Major Adverse Cardiovascular Events and Mortality Prediction by Circulating GDF-15 in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis

Abstract

Background: Growth differentiation factor 15 (GDF-15) is a homeostatic cytokine that regulates neural and cardio-metabolic functions, and its release is increased in response to stress, injury, and inflammation. In patients with coronary artery disease and heart failure (HF), three separate meta-analyses have found that elevated circulating GDF-15 was predictive of major adverse cardiovascular events (MACE), but none has evaluated its effects on incident MACE including HF and mortality hazard in type 2 diabetes. Methods: MEDLINE, EMBASE, and Scopus databases were queried. Articles that met the predefined eligibility criteria, including prospective studies that reported adjusted hazard ratios (aHRs), were selected according to the Cochrane Handbook and PRISMA guidelines. Study endpoints were (1) MACE including HF, and (2) all-cause mortality. Different GDF-15 concentration measurements were harmonized using a validated mathematical approach to express log2-transformed values in per standard deviation (SD). Study heterogeneity (I2), quality, and bias were assessed. Results: 19354 patients in 8 prospective studies were included. In 7 studies that reported 4247 MACE among 19200 participants, the incident rate was 22.1% during a median follow-up of 5.6 years. It was found that four of eight studies included HF decompensation or hospitalization as a component of MACE. In 5 studies that reported all-cause mortality, 1893 of 13223 patients died, at an incidence rate of 15.1% over 5.0 years. Of note, each 1 SD increase of log2[GDF-15] was associated with aHRs of 1.12 (1.09–1.15, I2 = 5%, p < 0.000001) and 1.27 (1.11–1.46, I2 = 86%, p = 0.00062) and for MACE and all-cause mortality, respectively. Conclusion: Elevated circulating level of GDF-15 was robustly predictive of MACE in patients with T2D but its prognostic significance in the prediction of mortality requires further studies.

Relationships between Circulating Biomarkers and Body Composition Parameters in Patients with Metabolic Syndrome: A Community-Based Study

“…A recent meta-analysis revealed that GDF-15 consistently adds prognostic information for myocardial infarction and stroke, CV death, and heart failure beyond clinical risk factors and cardiac biomarkers of CVDs [77]. The prognostic significance of elevated circulating GDF-15 levels has also been demonstrated for T2DM [78]. However, it remains unclear whether the effects of GDF-15 in MetS are causative or whether its levels are a consequence of the disease.…”

GDF-15 is a potential candidate biomarker for an elevated risk of cardiotoxicity in breast cancer patients receiving neoadjuvant dual anti-HER2 therapy

“…GDF-15 has been applied as a biomarker for predicting the risk of cardiovascular diseases and cardiovascular events (Adela and Banerjee, 2015;Havranek and Marek, 2021;May et al, 2021;Pence, 2022;Xie et al, 2022;Sawalha et al, 2023). For instance, GDF-15 is upregulated in patients with coronary artery disease (CAD) compared to non-CAD controls, yielding a diagnostic value with an AUC of 0.9 for CAD (Hassanzadeh Daloee et al, 2021); moreover, GDF-15 is greater in heart failure patients with ischemic heart disease than in controls without ischemic heart disease (Elsewify et al, 2022).…”

“…For instance, GDF-15 is upregulated in patients with coronary artery disease (CAD) compared to non-CAD controls, yielding a diagnostic value with an AUC of 0.9 for CAD (Hassanzadeh Daloee et al, 2021); moreover, GDF-15 is greater in heart failure patients with ischemic heart disease than in controls without ischemic heart disease (Elsewify et al, 2022). In addition, GDF-15 predicts the risk of major adverse cardiovascular events in patients with diabetes, as reported by a meta-analysis involving nearly twenty thousand patients (Xie et al, 2022). Furthermore, a very interesting metaanalysis reports that GDF-15 is consistently useful for prognostic prediction of the risk of cardiovascular death and hospitalization for heart failure among different types of atherosclerotic cardiovascular diseases (Kato et al, 2023).…”

“…Investigations of biomarkers that recognize the risk of cardiotoxicity early in breast cancer patients receiving anti-HER2 therapy are ongoing (Ponde et al, 2018;Gherghe et al, 2022). Growth differentiation factor 15 (GDF-15), a stress-responsive cytokine in the transforming growth factor (TGF) family, can regulate myocardial injury, the overloading status of cardiac pressure, and inflammatory infiltration (Adela and Banerjee, 2015;Pence, 2022); moreover, GDF-15 is correlated with the risk of cardiovascular diseases such as cardiac hypertrophy, acute coronary syndrome, and heart failure (Havranek and Marek, 2021;May et al, 2021;Sawalha et al, 2023) and is capable of predicting the risk of cardiovascular events and death Xie et al, 2022). Interestingly, a study reported that GDF-15 estimates the risk of cardiotoxicity in breast cancer patients receiving adjuvant therapy with trastuzumab, doxorubicin, and axanes (Putt et al, 2015).…”

Plasma Soluble Glycoprotein VI: A Biomarker of Bleeding

“…Biomarkers such as GDF-15 have been proposed as a specific biomarker of bleeding are limited by their lack of specificity, being also predictive of non-bleeding outcomes, including all-cause death and cardiovascular death, as well as major adverse cardiac events and the progression of chronic kidney disease (9)(10)(11)(12). Indeed, the biomarker-based ABC-bleeding and ABC-stroke scores demonstrated similar predictive ability for outcomes beyond stroke and bleeding, including myocardial infarction, acute heart failure, a composite of cardiovascular events, and all-cause deaths (13).…”