Diabetic Foot Ulcer as an Independent Risk Factor for Cardiovascular Mortality: A Systematic Review and Meta-Analysis...

Diabetic foot ulcer (DFU) is closely correlated with cardiovascular mortality, but the quantitative synthesis that underlies this association is limited. Additionally, the literature is limited in its reporting of the role of cardiac biomarkers and their influence on cardiovascular mortality among patients with DFU. This study aimed to examine the strength of association between DFU and cardiovascular disease (CVD)-specific mortality, and the role of specific cardiac parameters in increasing CVD-specific mortality risk. This systematic review and meta-analysis were conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. First, a narrative synthesis summarized hazard ratios (HRs) of markers such as B-type natriuretic peptide (BNP) levels, left ventricular ejection fraction, and diastolic dysfunction. For the quantitative meta-analysis, pooled HRs with 95% confidence intervals (CIs) of included studies were used as the primary measure of association between CVD mortality and DFU. Heterogeneity was quantified using the I² statistic (I² ≥ 50% indicating substantial heterogeneity). Subgroup analyses were performed for glycemic control (HbA1c ≥7%) and ulcer severity; continuous meta-regression was performed for mean age and median follow-up time (standardized to months). All analyses were conducted at the study level using aggregated data. A sensitivity analysis was also performed, including prospective cohort and case-control studies, and excluding studies at high risk of bias. Publication bias was assessed visually using funnel plots and by employing Egger's regression test. All statistical analyses were performed using software JAMOVI version 2.4.11. In total, 14 studies were included in the final meta-analysis, of which three were included in the qualitative synthesis. The pooled HR of 2.57 (k = 14, 95% CI = 1.85, 3.28, p < 0.001, I² = 98.45%) indicates a significant association between DFU and CVD mortality. The 95% prediction interval was 0.14-47.88, reflecting the wide range of true effects expected across heterogeneous DFU study settings. Sensitivity analysis stratifying by ulcer severity (k = 4) and study design (k = 8) reduced heterogeneity to I² of 0%; however, this result should be interpreted cautiously given the small number of studies per stratum (k = 4), which limits statistical power to detect true heterogeneity and likely reflects over-stratification rather than true homogeneity. However, the qualitative synthesis found that BNP (>100 pg/mL) was significantly associated with CVD mortality (HR = 4.846, 95% CI = 2.482, 9.461, p < 0.001). Similarly, QTc prolongation was associated with CVD-specific mortality (HR = 5.465, 95% CI = 2.818, 8.112, p = 0.039). This meta-analysis and qualitative synthesis highlight that cardiac biomarkers, including BNP (>100 pg/mL) and QTc prolongation, showed associations with CVD mortality in narrative synthesis; however, these findings are hypothesis-generating only, derived from three studies, and require confirmation in larger prospective studies before clinical recommendations can be made.