Neprilysin inhibition attenuates renal function deterioration in individuals with comorbid type 2 diabetes (T2D) and chronic heart failure when the renin-angiotensin system is maximally blocked, according to a study recently published in The Lancet Diabetes & Endocrinology.

Researchers performed a secondary intention-to-treat analysis of the double-blind, randomized PARADIGM-HF trial ( Identifier: NCT01035255). The original study included 8399 subjects with systolic dysfunction and chronic heart failure, 3784 of whom had diabetes and 4615 who did not, and compared the effects of valsartan/sacubitril (103 mg/97 mg twice per day) with enalapril (10 mg twice per day). This secondary analysis analyzed the estimated glomerular filtration rate (eGFR) during a follow-up period of 44 months.

In subjects with diabetes, eGFR decreased by 2.0 mL/min per 1.73 m2 per year (95% CI 1.9 to 2.1), although, in subjects without diabetes, it decreased by 1.1 mL/min per 1.73 m2 per year (1.0 to 1.2; <.0001).

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Participants treated with valsartan/sacubitril showed a slower rate of eGFR decrease than those treated with enalapril (-1.3 vs -1.8 mL/min per 1.73 m2 per year; <.0001).

Additionally, the beneficial effect was greater for participants with T2D than without (0.6 mL/min per 1.73 m2 per year [0.4 to 0.8] vs 0.3 mL/min per 1.73 m2 per year [0.2 to 0.5]; Pinteraction=.038). However, no explanation could be found as to why the effect is greater for those with diabetes.

When urinary cyclic guanosine monophosphate was accounted for in adjusting eGFR changes, valsartan/sacubitril no longer showed an apparent benefit over enalapril (=.41).

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Neprilysin inhibition has shown positive results in attenuating the degenerative effects of diabetic neuropathy, as neprilysin’s tendency to break down certain endogenous peptides is accelerated when vascular disease from T2D affects the tissue. This study aimed to examine the efficacy of neprilysin inhibition in treating renal disease in individuals with T2D.

The study researchers conclude that “[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.”


Clinical trial NCT01035255 was funded by Novartis.


Packer M, Claggett B, Lefkowitz MP, et al. 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 analysis of the PARADIGM-HF trial [published online April 13, 2018]. Lancet Diabetes Endocrinol. doi: 10.1016/S2213-8587(18)30100-1