Highlights
- Elevated baseline NT-proBNP (≥125 pg/mL) and rising levels over time are potent predictors of both HFpEF and HFrEF risk in patients with type 2 diabetes (T2D) and obesity.
- Intensive Lifestyle Intervention (ILI) significantly reduces the risk of Heart Failure with Preserved Ejection Fraction (HFpEF) specifically in patients with elevated baseline NT-proBNP.
- The benefit of ILI for HFpEF prevention is also concentrated in individuals who maintain stable or decreasing NT-proBNP levels over one year.
- ILI did not show a significant impact on Heart Failure with Reduced Ejection Fraction (HFrEF) risk, regardless of biomarker status.
Introduction: The Heart Failure Epidemic in Diabetes
Type 2 diabetes (T2D) is a well-established driver of heart failure (HF), a condition often categorized into two primary phenotypes: heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). Among patients with T2D, HFpEF is particularly prevalent, often driven by a combination of obesity, systemic inflammation, and metabolic derangements. Despite the known association between weight and cardiac stress, the original findings of the Look AHEAD (Action for Health in Diabetes) trial showed that an intensive lifestyle intervention (ILI) aimed at weight loss did not significantly reduce the overall incidence of major adverse cardiovascular events (MACE) in the general study population.
However, the heterogeneity of cardiovascular risk within the T2D population suggests that certain subgroups may derive substantial benefit from lifestyle modifications. N-terminal pro-B-type natriuretic peptide (NT-proBNP), a marker of myocardial wall stress, has emerged as a critical tool for risk stratification. This ancillary study of the Look AHEAD trial, recently published in JACC: Heart Failure, investigates whether NT-proBNP can serve not just as a prognostic marker, but as a prescriptive one—identifying those who are most likely to respond to intensive lifestyle interventions to prevent specific HF subtypes.
Study Design and Methodology
The researchers conducted a post-hoc ancillary study of the Look AHEAD trial, involving 3,959 adults with T2D and overweight or obesity. The cohort was randomized into two groups: the Intensive Lifestyle Intervention (ILI), which focused on caloric restriction and increased physical activity, and Diabetes Support and Education (DSE), which served as the control group.
The primary objective was to evaluate the relationship between NT-proBNP—both at baseline and its longitudinal change over one year—and the subsequent risk of HFpEF (LVEF ≥50%) and HFrEF (LVEF <50%). The researchers utilized a clinical threshold for NT-proBNP of 125 pg/mL to define “elevated” levels. Adjusted Cox proportional hazards models were used to determine the association between these biomarker profiles and HF outcomes, with specific attention paid to multiplicative interaction testing to identify heterogeneous treatment effects of the ILI.
Key Findings: NT-proBNP as a Predictor and Modifier
Prognostic Value of NT-proBNP
The study confirmed that NT-proBNP is a powerful prognostic tool. Participants with elevated baseline NT-proBNP (≥125 pg/mL) faced a significantly higher risk of developing both HFpEF and HFrEF. Furthermore, the trajectory of the biomarker mattered; those whose NT-proBNP levels increased over the first year of the study had a markedly higher risk of both HF subtypes compared to those whose levels remained stable or decreased.
The Interaction Between ILI and HFpEF Risk
The most striking finding was the differential impact of the lifestyle intervention based on baseline biomarker status. Among participants with elevated NT-proBNP at baseline, the ILI was associated with a 53% reduction in the risk of HFpEF compared to the DSE group (HR: 0.47; 95% CI: 0.24-0.90). Conversely, in participants with nonelevated baseline NT-proBNP, the ILI did not significantly reduce HFpEF risk, and the point estimate actually leaned toward higher risk (HR: 1.65; 95% CI: 0.93-2.91). The P-value for interaction was highly significant at 0.003.
Longitudinal Changes and Intervention Efficacy
The study also examined how one-year changes in NT-proBNP influenced the intervention’s success. For participants who achieved stable or decreasing NT-proBNP levels at the one-year mark, the ILI was associated with a significant reduction in HFpEF risk (HR: 0.58; 95% CI: 0.34-0.99). In contrast, those whose NT-proBNP levels increased despite being in the intervention or control groups did not see a benefit from ILI regarding HFpEF prevention (P for interaction = 0.01).
The HFrEF Divergence
Interestingly, the ILI did not significantly modify the risk of HFrEF across any NT-proBNP category. This suggests that the pathophysiology of HFrEF in T2D—often linked to ischemic events or specific genetic predispositions—may be less sensitive to weight-loss-driven lifestyle changes than the hemodynamically and inflammation-driven HFpEF phenotype.
Expert Commentary: Mechanistic Insights and Clinical Plausibility
The findings provide a compelling biological narrative. HFpEF in the context of obesity and T2D is frequently characterized by epicardial fat accumulation, systemic inflammation, and increased plasma volume, all of which contribute to elevated ventricular filling pressures. Intensive lifestyle interventions, which lead to weight loss and improved metabolic health, directly address these drivers. By reducing visceral adiposity and improving insulin sensitivity, ILI may lower the chronic wall stress that NT-proBNP reflects.
The fact that only those with elevated NT-proBNP benefited suggests a “sweet spot” for intervention. Patients with very low NT-proBNP may be at such low baseline risk for HFpEF that the incremental benefit of an ILI is statistically undetectable, or their risk may be driven by non-weight-related factors. For those with elevated biomarkers, the intervention acts as a targeted therapy to mitigate an already-active pathological process.
Clinical Implications: Toward Precision Prevention
These results have significant implications for the management of patients with T2D. Rather than a “one-size-fits-all” approach to lifestyle counseling, clinicians can use NT-proBNP to identify high-risk individuals who are most likely to achieve a hard clinical benefit from intensive weight loss programs. This could improve the cost-effectiveness of such programs and provide a motivational tool for patients, showing them a concrete biomarker target for their efforts.
In the era of SGLT2 inhibitors and GLP-1 receptor agonists—both of which reduce HF risk—the role of lifestyle remains foundational. This study suggests that NT-proBNP could help integrate lifestyle interventions into a comprehensive, personalized prevention strategy for diabetic cardiomyopathy.
Summary and Conclusion
The Look AHEAD Cardiac Biomarker Ancillary Study provides pivotal evidence that NT-proBNP is both a prognostic and a prescriptive biomarker in the context of T2D and obesity. While elevated and rising NT-proBNP levels signal an increased risk for all heart failure subtypes, the preventive power of intensive lifestyle interventions appears specifically tailored toward HFpEF in those with existing myocardial stress. These findings advocate for the routine use of cardiac biomarkers to refine risk assessment and guide the intensity of lifestyle interventions in clinical practice.
Funding and ClinicalTrials.gov
The Look AHEAD trial was funded by the National Institutes of Health (NIH) and other federal agencies. ClinicalTrials.gov Identifier: NCT00017953.
References
Chunawala Z, Patel KV, Garcia KR, et al. Cardiac Biomarkers, Intensive Lifestyle Intervention, and Heart Failure Subtypes in Diabetes: Look AHEAD Cardiac Biomarker Ancillary Study. JACC Heart Fail. 2025 Nov 6:102726. doi: 10.1016/j.jchf.2025.102726. PMID: 41204924.
