Growth Differentiation Factor 15 As a Composite Diabetic Cardiovascular Disease Indicator Including Heart Failure: A Systematic Review and Meta-Analysis

Introduction Recent studies suggested that growth differentiation factor 15 (GDF-15) may indicate heart failure and a constellation of cardiovascular co-morbidities in diabetic patients. Whereas N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) is a cardiac-specific biomarker, GDF-15 is non-tissue-specific and may be a useful marker of global cardiovascular disease (CVD) burden, particularly in diabetes. In this systematic review and meta-analysis, we summarized the effects of elevated GDF-15 on the composite outcome of cardiovascular disease, events, and/or death in diabetic patients. Methods MEDLINE, EMBASE, CINAHL and Cochrane Library were queried for articles published from inception until February 2020. Longitudinal studies that reported data about the relationship between GDF-15 levels and CVD outcomes in diabetic patients were included. Pooled hazard ratios (HRs) for mortality were calculated and presented with 95% confidence intervals (CIs). Prespecified I2 threshold values of 25%, 50%, and 75% were used to indicate low, moderate, and high levels of heterogeneity, respectively. The risk of bias in the included studies was evaluated according to the criteria established by the Cochrane collaboration. Publication bias was assessed using funnel plot analysis. Results Seven studies with a total 15,805 diabetic patients were included (Fig. 1). The median follow-up ranged from 1.5 to 7.9 years. Pooled effect estimate suggested that elevated GDF-15 levels at baseline was associated with an increased risk for composite CVD-related outcome(s) (per standard deviation (SD) increase in log(GDF-15): HR 1.26, 95% CI 1.12-1.42, P = 0.0001, I2 for heterogeneity 85%, n = 15,651 patients) (Fig. 2a). When an unadjusted study was excluded, the pooled effect estimate remained statistically significant, with improvement in heterogeneity (per SD increase in log(GDF-15): HR 1.16, 95% CI 1.11-1.20, P Conclusion Findings from this systematic review and meta-analysis suggest that elevated GDF-15 levels are associated with increased risk for incident cardiovascular endpoint(s) including acute cardiovascular events, heart failure and/or all-cause death in diabetic patients.