Elevated Natriuretic Peptides: A Potent Predictor of Heart Failure and Mortality in Asymptomatic Diabetes

Highlights

High Prevalence of Elevated Biomarkers

Approximately 40% of individuals with type 1 or type 2 diabetes without a prior diagnosis of heart failure exhibit elevated levels of natriuretic peptides (BNP ≥50 pg/mL or NT-proBNP ≥125 pg/mL), indicating a significant burden of subclinical cardiac stress.

Strong Prognostic Association

Elevated NT-proBNP levels are independently associated with a dramatically increased risk of incident heart failure and all-cause mortality. In both T1D and T2D, levels exceeding 300 pg/mL were linked to a 3.5 to 4.5-fold increase in risk compared to those with levels below 125 pg/mL.

Actionable Screening Strategy

The study provides robust evidence supporting the use of natriuretic peptide screening as a routine tool for risk stratification in the diabetic population, potentially identifying candidates for early initiation of disease-modifying therapies.

The Silent Burden: Diabetes and subclinical Heart Failure

Heart failure (HF) remains one of the most significant and frequent complications of both type 1 diabetes (T1D) and type 2 diabetes (T2D). The relationship between these conditions is bidirectional and complex, involving metabolic derangements, microvascular dysfunction, and structural myocardial changes often referred to as diabetic cardiomyopathy. One of the primary challenges in clinical practice is that HF often remains asymptomatic in its early stages (Stage B heart failure), particularly in patients with diabetes who may have limited physical activity or whose symptoms are attributed to other comorbidities.

N-terminal pro-brain natriuretic peptide (NT-proBNP) and B-type natriuretic peptide (BNP) are well-established biomarkers for hemodynamic stress and myocardial wall stretch. While their diagnostic value in acute HF is clear, their role as screening tools in the asymptomatic diabetic population has been a subject of intense investigation. Identifying individuals at high risk for progression to symptomatic HF (Stage C) or death is critical, as contemporary therapies such as sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have shown significant promise in reducing cardiovascular events.

Study Design and Methodology

The researchers utilized Optum’s de-identified Market Clarity Data to conduct a retrospective cohort study. The analysis focused on adults (aged ≥18 years) with a confirmed diagnosis of T1D or T2D who did not have a known history of heart failure. These individuals must have received an outpatient NP test (either BNP or NT-proBNP) between 2017 and 2023.

The final cohort included 116,466 eligible adults, subdivided into 2,990 individuals with T1D and 113,476 with T2D. The median age of the participants was 64 years, and 54% were female. The mean baseline HbA1c was 7.1%, suggesting relatively well-controlled glycemia on average across the population. The primary objective was to assess the association between baseline NP levels and the composite outcome of incident HF or all-cause mortality over a follow-up period of up to seven years.

Statistical analysis was performed using multivariable Cox proportional hazard models. These models were rigorously adjusted for potential confounders, including age, sex, body mass index (BMI), renal function (estimated glomerular filtration rate), and various cardiovascular comorbidities.

Key Findings: Quantifying the Risk

The results of the study underscore the high prevalence of subclinical cardiac dysfunction in the diabetic population and the potent prognostic power of natriuretic peptides.

Prevalence of Elevated NPs

A striking finding was the high frequency of elevated NP levels in patients presumed to be free of heart failure. Approximately 39.6% of individuals with T1D and 42.3% of individuals with T2D had NP levels above the standard screening thresholds (BNP ≥50 pg/mL or NT-proBNP ≥125 pg/mL). This suggests that a large proportion of the diabetic population may already be in Stage B heart failure.

Risk Stratification in Type 1 Diabetes

Among the T1D cohort, increased NT-proBNP levels showed a clear dose-response relationship with the composite outcome:
– NT-proBNP 125-300 pg/mL: Hazard Ratio (HR) of 2.04 (95% CI 1.35-3.07) compared to the reference group (300 pg/mL: HR of 4.48 (95% CI 3.11-6.47).

Risk Stratification in Type 2 Diabetes

Similar, highly significant trends were observed in the much larger T2D cohort:
– NT-proBNP 125-300 pg/mL: HR of 1.85 (95% CI 1.74-1.97).
– NT-proBNP >300 pg/mL: HR of 3.58 (95% CI 3.39-3.78).

When evaluating BNP levels, the findings were consistent with those of NT-proBNP, reinforcing the validity of using either biomarker for risk assessment. The high hazard ratios for mortality and incident HF even in the intermediate range (125-300 pg/mL) emphasize that even modest elevations in cardiac biomarkers should not be ignored in clinical practice.

Expert Commentary and Clinical Implications

Mechanistic Insights

The association between diabetes and elevated NPs is driven by several factors. Hyperglycemia, insulin resistance, and obesity contribute to myocardial fibrosis and stiffness. In T1D, long-standing glycemic variability and microvascular complications are primary drivers. In T2D, the frequent coexistence of hypertension, obesity, and renal disease further exacerbates myocardial stress. The elevation of NPs reflects the heart’s attempt to compensate for this increased wall tension and volume overload.

The Screening Paradigm Shift

Historically, NP testing has been reserved for patients presenting with dyspnea in the emergency department or for monitoring those with established HF. However, recent guidelines from the American Heart Association (AHA) and American College of Cardiology (ACC) have begun to suggest that NP-based screening may be beneficial for those at high risk of developing HF. This study provides the robust, real-world data needed to support these recommendations specifically for the diabetic population.

Study Limitations

While the study is large and geographically diverse, it is retrospective. The patients included were those who had an NP test ordered by their clinician, which may introduce selection bias; these patients might have had subtle symptoms or other clinical reasons for testing that were not fully captured in the database. Furthermore, while the study shows a strong association with mortality and incident HF, it does not directly prove that screening and subsequent intervention improve these outcomes—though clinical trials like PONTIAC and STOP-HF have previously suggested benefits of NP-guided care in similar high-risk groups.

Conclusion

This large-scale analysis confirms that elevated natriuretic peptide levels are highly prevalent and profoundly prognostic in individuals with type 1 and type 2 diabetes who do not have known heart failure. The high risk of incident heart failure and death associated with even moderately elevated NT-proBNP or BNP levels suggests that these biomarkers are indispensable tools for identifying the “vulnerable” diabetic patient.

For clinicians, these findings advocate for a lower threshold for NP testing in the outpatient setting. Identifying patients with elevated NPs allows for earlier optimization of cardioprotective therapies, more intensive management of comorbidities, and closer monitoring, ultimately aiming to prevent the transition from subclinical dysfunction to overt heart failure and premature death.

References

1. Pop-Busui R, Repetto E, Baron J, et al. Screening Natriuretic Peptide Levels Predicts Heart Failure and Death in Individuals With Type 1 and Type 2 Diabetes Without Known Heart Failure. Diabetes Care. 2025;48(12):2145-2153.
2. American Diabetes Association Professional Practice Committee. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2024. Diabetes Care. 2024;47(Suppl 1):S179-S218.
3. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79(17):e263-e421.
4. Huelsmann M, Neuhold S, Resl M, et al. PONTIAC (NT-proBNP Selected Prevention of Cardiac Events in a Population of Diabetic Patients Without a History of Cardiac Disease): a prospective randomized controlled trial. J Am Coll Cardiol. 2013;62(15):1365-1372.