Baseline Growth-differentiation Factor-15 Levels Research Articles

GDF15 AND REDUCED PHYSICAL FUNCTION FOLLOWING TOTAL KNEE REPLACEMENT: A STUDY OF PHYSICAL RESILIENCE AND AGING

Abstract The metabolic and inflammatory cytokine growth-differentiation factor 15 (GDF15) increases with age and negatively associates with physical and cognitive function in older adults. We hypothesized GDF15 also negatively associates with resilient outcomes after surgery. This hypothesis was tested in the SPRING study of physical resiliency after total knee replacement by assessing relationships between pre-operative plasma GDF15 levels and postoperative resilience measures including short physical performance battery (SPPB) scores, fatigability, and grip strength. GDF15 analyses and physical resilience were assessed in 127 SPRING participants (age 70±6 yrs, n=83 women). Baseline GDF15 levels correlated with age (r=0.263, P< 0.05); age-adjusted analyses were applied. In total, pre-operative GDF15 levels did not significantly correlate with functional measures at any timepoint. However, in men (n=44), GDF15 levels correlated with age (r=0.408, P< 0.05) and significant age-adjusted correlations were observed in fatigue (r=0.368, P< 0.05), gait speed (r=-0.428, P< 0.05), and SPPB score (r=-0.329, P< 0.05). Additionally, GDF15 levels correlated with chair stands at six months (r=-0.398, P< 0.05), SPPB score at six months (r=-0.384, P< 0.05), and gait speed after one year (r=-0.487, P< 0.05). GDF15 did not significantly correlate with changes in SPPB score (P>0.05). There were no significant correlations between GDF15 and any of these functional measures in women (r-value range: -0.259 to 0.107; p-value range: 0.112 to 0.969). Elevated pre-operative GDF15 appears to correlate with worsening physical function following knee replacement in men, but not women. Further investigation is necessary to understand the relationship between GDF15 and the biology of physical resiliency.

Abstract 15617: Association Between Growth Differentiation Factor-15 and Outcomes Among Patients With Heart Failure: A Systematic Literature Review

Background: Growth differentiation factor-15 (GDF-15) is upregulated during myocardial injury and stress, and is an emerging biomarker of adverse outcomes in patients with heart failure (HF). Although systematic literature reviews (SLRs) of GDF-15 and HF have been conducted, few assessed outcomes other than mortality. Aim: This SLR examined the association of GDF-15 levels with a broad range of outcomes in patients with HF. Methods: Following PRISMA guidelines, Embase and Medline were searched to identify articles published 1/1/2014–8/23/2022 reporting outcomes associated with GDF-15 in adults with HF. Both cross-sectional (assessed at the same time as GDF-15) and longitudinal outcomes were included. Results: Sixty-three publications met eligibility criteria: 45 were observational studies and 18 post hoc analyses of randomized controlled trials. A total of 19 outcomes were identified. The most frequently reported longitudinal outcomes were mortality (n=32), composite endpoints (e.g., death ± hospitalization; n=28) and hospitalization (n=11). The most common cross-sectional outcome was biomarkers of kidney function (n=22). Of 27 studies assessing all-cause mortality, 24 conducted multivariable analyses (MVA), of which 22 (91.7%) reported a significant, independent association between higher baseline GDF-15 and all-cause death. Among the 26 studies reporting association between baseline GDF-15 and composite endpoints, 19 used MVA and 13/19 (68.4%) reported at least one significant association. Among 10 studies assessing hospitalization and baseline GDF-15, 8/10 (80%) reported outcomes using MVA, of which 50% found a significant association. Twenty studies assessed the cross-sectional association between baseline GDF-15 levels and measures of kidney function. Of these, 7 used MVA and reported statistically significant associations. Conclusions: The results of the SLR suggest that GDF-15 is an independent predictor of mortality and other adverse, nonfatal outcomes in patients with HF. Better understanding of the potential prognostic role of GDF-15 in HF could improve clinical risk prediction and identify patients with HF who may warrant additional treatment optimization/intensification.

Circulating Growth Differentiation Factor 15 as a Biomarker in Patients with Unresected Locally Advanced Non-Small Cell Lung Cancer Treated with Chemo-Radiotherapy with or without Metformin

Growth differentiation factor 15 (GDF15) is a member of the TGFβ family suggested to have prognostic value in cancer. Plasma GDF15 levels are elevated in humans during cellular stress, chronic diseases, and cancer and in response to cytotoxic (chemotherapy and radiation) or metabolic (metformin) therapies. Currently, the effect of combined metformin and cytotoxic treatment on circulating GDF15 is not known, and it is unclear whether GDF15 can serve as a biomarker in patients receiving such therapy. To examine this question, we analyzed circulating GDF15 levels in stage IIIA or IIIB NSCLC patients that participated in the randomized phase II clinical trial OCOG-ALMERA (NCT02115464). In OCOG-ALMERA patients were randomized to treatment with concurrent platinum-based chemotherapy and chest radiotherapy (60-66 Gy), with or without consolidation chemotherapy (CRT) or the same treatment plus metformin (2000mg/d). Dosimetric parameters and survival outcomes were collected by the trial. EDTA Plasma was collected from patients at baseline, 2 weeks into CRT treatment, at completion of CRT and 6 months after treatment initiation and assayed for GDF15 using an ELISA method. Statistical analyses were conducted to explore potential associations between plasma GDF15 with survival and dosimetric parameters. Fifteen patients from the metformin arm and 18 from the control arms provided EDTA plasma for this analysis. Average baseline GDF15 levels for all participants were elevated compared to those reported for healthy individuals. Baseline plasma GDF15 was statistically prognostic for RFS and OS (hazard ratio = 1.19, 95% CI = 1.06 to 1.34, p = 0.005). GDF15 levels increased during CRT treatment reaching the highest value at the end of cytotoxic therapy. Addition of metformin to CRT treatment was associated with further increase in circulating GDF15 (p<0.001). Plasma GDF15 levels at 2 weeks of CRT were positively correlated with size of the radiotherapy clinical target volume and volumes of esophagus and heart receiving high dose radiotherapy. This work suggests that GDF15 may be a promising prognostic marker to predict response to standard chemoradiation therapy in NSCLC. Future studies should aim to validate these results in larger datasets and examine whether GDF15 may have value as early biomarker of radiation toxicity in lung cancer patients.

Growth differentiation factor 15 predicts cardiovascular events in stable coronary artery disease.

Growth differentiation factor 15 (GDF-15) has been explored as a potential biomarker for various inflammatory diseases and cardiovascular events. This study aimed to assess the predictive role of GDF-15 levels in cardiovascular events and all-cause mortality, considering traditional risk factors and other biomarkers. A prospective study was conducted and 3699 patients with stable coronary artery disease (CAD) were enrolled into the research. Baseline GDF-15 levels were measured. Median follow-up was 3.1 years during the study. We analyzed clinical variables and several biomarkers. Multivariable Cox regression analysis was performed to evaluate prognostic performance of GDF-15 levels in predicting myocardial infarction (MI), heart failure, stroke, cardiovascular death, and non-cardiovascular death. Baseline GDF-15 levels for 3699 patients were grouped by quartile (≤ 1153, 1153-1888, 1888-3043, > 3043 ng/L). Higher GDF-15 levels were associated with older age, male gender, history of hypertension, and elevated levels of N-terminal pro B-type natriuretic peptide (NT-pro BNP), soluble suppression of tumorigenesis-2 (sST2), and creatine (each with P < 0.001). Adjusting for established risk factors and biomarkers in Cox proportional hazards models, a 1 standard deviation (SD) increase in GDF-15 was associated with elevated risk of clinical events [hazard ratio (HR) = 2.18, 95% confidence interval (CI): (1.52-3.11)], including: MI [HR = 2.83 95% CI: (1.03-7.74)], heart failure [HR = 2.71 95% CI: (1.18-6.23)], cardiovascular and non-cardiovascular death [HR = 2.48, 95% CI (1.49-4.11)] during the median follow up of 3.1 years. Higher levels of GDF-15 consistently provides prognostic information for cardiovascular events and all cause death, independent of clinical risk factors and other biomarkers. GDF-15 could be considered as a valuable addition to future risk prediction model in secondary prevention for predicting clinical events in patient with stable CAD.

Decreased serum growth differentiation factor 15 levels after lifestyle intervention in patients with newly diagnosed type 2 diabetes mellitus

Recent studies noted that circulating growth differentiation factor 15 (GDF15) were closely related to metabolic states. Moreover, lifestyle intervention (LI) contributed to metabolic improvements among patients with diabetes. The study aimed to explore the changes of GDF15 levels and their influencing factors after 4 weeks of LI or LI combined with breakfast meal replacement (LI + MR) in newly diagnosed type 2 diabetes patients. A total of 84 patients with available serum samples at both baseline and Week-4 were enrolled in this biomarker substudy. All subjects underwent a 2-h 75 g oral glucose tolerance test at baseline and Week-4. Serum GDF15 levels were determined by a sandwich enzyme-linked immunosorbent assay. After 4 weeks of LI, GDF15 levels overall significantly decreased compared with baseline ( P < 0.05). ΔGDF15 levels were significantly and negatively associated with baseline GDF15 levels ( r = −0.450, P < 0.001). The optimal cut-off point of baseline GDF15 levels for predicting a GDF15 decrease after 4 weeks of LI was 904.57 pg/mL, with an area under curve of 0.699. Based on the cut-off point of 900 pg/mL, patients with baseline GDF15 ≥ 900 pg/mL had significantly decreased GDF15 levels after LI, while those <900 pg/mL had no significant changes. Regression models showed that baseline GDF15 level was an independent positive factor for the improvement of fasting plasma glucose and homeostasis model assessment for insulin resistance only in patients with baseline GDF15 levels ≥900 pg/mL. LI led to significantly decreased GDF15 levels among patients with newly diagnosed type 2 diabetes and its effect was more significant among patients with baseline GDF15 levels ≥900 pg/mL. • Growth differentiation factor 15 (GDF15) levels significantly decreased after 4 weeks of lifestyle intervention (LI). • The change of GDF15 levels between week-4 and baseline were negatively associated with the baseline GDF15 levels. • The effect of LI on the decrease of GDF15 levels was more significant among patients with baseline GDF15 levels ≥900 pg/ml.

1120-P: Association between the Inflammatory Marker GDF-15 and Kidney Disease Progression: Results from the CANVAS Trial

Introduction: Growth differentiation factor 15 (GDF-15) is a marker of inflammation and cellular injury. Small clinical studies have suggested that SGLT2 inhibitors exert anti-inflammatory effects. We examined the association of baseline GDF-15 with kidney outcomes in patients with type 2 diabetes mellitus (T2DM) participating in the CANagliflozin cardioVascular Assessment Study (CANVAS) study. We also assessed the effect of the SGLT2 inhibitor canagliflozin (CANA) on GDF-15. Methods: The CANVAS trial randomized 4330 people with T2DM at high cardiovascular risk to CANA or placebo. Plasma GDF-15 concentration was measured with GDF-15 Roche Elecsys assay at baseline and follow-up. The association between GDF-15 and the primary kidney outcome (40% eGFR decline, end-stage kidney disease, or renal death) was assessed using multivariable adjusted Cox regression. Linear mixed effects models were used to assess the effect of CANA versus placebo on GDF-15 levels. Results: We included 3557 CANVAS participants with available plasma samples (mean age 62.8 years, 33.1% female, mean eGFR 76.9 ml/min/1.73 m2, median uACR 11.6 mg/g, median GDF-15 1776.0 pg/ml). During a mean follow-up of 5.7 years, 137 kidney outcomes occurred. Higher GDF-15 levels were independently associated with higher risk of kidney events (HR 1.98 [95% CI 1.40 to 2.81] per log increment GDF-15). Treatment with CANA modestly lowered GDF-15 compared to placebo (-2% [95% CI -5 to 0; p=0.046]). The effect of CANA on the kidney outcome (HR 0.56, 95% CI 0.40-0.79) was consistent regardless of baseline GDF-15 levels (p-interaction=0.75). GDF-15 did however not mediate the renal protective effect of CANA (percent mediation 3.9% [95% CI -3.6 to 14.0]). Conclusion: CANA modestly lowers GDF-15, which is independently associated with a higher risk of kidney disease progression in patients with T2DM at high cardiovascular risk. The modest reduction in GDF-15 with CANA did not mediate the renal protective effect of CANA. Disclosure J. Li: Employee; Self; George Institute. T. Sen: None. B. Neal: Research Support; Self; Janssen Research &amp; Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. B.L. Neuen: Research Support; Self; Australian National Health and Medical Research Council Postgraduate Scholarship, Oxford Australia Clarendon Scholarship from the University of Oxford, University Postgraduate Award from UNSW Sydney. Other Relationship; Self; Janssen Research &amp; Development, LLC. V. Perkovic: Other Relationship; Self; See Other Relationship field. D. de Zeeuw: Advisory Panel; Self; AbbVie Inc., Bayer AG, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Janssen Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. K.W. Mahaffey: Consultant; Self; Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support; Self; Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson &amp; Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. Y. Yavin: Employee; Self; Janssen Research &amp; Development, LLC. N. Rosenthal: None. M.K. Hansen: Employee; Self; Janssen Research &amp; Development, LLC. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. Funding Janssen Research &amp; Development, LLC

Growth-differentiation factor 15 as a predictor of mortality in patients with heart failure: a meta-analysis.

Measurement of the biomarker growth-differentiation factor 15 (GDF-15) in patients with heart failure may help in risk stratification. We assessed the relationship between GDF-15 and mortality in patients with heart failure by conducting a meta-analysis. PubMed, Embase, ISI Web of Science, SCOPUS, and Cochrane Library databases were searched for studies that reported data on the baseline GDF-15 levels and all-cause or cardiovascular mortality. Pooled hazard ratios for mortality were calculated and presented with 95% confidence intervals (CIs). Potential sources of heterogeneity were assessed by meta-regression, subgroup, and sensitivity analyses. Eight studies with a total of 4126 heart failure patients were included. Pooled results showed that overexpression of GDF-15 was associated with poor survival in heart failure patients (log unit GDF-15: hazard ratio = 1.86, 95% CI = 1.37-2.52). Subgroup analyses revealed similar results. However, there was evidence of heterogeneity and publication bias. The association disappeared after correction using the trim-and-fill method (log unit GDF-15: hazard ratio 1.07, 95% CI 0.80-1.42). The results of this meta-analysis indicate an association of elevated GDF-15 levels with increased risk of mortality in patients with heart failure. However, the results should be interpreted with caution due to substantial heterogeneity and publication bias among the studies included in the meta-analysis.

Association of Growth Differentiation Factor 15 with Mortality in a Prospective Hemodialysis Cohort

Background/Aims: Cardiovascular disease and protein-energy wasting are among the strongest predictors of the high mortality of dialysis patients. In the general population, the novel cardiovascular and wasting biomarker, growth differentiation factor 15 (GDF15), is associated with decreased survival. However, little is known about GDF15 in dialysis patients. Methods: Among prevalent hemodialysis patients participating in a prospective study (October 2011 to August 2015), we examined the association of baseline GDF15 levels with all-cause mortality using unadjusted and case mix-adjusted death hazard ratios (HRs) that controlled for age, sex, race, ethnicity, diabetes, and dialysis vintage. Results: The mean age ± SD of the 203 patients included in the study was 53.2 ± 14.5 years, and the cohort included 41% females, 34% African-Americans, and 48% Hispanics. GDF15 levels (mean ± SD 5.94 ± 3.90 ng/mL; range 1.58-39.8 ng/mL) were higher among older patients and were inversely associated with serum creatinine concentrations as a surrogate for muscle mass. Each 1.0 ng/mL increase in GDF15 was associated with an approximately 17-18% higher mortality risk in the unadjusted and case mix models (p < 0.05). Increments of about 1 SD (a 4.0 ng/mL increase in GDF15) were associated with a nearly 2-fold higher death risk. The highest GDF15 tertile was associated with higher mortality risk (reference: lowest tertile): the HRs (95% CI) were 3.19 (1.35-7.55) and 2.45 (1.00-6.00) in the unadjusted and the case mix-adjusted model, respectively. These incremental death trends were confirmed in cubic spline models. Conclusion: Higher circulating GDF15 levels are associated with higher mortality risk in hemodialysis patients. Future studies are needed to determine whether GDF15 may represent a novel therapeutic target for cardiovascular disease, wasting, and death in this population.

Serial Measurement of Growth-Differentiation Factor-15 in Heart Failure

Background— Growth-differentiation factor-15 (GDF-15) is emerging as a prognostic biomarker in patients with coronary artery disease. Little is known about GDF-15 as a biomarker in patients with heart failure. Methods and Results— The circulating concentration of GDF-15 was measured at baseline (n=1734) and at 12 months (n=1517) in patients randomized in the Valsartan Heart Failure Trial (Val-HeFT). GDF-15 levels at baseline ranged from 259 to 25 637 ng/L and were abnormally high (&gt;1200 ng/L) in 85% of patients. Higher levels were associated with features of worse heart failure and biomarkers of neurohormonal activation, inflammation, myocyte injury, and renal dysfunction. Baseline GDF-15 levels (per 100 ng/L) were associated with the risks of mortality (hazard ratio, 1.017; 95% confidence interval, 1.014 to 1.019; P &lt;0.001) and first morbid event (hazard ratio, 1.020; 95% confidence interval, 1.017 to 1.023; P &lt;0.001). In a comprehensive multiple-variable Cox regression model that included clinical prognostic variables, B-type natriuretic peptide, high-sensitivity C-reactive protein, and high-sensitivity troponin T, GDF-15 remained independently associated with mortality (hazard ratio, 1.007; 95% confidence interval, 1.001 to 1.014; P =0.02) but not first morbid event. At 12 months, the GDF-15 levels had increased by a similar amount in the placebo and valsartan groups ( P =0.94). Increases in GDF-15 over 12 months were independently associated with the risks of future mortality and first morbid event also after adjustment for clinical prognostic variables, B-type natriuretic peptide, high-sensitivity C-reactive protein, and high-sensitivity troponin T and their changes. Conclusions— GDF-15 reflects information from several pathological pathways and provides independent prognostic information in heart failure. GDF-15 levels increase over time, suggesting that GDF-15 reflects a pathophysiological axis that is not completely addressed by the therapies prescribed in Val-HeFT.