Sacubitril/Valsartan Showed Slowed Kidney Function Decline in Patients With, Without Diabetes

Milton Packer, MD

In a secondary analysis of the PARADIGM-HF phase 3 trial of sacubitril/valsartan (Entresto, Novartis), the therapy was shown to aid in the preservation of kidney function in patients with heart failure with reduced ejection fraction (HFrEF).

Patients with HFrEF that were treated with 97 mg/103 mg twice daily sacubitril/valsartan had a slower rate of decline over the 44-month follow-up period, as measured by estimated glomerular filtration rate (eGFR) than their counterparts treated with 10 mg twice daily enalapril, an ACE inhibitor. For patients with both HFrEF and diabetes, the benefit was doubled.

“These results suggest that in addition to the established benefits on heart failure, Entresto treatment also helps to preserve kidney function. This is important because impaired kidney function is associated with poorer outcomes in patients with heart failure,” Shreeram Aradhye, MD, the chief medical officer and global head of Medical Affairs at Novartis, said in a statement. “The benefit is particularly significant for people with chronic heart failure who also have diabetes, which is an independent risk factor for kidney damage.”

In PARADIGM-HF analysis, led by Milton Packer, MD, the Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center, it was observed that patients without diabetes (n = 4615) experienced loss of kidney function twice as fast as the trial’s general population, and those with diabetes (n = 3784) experienced lessened kidney function 4-fold quicker when taking the neprilysin inhibitor.

"These findings are very consistent with experimental evidence that has pointed to a role of deficient cyclic GMP signaling within the kidney in the pathogenesis of the renal injury seen in diabetes," Packer told MD Magazine. "Our findings strongly support the conduct of future trials of neprilysin inhibition in the prevention of diabetic nephropathy."

Patients without diabetes on sacubitril/valsartan showed an eGFR loss of —1.1 ml/min/1.73 m² per year (95% CI, 1.0 to 1.2) compared to —2.0 ml/min/1.73 m² per year (95% CI, 1.9 to 2.1) for patients with diabetes (P <.0001). Compared to patients on enalapril, the rate of kidney function decline was slower (—1.3 ml/min/1.73 m² per year vs. —1.8 ml/min/1.73 m² per year; P <.0001).

"This means that neprilysin inhibition boosted the effects of conventional inhibition of the renin-angiotensin system, not only with respect to its effects on heart failure but also with respect to its effects on renal function in diabetic patients," Packer said. "Importantly, in our analysis, the benefits of neprilysin inhibition on the kidney were entirely independent of its effects on the heart."

The benefit for patients without diabetes was +0.3 ml/min/1.73 m² per year (95% CI, 0.2 to 0.5) with sacubitril/valsartan, and for those with concurrent diabetes, the benefit was doubled to +.06 ml/min/1.73 m² (95% CI, 0.4 to 0.8; P_interaction = .038). According to the study authors, this increased neprilysin inhibition benefit could not be explained by the therapy’s impact on the course of HF or hemoglobin A1C.

When the findings in eGFR were adjusted for urinary cyclic guanosine monophosphate, the incremental benefit for patients with diabetes was no longer clear (P = .41).

The authors of the analysis concluded 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 HF.”

“Given [the findings of the original PARADIGM-HF evaluation], it was important to see if adding a neprilysin inhibitor might also boost the effects of the renin-angiotensin system alone with respect to its benefits on the development of diabetic nephropathy," Packer said. "The design of the PARADIGM-HF trial allowed us to address this question. We knew that neprilysin inhibition had favorable effects on renal function in previous experimental and clinical studies. But [we wanted to know] were these benefits particularly apparent in patients with diabetes in the patients enrolled in the PARADIGM-HF trial?"

The findings have significant implications, as it is estimated that up to 40% of patients with HF have accompanying diabetes, which is associated with a higher risk of chronic kidney disease and, ultimately, poorer cardiovascular outcomes.

The therapy previously showed a reduced risk of cardiovascular death by 20%, a reduction in HF-related hospitalization by 21%, and a reduction in all-cause death by 16% when compared to enalapril. In another analysis of the large PARADIGM-HF trial, sacubitril/valsartan also showed slowed renal function decline in patients with HF—even in those with chronic kidney disease.

The analysis, “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,” was published in The Lancet Diabetes & Endocrinology.