Neprilysin Inhibition and Glycemic Control in Cardiovascular Health

Neprilysin is a zinc-dependent metallopeptidase that degrades a wide spectrum of vasoactive and metabolic peptides, including natriuretic peptides and glucagon-like peptide-1 (GLP-1). Inhibition of neprilysin has emerged as a dual-purpose therapeutic strategy that not only alleviates cardiac remodelling and improves haemodynamics but also modulates glucose metabolism. By preserving endogenous levels of GLP-1 and other incretins, neprilysin inhibitors enhance insulin secretion and diminish insulin resistance. Concurrent blockade of the renin–angiotensin system further attenuates adverse cardiac and vascular remodelling while exerting complementary benefits on glycaemic parameters. Clinical translation has centred on angiotensin receptor neprilysin inhibitors (ARNIs), which have demonstrated improved exercise tolerance and reduced hospitalisation in heart failure populations. Emerging evidence indicates that these agents may also lower long-term glycosylated haemoglobin (HbA1c), delay the need for exogenous insulin and mitigate the progression to overt diabetes. The convergence of cardiovascular and metabolic pathways underscores the global importance of neprilysin inhibition, with potential applications extending from heart failure management to integrated cardiometabolic risk reduction.

Research from Nature Portfolio

Recent studies have investigated the real-world impact of angiotensin receptor neprilysin inhibition on glycaemic control among patients with chronic heart failure and diabetes. In a large single-centre cohort, treatment with an ARNI was associated with small but statistically significant reductions in HbA1c at six, twelve and twenty-four months compared with conventional ACE inhibitors or ARBs. Although adjustment for confounding variables attenuated some differences, patients receiving the neprilysin inhibitor experienced a delayed initiation of insulin therapy and a lower cumulative incidence of insulin requirement. These findings suggest that neprilysin inhibition in routine practice may confer modest incremental glycaemic benefit in a high-risk cardiovascular population.

Neprilysin Inhibition and Glycemic Control in Cardiovascular Health publication trend

The graph below shows the total number of articles in neprilysin inhibition and glycemic control in cardiovascular health across all publications each year (not limited to Nature Index journals).

Technical terms

Neprilysin: A membrane-bound zinc metallopeptidase that degrades vasoactive and metabolic peptides.

ARNI (Angiotensin receptor neprilysin inhibitor): A combined agent that inhibits neprilysin and blocks angiotensin II receptors.

Glucagon-like peptide-1 (GLP-1): An incretin hormone that enhances insulin secretion and suppresses glucagon release.

HbA1c (Glycated haemoglobin): The proportion of haemoglobin covalently bound to glucose, reflecting average blood glucose over several months.

Insulin resistance: A reduced responsiveness of tissues to insulin, leading to impaired glucose uptake and hyperglycaemia.

References

1. Effects of neprilysin and neprilysin inhibitors on glucose homeostasis: Controversial points and a promising arena. Journal of Diabetes (2023).
2. Effects of sacubitril/valsartan on glycemia in patients with diabetes and heart failure: the PARAGON-HF and PARADIGM-HF trials. Cardiovascular Diabetology (2022).
3. Effect of sacubitril/valsartan and ACEI/ARB on glycaemia and the development of diabetes: a systematic review and meta-analysis of randomised controlled trials. BMC Medicine (2022).
4. Real-world experience of angiotensin receptor neprilysin inhibitor on the glucose-lowering effect. Scientific Reports (2022).