Abstract
Aims
Associations between growth differentiation factor‐15 (GDF‐15), cardiovascular outcomes, and exercise capacity among patients with a recent hospitalization for heart failure (HHF) and heart failure with reduced ejection fraction (HFrEF) are unknown. We utilized data from the ‘Functional Impact of GLP‐1 for Heart Failure Treatment’ (FIGHT) study to address these knowledge gaps.
Methods and results
FIGHT was a randomized clinical trial testing the effect of liraglutide (vs. placebo) among 300 participants with HFrEF and a recent HHF. Multivariable regression models evaluated associations between baseline GDF‐15 and change in GDF‐15 (per 1000 pg/mL increase from baseline to 30 days) with clinical outcomes (at 180 days) and declines in exercise capacity (6 min walk distance ≥ 45 m). At baseline (n = 249), median GDF‐15 value was 3221 pg/mL (interquartile range 1938–5511 pg/mL). Participants in the highest tertile of baseline GDF‐15 were more likely to be male and have more co‐morbidities. After adjustment, an increase in GDF‐15 over 30 days was associated with higher risk of death or HHF [hazard ratio 1.35, 95% confidence interval (CI) 1.11–1.64]. In addition, higher baseline GDF‐15 (per 1000 pg/mL until 6000 pg/mL) and an increase in GDF‐15 over 30 days were associated with declining 6 min walk distance (odds ratio 1.26, 95% CI 1.02–1.55 and odds ratio 1.37, 95% CI 1.12–1.69, respectively). GDF‐15 levels remained stable among participants randomized to liraglutide.
Conclusions
An increase in GDF‐15 over 30 days among patients in HFrEF was independently associated with an increased risk of cardiovascular events and declining exercise capacity. These results support the value of longitudinal GDF‐15 trajectory in informing risk of heart failure disease progression.
Keywords: GDF‐15, Heart failure, Liraglutide, GLP‐1 receptor agonist
Introduction
Patients with recent hospitalization for heart failure (HHF) and heart failure with reduced ejection fraction (HFrEF) are at high risk for readmission and mortality. 1 , 2 , 3 Strategies to identify disease progression and increased risk of adverse outcomes in this patient group remain a clinical priority. Growth differentiation factor‐15 (GDF‐15) is a member of the transforming growth factor‐β family and is secreted from multiple cell groups including adipocytes and myocytes in response to oxidative stress, mechanical strain, and ischaemia. 4 There is little information on the prognostic role of a single value or a change in GDF‐15 in patients with HFrEF with recent HHF. Furthermore, prior studies have demonstrated conflicting associations of GDF‐15 and exercise capacity in chronic stable HFrEF. 5 , 6 The association of GDF‐15 with exercise capacity and clinical outcomes has not been explored in the high‐risk population of people with HFrEF with worsening heart failure (HF). Recent evidence suggests that GDF‐15 may interact with the glucagon‐like peptide‐1 (GLP‐1) signalling pathway. 7 , 8 GLP‐1 receptor agonists reduce risk of adverse cardiovascular (CV) outcomes in patients with type 2 diabetes and are safe in patients with HF. 9 , 10 There is now potential to determine whether direct therapeutic modulation of this pathway impacts GDF‐15 levels and HF risk. 11 , 12 , 13 , 14 , 15 To address these knowledge gaps, we used data from the Functional Impact of GLP‐1 for Heart Failure Treatment (FIGHT) study 16 to identify (i) whether GDF‐15 is associated with an increased risk of subsequent CV outcomes; (ii) whether GDF‐15 is associated with declining exercise capacity, change in echocardiographic parameters, and change in HF symptoms; and (iii) whether liraglutide, a GLP‐1 receptor agonist, impacts circulating GDF‐15 levels in people with HFrEF with recent HF hospitalization.
Methods
The results of the FIGHT trial have been previously reported. 16 FIGHT was a double‐blind, placebo‐controlled, randomized clinical trial designed to test the efficacy, safety, and tolerability of liraglutide (vs. placebo) among 300 participants with HFrEF and a recent HHF (within the prior 2 weeks). The primary endpoint was a composite global rank score of time to death, time to rehospitalization for HF, and change in N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) level at 180 days compared with baseline.
Biomarker assessment
Blood samples were obtained at baseline, 30, 90, and 180 days. Samples were collected from the peripheral vein into EDTA‐containing tubes, centrifuged immediately, and stored at −70°C for subsequent analysis. GDF‐15 concentrations were measured in a core laboratory from samples using sensitive sandwich‐immunoassay monoclonal antibodies (Elecsys GDF‐15 assay, Roche Diagnostics, Indianapolis, Indiana). 17
Study endpoints
This is a post hoc and hypothesis‐generating analysis of the FIGHT trial. The primary endpoint of interest for the present analysis was 180 day death or HF hospitalization. Secondary endpoints included a decrease in exercise capacity, defined as a ≥45 m decrease in 6 min walk distance (6MWD); improvement in patient‐reported quality of life, defined as an increase in Kansas City Cardiomyopathy Questionnaire (KCCQ) ≥ 5 points; and worsening left ventricular (LV) function, defined as either a 5% decrement in left ventricular ejection fraction (LVEF) or a 5% increase in LV volumes. The changes in secondary endpoints were assessed between baseline and 180 days.
Statistical analysis
The associations between GDF‐15 tertile and baseline characteristics were described (Table 1 ). Categorical variables were presented as counts (percentages), and differences between the two groups were assessed using the Pearson χ 2 test or the Fisher exact test. Continuous variables were presented as median, 25th and 75th percentiles, and differences between the three groups were assessed using the Kruskal–Wallis test. Modelling was performed with complete case analysis. There were 249 patients at baseline with GDF‐15 measurements. The biomarker subset population was demographically similar to the overall clinical trial population. For the clinical outcomes of interest, Cox proportional hazard models were used (the proportional hazards assumption was assessed and met). Logistic regression assessed the relationship between baseline and a change in GDF‐15 (from baseline to 30 days) and a decrease in KCCQ ≥ 5 points, a decrease in 6MWD ≥ 45 m, and worsening LV function (defined as either a 5% decrement in LVEF or a 5% increase in LV volumes).
Table 1.
Baseline demographics by tertile of growth differentiation factor‐15
| Characteristic | Overall (N = 249) | Tertile 1 (N = 83) | Tertile 2 (N = 83) | Tertile 3 (N = 83) | P‐value |
|---|---|---|---|---|---|
| Demographics | |||||
| Age, years: n, median (25th–75th) | 249, 61 (53–68) | 83, 54 (43–62) | 83, 63 (55–69) | 83, 65 (59–72) | <0.001 |
| Female | 53/249 (21.3%) | 23/83 (27.7%) | 17/83 (20.5%) | 13/83 (15.7%) | 0.2 |
| White | 147/249 (59.0%) | 31/83 (37.3%) | 52/83 (62.7%) | 64/83 (77.1%) | <0.001 |
| Weight, kg (median, 25th–75th) | 209 (171–252) | 217 (178–265) | 213 (168–246) | 202 (163–238) | 0.08 |
| Body mass index, (median, 25th–75th) | 31.5 (25.2–36.4) | 33.2 (27.3–37.9) | 31.1 (25.5–36.4) | 29.8 (23.9–35.6) | 0.07 |
| Ejection fraction: n, median (25th–75th) | 249, 22.0 (17.0–25.0) | 83, 20.0 (15.0–25.0) | 83, 25.0 (17.0–27.0) | 83, 23.0 (18.0–25.0) | 0.2 |
| Systolic blood pressure, mmHg: n, median (25th–75th) | 248, 108 (99–118) | 83, 110 (100–118) | 83, 106 (98–118) | 82, 108 (98–118) | 0.7 |
| Heart rate, b.p.m.: n, median (25th–75th) | 249, 75 (68–86) | 83, 77 (69–88) | 83, 72 (67–80) | 83, 75 (66–87) | 0.1 |
| Jugular venous pressure | 0.07 | ||||
| Not elevated/not distended | 131/242 (54.1%) | 52/82 (63.4%) | 43/81 (53.1%) | 36/79 (45.6%) | |
| Elevated/distended | 111/242 (45.9%) | 30/82 (36.6%) | 38/81 (46.9%) | 43/79 (54.4%) | |
| Not done | 0/242 (0.0%) | 0/82 (0.0%) | 0/81 (0.0%) | 0/79 (0.0%) | |
| Co‐morbidities | |||||
| Hypertension | 199/248 (80.2%) | 67/83 (80.7%) | 65/83 (78.3%) | 67/82 (81.7%) | 0.9 |
| Heart failure aetiology: ischaemic | 209/249 (83.9%) | 67/83 (80.7%) | 77/83 (92.8%) | 65/83 (78.3%) | 0.03 |
| Atrial fibrillation history | 118/247 (47.8%) | 26/82 (31.7%) | 38/82 (46.3%) | 54/83 (65.1%) | <0.001 |
| Diabetes | 146/249 (58.6%) | 39/83 (47.0%) | 53/83 (63.9%) | 54/83 (65.1%) | 0.03 |
| Obstructive sleep apnoea | 92/233 (39.5%) | 37/78 (47.4%) | 27/77 (35.1%) | 28/78 (35.9%) | 0.2 |
| Orthopnoea | 105/240 (43.8%) | 34/82 (41.5%) | 32/81 (39.5%) | 39/77 (50.6%) | 0.5 |
| COPD | 52/249 (20.9%) | 15/83 (18.1%) | 17/83 (20.5%) | 20/83 (24.1%) | 0.6 |
| NYHA class | 0.1 | ||||
| I | 5/246 (2.0%) | 2/82 (2.4%) | 3/82 (3.7%) | 0/82 (0.0%) | |
| II | 77/246 (31.3%) | 24/82 (29.3%) | 31/82 (37.8%) | 22/82 (26.8%) | |
| III | 153/246 (62.2%) | 55/82 (67.1%) | 43/82 (52.4%) | 55/82 (67.1%) | |
| IV | 11/246 (4.5%) | 1/82 (1.2%) | 5/82 (6.1%) | 5/82 (6.1%) | |
| Medications at enrolment | |||||
| ACE inhibitor or ARB | 176/247 (71.3%) | 73/83 (88.0%) | 61/81 (75.3%) | 42/83 (50.6%) | <0.001 |
| Beta‐blockers | 232/249 (93.2%) | 78/83 (94.0%) | 81/83 (97.6%) | 73/83 (88.0%) | 0.05 |
| Aldosterone antagonist | 149/247 (60.3%) | 57/83 (68.7%) | 54/82 (65.9%) | 38/82 (46.3%) | 0.006 |
| Any furosemide equivalent diuretic | 247/249 (99.2%) | 83/83 (100.0%) | 82/83 (98.8%) | 82/83 (98.8%) | 1.0 |
| Laboratory values | |||||
| Sodium, mEq/L: n, median (25th–75th) | 247, 137 (134–139) | 81, 137 (135–139) | 83, 136 (134–138) | 83, 137 (134–139) | 0.1 |
| Blood urea nitrogen, mg/dL: n, median (25th–75th) | 247, 31.0 (22.0–47.0) | 81, 24.0 (17.0–31.0) | 83, 32.0 (24.0–46.0) | 83, 42.0 (29.4–56.0) | <0.001 |
| Creatinine (mg/dL): n, median (25th–75th) | 247, 1.5 (1.1–1.9) | 81, 1.2 (1.0–1.4) | 83, 1.5 (1.2–1.8) | 83, 1.8 (1.5–2.3) | <0.001 |
| Core lab NT‐proBNP (pg/mL): n, median (25th–75th) | 248, 1927 (1046–4280) | 83, 1296 (918.6–2085) | 83, 1936 (1140–4685) | 82, 3414 (1504–8393) | <0.001 |
| eGFR (mL/min/1.73 m2): n, median (25th–75th) | 247, 49.2 (36.2–66.4) | 81, 66.5 (52.2–84.7) | 83, 47.3 (37.5–59.1) | 83, 36.4 (28.3–49.2) | <0.001 |
| Baseline hs‐TnT (mg/L): n, median (25th–75th) | 248, 29.9 (16.2–53.5) | 82, 17.4 (10.0–34.7) | 83, 31.5 (17.8–51.9) | 83, 38.6 (25.0–68.6) | <0.001 |
| Liraglutide treatment | 126/249 (50.6%) | 42/83 (50.6%) | 46/83 (55.4%) | 38/83 (45.8%) | 0.5 |
ACE, angiotensin‐converting enzyme; ARB, angiotensin receptor blocker; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; hs‐TnT, high‐sensitivity troponin T; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide; NYHA, New York Heart Association.
Regression models were adjusted for age, sex, diabetes mellitus, LVEF, estimated glomerular filtration rate, NT‐proBNP, troponin, history of myocardial infarction, body mass index, and atrial fibrillation (with baseline GDF‐15 added to the models assessing the association between change in GDF‐15 and outcomes). All continuous variables were tested for linearity assumption, and the log transformation or two‐piece linear splines were applied to some variables that violated the assumption. An interaction term of GDF‐15 and randomized treatment evaluated whether GDF‐15 modified the relationship between randomized treatment and outcomes. In addition, we evaluated an expanded model that included all the variables as indicated earlier and added history of myocardial infarction, body mass index, and history of atrial fibrillation. Data were analysed using SAS Version 9.4 software (SAS, Cary, North Carolina). Statistical significance was based on a P‐value of ≤0.05.
Results
Baseline demographics
Among 300 participants enrolled in FIGHT, 249 (83%) had data for baseline GDF‐15 concentration. Median baseline GDF‐15 value was 3221 pg/mL (interquartile range 1938–5511 pg/mL). Participants in the highest tertile of baseline GDF‐15 were more likely to be older and male and tended to have higher concentrations of NT‐proBNP and troponin and lower estimated glomerular filtration rate (Table 1 ).
Association between baseline growth differentiation factor‐15 and outcomes
After multivariable adjustment, higher baseline GDF‐15 (per 1000 pg/mL increase) was not associated with 180 day clinical outcomes including death or HHF [adjusted hazard ratio 1.05, 95% confidence interval (CI) 1.00–1.11] (Table 2 ). The association between baseline GDF‐15 and 6MWD was non‐linear: a higher baseline GDF‐15 (per 1000 pg/mL) was associated with a 45 m lower 6MWD [adjusted odds ratio (aOR) 1.26, 95% CI 1.02–1.55] until 6000 pg/mL, where higher GDF‐15 values were not associated with 6MWD (aOR 0.92, 95% CI 0.80–1.05). Baseline GDF‐15 was not associated with decreases in KCCQ (aOR 1.00, 95% CI 0.91–1.08) or worsening LV function (aOR 1.07, 95% CI 0.95–1.19).
Table 2.
Associations of baseline and change in growth differentiation factor‐15 and clinical outcomes from Cox models
| Unadjusted | Adjusted a | ||||
|---|---|---|---|---|---|
| Outcomes | Description | Hazard ratio (95% CI) | P‐value | Hazard ratio (95% CI) | P‐value |
| Baseline GDF‐15 | |||||
| 180 day death or HF hospitalization | Baseline GDF‐15 per 1000 pg/mL | 1.05 (1.01, 1.10) | 0.029 | 1.05 (1.00, 1.11) | 0.069 |
| 180 day death or CV hospitalization | Baseline GDF‐15 per 1000 pg/mL | 1.03 (0.98, 1.08) | 0.234 | 1.02 (0.97, 1.08) | 0.458 |
| 180 day death or any hospitalization | Baseline GDF‐15 per 1000 pg/mL | 1.05 (1.00, 1.09) | 0.037 | 1.04 (0.99, 1.09) | 0.114 |
| 180 day death | Baseline GDF‐15 per 1000 pg/mL | 1.11 (1.03, 1.20) | 0.005 | 1.06 (0.96, 1.16) | 0.226 |
| Change in GDF‐15 | |||||
| 180 day death or HF hospitalization | Change in GDF‐15 per 1000 pg/mL increase up to −500 pg/mL | 0.95 (0.83, 1.09) | 0.472 | 1.09 (0.87, 1.36) | 0.439 |
| Change in GDF‐15 per 1000 pg/mL increase above −500 pg/mL | 1.39 (1.15, 1.68) | <0.001 | 1.35 (1.11, 1.64) | 0.003 | |
| 180 day death or CV hospitalization | Change in GDF‐15 per 1000 pg/mL: baseline to 30 days | 1.14 (0.99, 1.32) | 0.060 | 1.22 (1.06, 1.40) | 0.006 |
| 180 day death or any hospitalization | Change in GDF‐15 per 1000 pg/mL: baseline to 30 days | 1.10 (0.97, 1.25) | 0.134 | 1.25 (1.08, 1.44) | 0.003 |
| 180 day death | Change in GDF‐15 per 1000 pg/mL: 30 days to baseline | 1.12 (0.91, 1.38) | 0.280 | 1.16 (1.00, 1.34) | 0.052 |
CI, confidence interval; CV, cardiovascular; GDF‐15, growth differentiation factor‐15; HF, heart failure.
The hazard ratio is for 1 k increase in the change of GDF‐15.
Adjusted for baseline GDF‐15, age, sex, diabetes mellitus, left ventricular ejection fraction, estimated glomerular filtration rate, N‐terminal pro‐brain natriuretic peptide, and troponin.
Association between 30 day change in growth differentiation factor‐15 and outcomes
A 30 day increase in GDF‐15 was associated with higher risk of death or HHF at 180 days (per 1000 pg/mL GDF‐15 above a change of −500 pg/mL; adjusted hazard ratio 1.35, 95% CI 1.11–1.64) (Table 2 ). An increase in GDF‐15 over 30 days (per 1000 pg/mL from baseline to 30 days) was associated with an increased risk of declining 6MWD of more than 45 m (aOR 1.37, 95% CI 1.12–1.69). Change in GDF‐15 was not associated with change in KCCQ score. The results from the expanded model were consistent with these findings (Tables A1 and A2 ).
Interaction of liraglutide and growth differentiation factor‐15
Neither baseline GDF‐15 nor 30 day change in GDF‐15 modified the association between randomization to liraglutide versus placebo and changing KCCQ score, 6MWD, worsening LV function, or clinical outcomes at 180 days (all interaction P‐values > 0.05). Randomization to liraglutide versus placebo did not change GDF‐15 across follow‐up, with no statistical difference between changes in GDF‐15 from baseline to 30, 90, and 180 days (P > 0.05 at all time points; Figure 1 ).
Figure 1.
Growth differentiation factor‐15 (GDF‐15) over time by baseline randomization arm.
Discussion
Among participants with HFrEF who had a recent HHF in the FIGHT trial, we identified the following major findings: (i) an increase in GDF‐15 over time was associated with an increased risk of subsequent CV events; (ii) higher baseline and increasing GDF‐15 over 30 days were both associated with declining exercise capacity as measured by the 6MWD; and (iii) treatment with liraglutide did not impact GDF‐15 levels. These results suggest that short‐term changes in GDF‐15 have a role in identifying HF disease progression in people with HFrEF with a recent HHF.
The prognostic role of GDF‐15 in stable people with HFrEF has been demonstrated in several studies. 5 , 18 , 19 , 20 , 21 Our results are unique and extend on prior results as they demonstrate the prognostic value of short‐term changes in GDF‐15 beyond the baseline value. Furthermore, the prognostic role of a change in GDF‐15 in people with HFrEF with recent HHF had not been previously described. These results reinforce prior data identifying associations between 1 year changes in GDF‐15 and CV outcomes and support the incremental value of GDF‐15 trajectory beyond results of a singular measurement. 18 Our findings contrast with prior analyses in ambulatory HFrEF and people with HF with preserved ejection fraction, where GDF‐15 and other novel biomarkers (ST‐2 and galectin‐3) were only mildly associated with a change in functional parameters. 6
Identifying people with HFrEF who may functionally decline overtime remains a clinically important endeavour, yet identifying a biomarker that can serve as a surrogate for exercise capacity remains challenging. 6 The Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF‐ACTION) trial suggested that among participants with chronic stable HFrEF, higher baseline GDF‐15 was associated with greater baseline impairments in exercise capacity. 5 Similar results were seen in the ‘Iron Repletion effects On Oxygen UpTake in Heart Failure’ (IRONOUT) trial. 6 The current results extend these prior data by suggesting that both baseline and 30 day change in GDF‐15 are associated with a subsequent decline in 6MWD, highlighting the potential role of serial GDF‐15 in identifying people at high risk for worsening functional status following HHF. This aligns with prior analysis demonstrating the strength of serial biomarker measurement in HF. 22 Furthermore, ongoing trials are now evaluating the role of GDF‐15‐based titration of HF therapies. 23
Growth differentiation factor‐15 is now emerging as a possible endocrine signal of nutritional stress and a target for weight loss as it potentially acts through the GLP‐1 signalling pathway. 8 , 24 Liraglutide has also demonstrated efficacy in reducing weight. 25 , 26 , 27 To our knowledge, our analysis is the first to demonstrate that GDF‐15 levels are not impacted by a GLP‐1 receptor agonist. GDF‐15 levels were not modified by valsartan (vs. placebo) 18 or sacubitril/valsartan (vs. enalapril). 20 Our results extend these prior results and provide potential insight into the role of GDF‐15 in HFrEF, suggesting that GDF‐15 is not modified by therapeutic regulation of the GLP‐1, renin–angiotensin, or neprilysin pathways.
Limitations
Our results are subject to the limitations of a post hoc analysis. The FIGHT trial may not be representative of all people with HFrEF. Not all participants had samples, and some participants were censored after baseline due to death; therefore, the results may not be generalizable. However, the use of available samples to conduct repeated measurements of GDF‐15 at baseline and 30 days in the context of a randomized trial enables a hypothesis‐generating exploration of the prognostic value of GDF‐15 and changes in GDF‐15 with liraglutide. Our study sample size may be unable to detect small but meaningful differences in GDF‐15 levels in treatment groups. The shorter duration of follow‐up of the FIGHT trial may have limited our ability to identify further association between baseline GDF‐15, clinical outcomes, and treatment groups. We did not provide data on use of metformin as the FIGHT trial includes both patients with and without diabetes mellitus. Hence, any adjustment of results based on metformin use at baseline would be confounded by indication and could erroneously create associations. Guideline‐directed medical therapy was not optimally used in our population, which may impact biomarker levels—however, these results are reflective of the real‐world use of medical therapy in patients with HFrEF and worsening HF. 28
Conclusion
In people with HFrEF with a recent HHF, change in GDF‐15 over time was significantly associated with HF disease progression including CV outcomes and declining exercise capacity. GDF‐15 levels remained stable among individuals randomized to liraglutide. While future studies will be needed to confirm these results, our findings reinforce the potential role of evaluating trajectories of GDF‐15 in people with HFrEF for forecasting risk of clinical events and worsening functional status.
Conflict of interest
A.S. reports receiving support from Canada Institute for Health Research ‐ (Grant Number: 175095), the Fonds de Recherche Santé Quebec (FRSQ) Junior 1 clinician scholars programme, Alberta Innovates Health Solution, European Society of Cardiology young investigator grant, Roche Diagnostics, Boeringer‐Ingelheim, Novartis, and Takeda. M.F. reports consulting fees from AxonTherapies and Daxor. R.M. reported honoraria from Roche. S.J.G. has received a Heart Failure Society of America/Emergency Medicine Foundation Acute Heart Failure Young Investigator Award funded by Novartis; has received research support from Amgen, Bristol‐Myers Squibb, and Novartis; serves on advisory boards for Amgen and Cytokinetics; and serves as a consultant for Amgen and Merck. There are no additional conflicts to disclose.
Funding
Funding for this analysis and GDF‐15 assays were provided by Roche Diagnostics. The FIGHT trial was funded by the National, Heart, Lung, and Blood Institute (NHLBI).
Appendix A.
Table A1.
Association of baseline growth differentiation factor‐15 and outcomes
| Unadjusted | Adjusted a | ||||
|---|---|---|---|---|---|
| Outcomes | Description | Hazard ratio (95% CI) | P‐value | Hazard ratio (95% CI) | P‐value |
| 180 day death or HF hospitalization | Baseline GDF‐15 per 1000 pg/mL | 1.05 (1.01, 1.10) | 0.029 | 1.06 (1.00, 1.11) | 0.052 |
| 180 day death or CV hospitalization | Baseline GDF‐15 per 1000 pg/mL | 1.03 (0.98, 1.08) | 0.234 | 1.02 (0.97, 1.08) | 0.420 |
| 180 day death or any hospitalization | Baseline GDF‐15 per 1000 pg/mL | 1.05 (1.00, 1.09) | 0.037 | 1.05 (1.00, 1.10) | 0.073 |
| 180 day death | Baseline GDF‐15 per 1000 pg/mL | 1.11 (1.03, 1.20) | 0.005 | 1.06 (0.96, 1.16) | 0.273 |
CI, confidence interval; CV, cardiovascular; GDF‐15, growth differentiation factor‐15; HF, heart failure.
The hazard ratio is for 1 k increase in GDF‐15.
Adjusted for age, sex, diabetes mellitus, left ventricular ejection fraction, estimated glomerular filtration rate, N‐terminal pro‐brain natriuretic peptide, troponin, history of myocardial infarction, body mass index, and atrial fibrillation.
Table A2.
Association of change in growth differentiation factor‐15 and outcomes
| Unadjusted | Adjusted a | ||||
|---|---|---|---|---|---|
| Outcomes | Description | Hazard ratio (95% CI) | P‐value | Hazard ratio (95% CI) | P‐value |
| 180 day death or HF hospitalization | Change in GDF‐15 per 1000 increase up to −500 | 0.95 (0.83, 1.09) | 0.472 | 1.09 (0.87, 1.38) | 0.462 |
| Change in GDF‐15 per 1000 increase above −500 | 1.39 (1.15, 1.68) | <0.001 | 1.40 (1.13, 1.73) | 0.002 | |
| 180 day death or CV hospitalization | Change in GDF‐15 per 1000 pg/mL: 30 days to BS | 1.14 (0.99, 1.32) | 0.060 | 1.23 (1.05, 1.43) | 0.008 |
| 180 day death or any hospitalization | Change in GDF‐15 per 1000 pg/mL: 30 days to BS | 1.10 (0.97, 1.25) | 0.134 | 1.30 (1.12, 1.52) | <0.001 |
| 180 day death | Change in GDF‐15 per 1000 pg/mL: 30 days to BS | 1.12 (0.91, 1.38) | 0.280 | 1.15 (0.99, 1.35) | 0.071 |
BS, baseline; CI, confidence interval; CV, cardiovascular; GDF‐15, growth differentiation factor‐15; HF, heart failure.
The hazard ratio is for 1 k increase in the change of GDF‐15.
Adjusted for baseline GDF‐15, age, sex, diabetes mellitus, left ventricular ejection fraction, estimated glomerular filtration rate, N‐terminal pro‐brain natriuretic peptide, troponin, history of myocardial infarction, body mass index, and atrial fibrillation.
Sharma, A. , Greene, S. , Vaduganathan, M. , Fudim, M. , Ambrosy, A. P. , Sun, J.‐L. , McNulty, S. E. , Hernandez, A. F. , Borlaug, B. A. , Velazquez, E. J. , Mentz, R. J. , DeVore, A. D. , Alhanti, B. , Margulies, K. , and Felker, G. M. (2021) Growth differentiation factor‐15, treatment with liraglutide, and clinical outcomes among patients with heart failure. ESC Heart Failure, 8: 2608–2616. 10.1002/ehf2.13348.
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