Natriuretic Peptide Deficiency: A Hidden Risk Factor for Heart Disease and Metabolic Disease | Research

The takeaway

Low natriuretic peptide levels — influenced by obesity, diabetes, age, sex, race, and genetics — may predispose people to cardiometabolic disease, opening the door to precision medicine interventions.

NP deficiency precedes disease
Lower natriuretic peptide concentrations predict future cardiometabolic disease, suggesting a window for preventive intervention before overt illness develops

What the researchers found

A state of partial natriuretic peptide deficiency — characterized by lower plasma NP concentrations — appears to be integral to conditions that precede overt cardiometabolic disease, particularly obesity and type 2 diabetes. Multiple factors affect NP levels: age, sex, race, genetics, and diurnal rhythms. The review highlights that O-glycosylation of NP precursor peptides is highly variable and affects both biomarker measurement accuracy and actual cardiovascular effects. An important proportion of people may have reduced effective NP bioactivity (receptor activation and physiological effects) even when measured peptide levels appear adequate.

Why it matters

NPs are already among the most widely used cardiac biomarkers, but this review reframes how we think about them. Instead of only measuring NPs to diagnose heart failure, clinicians could potentially identify people at risk for future cardiometabolic disease by detecting low NP states early. This paradigm shift — from reactive diagnosis to preventive risk assessment — could enable earlier interventions in at-risk populations.

How the study worked

Narrative review published in Endocrine Reviews, synthesizing evidence from clinical studies, biomarker research, molecular biology studies of NP biosynthesis, and epidemiological data on NP levels across different populations and disease states.

What this study cannot tell us

This is a narrative review that proposes a conceptual framework rather than presenting new experimental data. The causal relationship between NP deficiency and cardiometabolic disease development is not definitively established — low NPs could be a consequence rather than a cause. Clinical trials testing NP supplementation or enhancement strategies in at-risk populations have not been completed. The complexity of NP O-glycosylation makes accurate measurement challenging.

How to read the evidence

This is a narrative review in a high-impact journal (Endocrine Reviews) that synthesizes evidence from multiple lines of research. While it provides a compelling conceptual framework, the NP deficiency hypothesis has not been validated through prospective interventional trials.

When this study was published

Published in 2023, this review captures the current state of understanding about natriuretic peptide biology and its clinical implications, building on decades of NP biomarker research.

The bigger picture

Natriuretic peptides sit at the intersection of cardiology, endocrinology, and metabolic medicine. The concept of NP deficiency as a treatable condition — rather than just a biomarker abnormality — could reshape preventive cardiovascular medicine. As precision medicine advances, identifying individuals with reduced NP bioactivity and correcting it pharmacologically could prevent heart failure, obesity-related complications, and metabolic syndrome before they develop.

Questions still open

Could pharmacological correction of natriuretic peptide deficiency prevent the development of heart failure in obese or diabetic patients?
Should NP levels be routinely screened in at-risk populations to identify those with cardiometabolic vulnerability?
Do therapies that secondarily increase NP levels (like neprilysin inhibitors) already provide benefit partly by correcting NP deficiency?

Common questions

What are natriuretic peptides and why are they important for heart health?

Natriuretic peptides (NPs) are hormones produced by the heart that help control blood pressure by promoting sodium excretion and relaxing blood vessels. They also have metabolic effects, helping regulate fat metabolism and blood sugar. Doctors commonly measure BNP and NT-proBNP to diagnose heart failure (where levels are high), but this review highlights that chronically low NP levels may be equally important — potentially signaling future risk for heart and metabolic disease.

Why might some people naturally have lower natriuretic peptide levels?

Multiple factors reduce NP levels: obesity (fat tissue increases NP breakdown), type 2 diabetes, male sex, Black race, certain genetic variants, and even time of day (NP levels fluctuate on a daily cycle). Additionally, the body modifies NP precursors through a process called O-glycosylation, which varies between individuals and affects how much active, functional NP is actually produced. All these factors can leave some people with less NP protection than others.

Read the original research

A State of Natriuretic Peptide Deficiency.

Endocrine reviews, 44(3), 379-392

View on PubMed ↗Publisher’s paper ↗

Citation

Nyberg, Michael; Terzic, Dijana; Ludvigsen, Trine P; Mark, Peter D; Michaelsen, Natasha B; Abildstrøm, Steen Z; Engelmann, Mads; Richards, A Mark; Goetze, Jens P. (2023). A State of Natriuretic Peptide Deficiency.. Endocrine reviews, 44(3), 379-392. https://doi.org/10.1210/endrev/bnac029