Effect of neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin-angiotensin system: A secondary anaylisis of the PARADIGM-HF trial

Background: Neprilysin inhibition has favourable effects on experimental diabetic nephropathy. We sought to assess the effects of neprilysin inhibition on the course of renal function in patients with type 2 diabetes. Methods: In the randomised, double-blind PARADIGM-HF trial, the effects of sacubitril/valsartan (97 mg/103 mg twice daily) were compared with enalapril (10 mg twice daily) in 8399 patients with mild-to-moderate chronic heart failure and systolic dysfunction. In this secondary intention-to-treat analysis, we assessed the change in estimated glomerular filtration rate (eGFR) over a 44-month follow-up period in patients with (n=3784) and those without (n=4615) diabetes. PARADIGM-HF is registered with ClinicalTrials.gov, number NCT01035255. Findings: eGFR decreased by 1·1 mL/min per 1·73 m2 per year (95% CI 1·0–1·2) in patients without diabetes, but by 2·0 mL/min per 1·73 m2 per year (1·9–2·1) in those with diabetes (p < 0·0001). Compared with patients treated with enalapril, those treated with sacubitril/valsartan had a slower rate of decline in eGFR (−1·3 vs −1·8 mL/min per 1·73 m2 per year; p < 0·0001), and the magnitude of the benefit was larger in patients with versus those without diabetes (difference 0·6 mL/min per 1·73 m2 per year [95% CI 0·4–0·8] in patients with vs 0·3 mL/min per 1·73 m2 per year [0·2–0·5] in those without diabetes; pinteraction=0·038). The greater effect of neprilysin inhibition in patients with diabetes could not be explained by the effects of treatment on the course of heart failure or on HbA1c. The incremental benefit of sacubitril/valsartan in patients with diabetes was no longer apparent when changes in eGFR were adjusted for urinary cyclic guanosine monophosphate (p=0·41). Interpretation: In patients in whom the renin-angiotensin system is already maximally blocked, the addition of neprilysin inhibition attenuates the effect of diabetes to accelerate the deterioration of renal function that occurs in patients with chronic heart failure. Funding: Novartis.