GDF-15 as an integrative cardiometabolic biomarker

Growth Differentiation Factor 15 (GDF-15) is a stress-inducible cytokine that is abundantly expressed in cardiomyocytes, adipose tissue, macrophages, endothelial cells, and vascular smooth muscle cells. The levels of this biomarker increase in response to tissue injury, inflammation, and metabolic stress and are elevated in the presence of primary cardiometabolic diseases, such as type 2 diabetes, obesity, hypertension, atherosclerosis, heart failure, and chronic kidney disease. This is articulated in a clinical chemistry narrative review, which elucidates why GDF-15 can be characterized as an integrative biomarker. This characterization is due to the shared pathophysiological processes of metabolic stress, inflammation, oxidative/mitochondrial stress, and tissue injury across these conditions, as well as its clinical applications in risk assessment, prognosis, and monitoring. We also briefly present modern methods to measure circulating GDF-15 (primarily immunoassays, with new mass-spectrometry techniques being developed) and note that inter-assay variability and assay standardization are considered to be the major impediments to clinical application. The most significant determinants of biological variability (age, sex, renal function, genetic variation, and comorbidities), by which reference intervals and longitudinal interpretation are affected, are also highlighted. Increased GDF-15 is consistently associated with poor outcomes in diabetes, obesity, hypertension, heart failure, and atherosclerosis, such as cardiovascular events, kidney failure, and death. Nonetheless, prognostic cutoffs have been proposed variably across studies, populations, and measurement platforms. Therefore, these thresholds should be approached with caution until harmonized assays and clinically validated decision limits established through prospective studies are available. GDF-15 is a powerful integrative biomarker of metabolic stress, inflammation, and tissue injury in cardiometabolic diseases. Its introduction into clinical practice may enhance early risk stratification, personalize therapeutic interventions and monitor disease progression. Future studies should focus on optimizing the standardization of assays, developing evidence-based reference intervals (and reference change values), and elucidating clinically practical decision limits and therapeutic implications of the GDF-15 pathway in the treatment of cardiometabolic diseases.