Highlight
- Hypertensive adults with concurrent prediabetes and subclinical myocardial injury (hs-cTnI) or stress (NT-proBNP) face a four-to-fivefold increased risk of incident heart failure compared to those with normoglycemia and normal biomarker levels.
- Longitudinal increases (≥25% over 12 months) in cardiac biomarkers in patients with prediabetes further compound the risk, suggesting that dynamic monitoring is clinically valuable.
- The findings advocate for a shift in risk stratification, moving beyond blood pressure control to include glycemic status and biomarker profiling in the management of hypertensive populations.
The Hidden Intersection of Hypertension and Glycemic Dysregulation
Hypertension remains the leading modifiable risk factor for heart failure (HF) globally. However, the progression from high blood pressure to clinical heart failure is not a linear path; it is often accelerated by metabolic comorbidities. Among these, prediabetes—a state of intermediate hyperglycemia—occupies a critical yet often underappreciated position. While the transition from diabetes to heart failure is well-documented, the impact of prediabetes, especially when coupled with early signs of cardiac strain, has remained less clear.
Subclinical myocardial injury, detected by high-sensitivity cardiac troponin I (hs-cTnI), and subclinical myocardial stress, measured via N-terminal pro-B-type natriuretic peptide (NT-proBNP), serve as early warning signs. In hypertensive patients, these biomarkers can indicate structural and functional changes occurring long before symptoms manifest. The recent study by Kaze et al., published in JAMA Cardiology, explores whether the synergy between prediabetes and these biomarkers creates a ‘perfect storm’ for heart failure development.
Study Design: Leveraging the SPRINT Cohort
This post hoc prospective cohort study utilized data from the Systolic Blood Pressure Intervention Trial (SPRINT), a landmark study that examined intensive versus standard blood pressure control. The researchers analyzed 8,234 participants who had hypertension but were free of diabetes and prior heart failure at baseline. The study was divided into two primary analyses: a cross-sectional baseline biomarker assessment and a longitudinal analysis of biomarker change over 12 months.
Prediabetes was defined according to standard guidelines as a fasting plasma glucose (FPG) level of 100 to 125 mg/dL. Subclinical myocardial injury was defined as hs-cTnI levels ≥6 ng/L in men and ≥4 ng/L in women. Subclinical myocardial stress was defined as NT-proBNP levels ≥125 pg/mL. For the longitudinal analysis, a significant change was defined as a 25% or greater increase in biomarker concentrations from baseline to the one-year mark. The primary outcome was adjudicated incident heart failure over a median follow-up of 3.2 years.
Key Findings: The Compounding Effect of Prediabetes and Cardiac Biomarkers
The results of the analysis provide a stark illustration of how metabolic and cardiac stressors interact. Of the 8,234 participants, nearly 40% (3,271) had prediabetes at baseline. Furthermore, 35.7% exhibited subclinical myocardial injury, and 43.6% showed subclinical myocardial stress. During the follow-up period, 122 participants developed incident heart failure.
Baseline Risk Stratification
The researchers observed a graded increase in heart failure risk across glycemic and biomarker categories. Compared with the reference group (normoglycemia and no biomarker elevation), those with prediabetes alone showed a modest increase in risk. However, the risk skyrocketed when prediabetes was paired with biomarker elevation:
- Prediabetes + Myocardial Injury (hs-cTnI): Hazard Ratio (HR) of 4.20 (95% CI, 2.31-7.63).
- Prediabetes + Myocardial Stress (NT-proBNP): Hazard Ratio (HR) of 5.20 (95% CI, 2.52-10.70).
Interestingly, the risk associated with having both prediabetes and elevated biomarkers was substantially higher than the risk associated with either factor in isolation, suggesting a synergistic rather than merely additive effect.
Longitudinal Dynamics: The Danger of Rising Levels
The longitudinal analysis included 7,449 participants and focused on the 12-month change in biomarkers. Even after adjusting for baseline levels and randomized treatment groups (intensive vs. standard BP control), a 25% or greater increase in biomarkers in the presence of prediabetes was a potent predictor of heart failure. For those with prediabetes and an increasing hs-cTnI, the HR for incident HF was 3.05 (95% CI, 1.58-5.88). For those with prediabetes and increasing NT-proBNP, the HR was 2.39 (95% CI, 1.28-4.46).
Mechanistic Insights: Why the Synergy Exists
The biological plausibility of these findings lies in the overlapping pathways of hypertensive and metabolic damage. Hypertension causes mechanical wall stress and left ventricular hypertrophy. Prediabetes introduces systemic inflammation, oxidative stress, and the accumulation of advanced glycation end products (AGEs). These metabolic factors promote myocardial fibrosis and microvascular dysfunction.
When a hypertensive heart is already under mechanical strain (elevated NT-proBNP) or suffering from low-level chronic ischemia and cardiomyocyte death (elevated hs-cTnI), the addition of a dysglycemic environment appears to impair the compensatory mechanisms of the myocardium. This accelerates the transition from compensated hypertrophy to overt heart failure.
Clinical Implications: Moving Toward Personalized Prevention
These findings have significant implications for the clinical management of hypertension. Currently, many clinicians focus primarily on achieving blood pressure targets. However, the SPRINT data suggests that glycemic status and cardiac biomarkers provide critical prognostic information that blood pressure alone does not capture.
Screening and Stratification
The integration of hs-cTnI and NT-proBNP testing into the routine care of hypertensive patients with prediabetes could identify a high-risk phenotype that requires more aggressive intervention. This ‘biomarker-positive prediabetic’ group may benefit from earlier use of cardioprotective therapies, such as SGLT2 inhibitors or GLP-1 receptor agonists, which have demonstrated benefits in both metabolic and cardiovascular domains.
Monitoring Disease Progression
The longitudinal data highlights that a single measurement may not be enough. Tracking the trajectory of these biomarkers can help clinicians identify patients whose cardiac health is actively deteriorating, allowing for timely adjustments in therapy before the onset of symptomatic heart failure.
Expert Commentary and Limitations
While the study is robust, it is important to acknowledge certain limitations. As a post hoc analysis of the SPRINT trial, the findings are limited to a population of adults with hypertension and high cardiovascular risk. The generalizability to lower-risk populations or those without hypertension remains to be seen. Additionally, while the association is strong, the study is observational in nature, meaning we cannot definitively conclude that treating prediabetes or lowering biomarker levels will directly prevent heart failure in this specific context.
Experts suggest that the next step in this research should involve randomized controlled trials to determine if targeted interventions in this high-risk ‘double-hit’ population (hypertension + prediabetes + biomarker elevation) can effectively reduce the incidence of heart failure.
Conclusion
The study by Kaze et al. reinforces the necessity of a holistic approach to cardiovascular risk. For the millions of adults living with hypertension, the presence of prediabetes is not a benign metabolic state; it is a catalyst for cardiac decline when subclinical injury or stress is present. By incorporating glycemic assessment and biomarker profiling into clinical practice, healthcare providers can better stratify risk and potentially intercept the progression toward heart failure.
References
Kaze AD, Juraschek SP, Cohen JB, Singh S, Ndumele CE, Ballantyne CM, Berry JD, Echouffo-Tcheugui JB. Prediabetes, Subclinical Myocardial Injury or Stress, and Heart Failure Risk for Adults With Hypertension. JAMA Cardiol. 2026 Jan 14:e254927. doi: 10.1001/jamacardio.2025.4927.
