A defective natriuretic peptide system is causally linked to obesity and type 2 diabetes risk, and drugs that boost these cardiac peptide hormones could offer a novel therapeutic approach to metabolic disease.
Low NP levels predict type 2 diabetes riskEpidemiological data shows that people with low circulating natriuretic peptide levels are at significantly increased risk of developing type 2 diabetes — suggesting these heart hormones play a protective metabolic role.
What the researchers found
The review synthesizes evidence that natriuretic peptide (NP) system deficiency is both associated with and potentially causal of obesity and type 2 diabetes:
- Epidemiological studies show low NP levels predict future T2D risk
- NPs signal through NPRA/cGMP and have direct metabolic effects in fat tissue, muscle, liver, and pancreas
- NPs promote fat oxidation (fat burning), browning of white fat, and insulin secretion
- Obese individuals typically have paradoxically low NP levels, which may perpetuate metabolic dysfunction
- Two degradation pathways — the clearance receptor NPRC and neutral endopeptidases (NEP) — could be targeted to raise circulating NP levels
- Recombinant ANP and BNP already exist as treatments for heart failure and could potentially be repurposed
Why it matters
While GLP-1 drugs dominate the obesity drug conversation, natriuretic peptides represent a completely different and complementary approach. These cardiac hormones act on fat tissue, muscle, and the pancreas through pathways distinct from incretins. If NP-boosting strategies can safely improve metabolic health, they could be used alongside or instead of GLP-1 drugs, particularly in patients with both heart failure and obesity — where NP deficiency may contribute to both conditions.
How the study worked
This is a narrative review examining epidemiological, clinical, and preclinical evidence on the natriuretic peptide system's role in metabolism. The author reviews molecular mechanisms of NP action in metabolic target tissues, the epidemiological association between NP deficiency and cardiometabolic risk, and potential therapeutic strategies for targeting the NP pathway.
What this study cannot tell us
The review relies heavily on observational associations and preclinical data. While low NP levels correlate with metabolic risk, causation is difficult to establish definitively. Recombinant NPs require intravenous infusion and have potent blood pressure-lowering effects that may limit their use as metabolic drugs. The specificity of targeting NP degradation pathways (NPRC, NEP) for metabolic versus cardiovascular effects is unclear. No clinical trials specifically testing NP-based approaches for obesity or T2D are described.
How to read the evidence
This is a narrative review by a single expert, synthesizing epidemiological associations, preclinical mechanistic data, and clinical observations. While the hypothesis is well-supported by converging evidence from multiple fields, direct clinical trial evidence for NP-based metabolic therapy is absent.
When this study was published
Published in 2016, this review anticipated several developments that have since materialized, including the metabolic benefits observed with neprilysin inhibitors in heart failure patients. The concepts remain relevant as the field continues to explore NP-metabolism connections.
The bigger picture
This review opened a new perspective on the heart-metabolism axis. The concept that cardiac peptide hormones are not just markers of heart disease but active regulators of metabolism has significant implications. The subsequent development of sacubitril/valsartan (Entresto), which blocks neprilysin to raise NP levels and is now approved for heart failure, provides a clinical validation of this concept. Whether similar approaches could be optimized for metabolic disease remains an active area of investigation.
Questions still open
- Could neprilysin inhibitors like sacubitril (already used in heart failure) be repurposed as metabolic drugs for obese or diabetic patients?
- Is the low natriuretic peptide level in obesity a cause or consequence of excess fat tissue?
- Could combining NP-boosting strategies with GLP-1 drugs produce additive metabolic benefits?
Common questions
What are natriuretic peptides and what do they do besides indicate heart failure?
Why do obese people have low natriuretic peptide levels?
Read the original research
Targeting cardiac natriuretic peptides in the therapy of diabetes and obesity.
Expert opinion on therapeutic targets, 20(12), 1445-1452
Citation
Moro, Cedric. (2016). Targeting cardiac natriuretic peptides in the therapy of diabetes and obesity.. Expert opinion on therapeutic targets, 20(12), 1445-1452.