocrinology.
This benefit of neprilysin inhibition was greatest in patients with diabetes, in whom the annual kidney function decline was attenuated by 0.6 mL/min per 1.73 m2, compared with just 0.3 mL/min per 1.73 m2 in those without. The effect remained significantly greater in patients with diabetes than in those without after accounting for factors including systolic blood pressure at baseline and during follow-up, heart rate, severity of heart failure, and use of other medications.
Patients taking sacubitril/valsartan had marked increases in urinary cyclic guanosine monophosphate (cGMP) and circulating B-type natriuretic peptide during 8 months of treatment, whereas those taking enalapril did not.
Milton Packer (Baylor University Medical Center, Dallas, Texas, USA) and study co-authors believe that this may underlie the positive effect of neprilysin inhibition on kidney function, given the “effects of increased renal cGMP on proximal tubular reabsorption of sodium and protein, tubuloglomerular feedback, and renal fibrosis that have been shown in experimental models.”
Indeed, the effect of sacubitril/valsartan on kidney function decline lost statistical significance after accounting for the increases in cGMP, supporting its critical role.
And the researchers point out that effects of increased cGMP are likely to be particularly important in patients with diabetes, “because this disorder blunts the release of and responses to endogenous natriuretic peptides, including their ability to generate cGMP in the kidney.”
Of note, neprilysin inhibition was associated with worsening of albuminuria, despite its positive effects on kidney function, but Packer and team believe this to be a “direct effect of endogenous natriuretic peptides and increased renal cGMP to block the reabsorption of protein in the proximal tubule.”
They add that their study excluded patients with advanced renal insufficiency, “and further work is needed to extrapolate these findings to patient populations that were not studied.”
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