Adding a neprilysin inhibitor markedly slows kidney decline in comorbid CHF and diabetes

Neprilysin inhibition with sacubitril/valsartan substantially slows kidney deterioration secondary to diabetes in chronic heart failure (CHF) patients whose renin-angiotensin system is already maximally blocked, according to a new study published in The Lancet Diabetes & Endocrinology. This beneficial effect was observed even though sacubitril/valsartan raised protein excretion.

“This is the first double-blind, randomized controlled trial of neprilysin inhibition to assess the effect of treatment on the course of renal disease in patients with type 2 diabetes,” wrote researchers led by Milton Packer, MD, Baylor Heart and Vascular Hospital, Baylor University Medical Center, Dallas, TX.

Neprilysin hastens the breakdown of various endogenous peptides that exert vasodilator, natriuretic, and antifibrotic effects. The activity of neprilysin is higher in tissues that are impacted by vascular disease due to type 2 diabetes.

The heightened activity of neprilysin could be why diabetes curbs the release and response of natriuretic peptides, as well as the ability of these endogenous peptides to form cyclic guanosine monophosphate (cGMP) at the level of the renal glomerulus. Furthermore, lowered activity of these endogenous peptides alters kidney structure and function. Conversely, researchers have shown that potentiation of these endogenous peptides could slow the pathogenesis of diabetic nephropathy, suggesting the clinical utility of inhibiting neprilysin in those with diabetic kidney disease.

The PARADIGM-HF trial had examined the effects of sacubitril/valsartan (an angiotensin receptor neprilysin inhibitor) vs enalapril (an angiotensin converting enzyme inhibitor) in patients both with and without diabetes who exhibited mild-to-moderate CHF caused by left ventricular systolic dysfunction.

Notably, findings from this initial trial indicated that sacubitril/valsartan, when compared with enalapril, decreased the risk of cardiovascular death and hospitalization secondary to heart failure. Moreover, Dr. Packer and colleagues prospectively evaluated the effects of neprilysin inhibition on the clinical course of chronic kidney disease in patients both with and without type 2 diabetes, with an eye towards future analysis. Specifically, the investigators assessed the efficacy of sacubitril/valsartan (97 mg/103 mg BID) vs enalapril (10 mg BID) in 8,399 patients.

The current study is a secondary intention-to-treat analysis of neprilysin inhibition on kidney function in patients with and without type 2 diabetes in the PARADIGM-HF trial. In this analysis, Dr. Packer and colleagues followed changes in estimated glomerular filtration rate (eGFR) in 3,784 diabetic patients and 4,615 patients without the disease for up to 44 months.

The investigators found that patients without diabetes but with CHF exhibited a rate of decline in eGFR that was twice that of the general population. Moreover, diabetes compounded this decline in eGFR by an additional factor of 2, even though these diabetic patients were taking high doses of ACE inhibitors usually accompanied by a mineralocorticoid receptor antagonist.

Dr. Packer and coauthors also found that neprilysin inhibition with sacubitril/valsartan in patients with comorbid CHF and diabetes who were taking high doses of drugs that inhibited the renin-angiotensin system decelerated the yearly rate of eGFR decline by 0.6 mL/min per 1.73 m² vs enalapril (95% CI: 0.4–0.8, P < 0.0001). In contrast, deceleration in the yearly eGFR decline in CHF patients without diabetes was 0.3 mL/min per 1.73 m² per year (95% CI: 0.2–0.5, P=0.038).

Importantly, the increased benefit of neprilysin inhibition in diabetic patients was neither due to the effects of sacubitril/valsartan treatment on heart failure nor to the effects of this treatment on glycemic control (HbA_1c), and held despite higher urinary protein excretion with the drug. However, these effects disappeared when changes in eGFR were controlled for urinary cGMP (P=0.41), thus implicating increased levels of this second messenger as potentially playing a role.

“Although neprilysin inhibition increased urinary concentrations of cGMP in both patients with and those without diabetes,” the authors wrote, “the physiological effect of this change is likely to have been more important in diabetes, because this disorder blunts the release of and responses to endogenous natriuretic peptides, including their ability to generate cGMP in the kidney.”

Finally, the authors reflected that, “the finding that neprilysin inhibition has favorable effects on the course of renal disease, when added to high doses of drugs that block the renin-angiotensin system and have benefits on diabetic nephropathy, has important implications for the care of type 2 diabetes, independent of efforts to lower blood glucose in these patients.”

This study was funded by Novartis.