Growth differentiation factor-15 and fibroblast growth factor-23 are associated with mortality in type 2 diabetes – An observational follow-up study

Frimodt‐Møller, Marie; Scholten, Bernt Johan von; Reinhard, Henrik; Jacobsen, Peter Karl; Hansen, Tine W.; Persson, Frederik; Parving, Hans‐Henrik; Rossing, Peter

doi:10.1371/journal.pone.0196634

Cited by 37 publications

(20 citation statements)

References 40 publications

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“…The main finding of our study is that plasma FGF23 levels are independently associated with mortality and MACE in patients with type 2 diabetes and normal or mildly impaired kidney function. This observation extends previous studies in CKD patients and patients with type 2 diabetes (1,(8)(9)(10). Interestingly, the associations in our study restricted to patients with an eGFR $60 mL/min/1.73 m 2 persisted after adjustment for eGFR, linking a higher FGF23 level with adverse outcomes even in patients without impaired kidney function.…”

Section: Discussionsupporting

confidence: 89%

Fibroblast Growth Factor 23 and Mortality in Patients With Type 2 Diabetes and Normal or Mildly Impaired Kidney Function

et al. 2019

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To study whether fibroblast growth factor 23 (FGF23) is associated with adverse outcomes in patients with type 2 diabetes and normal or mildly impaired kidney function. RESEARCH DESIGN AND METHODS We analyzed C-terminal FGF23 levels in 310 patients with type 2 diabetes and estimated glomerular filtration rate ‡60 mL/min/1.73 m 2. Associations of FGF23 with all-cause mortality and major adverse cardiovascular events (MACE) were studied by Cox regression. RESULTS During a follow-up of 5.8 years (3.3-6.5), 47 patients developed MACE and 28 patients died. FGF23 was associated with an increased risk of all-cause mortality (age-and sex-adjusted hazard ratio 2.78 [95% CI 1.76-4.40]) and MACE (1.67 [1.12-2.49]). Results were similar after additional adjustment for other potential confounders and were consistent upon replication in an independent cohort. CONCLUSIONS In patients with type 2 diabetes and normal or mildly impaired kidney function, FGF23 is associated with an increased risk of cardiovascular events and mortality. In patients with chronic kidney disease (CKD), a higher plasma fibroblast growth factor 23 (FGF23) level has been consistently associated with an increased cardiovascular morbidity and mortality risk (1). Circulating levels of FGF23 increase early in the course of CKD (1), and kidney function is among the strongest determinants of FGF23 levels (2). Alternatively, type 2 diabetes, the most important cause of CKD, is accompanied by abnormalities in bone and mineral metabolism and elevated plasma FGF23 levels (3-5). Currently, it is unknown whether FGF23 is linked with adverse outcomes in patients with type 2 diabetes and normal or mildly impaired kidney function. Therefore, we aimed to investigate whether FGF23 levels are associated with mortality and cardiovascular events in patients with type 2 diabetes and an estimated glomerular filtration rate (eGFR) $60 mL/min/1.73 m 2. RESEARCH DESIGN AND METHODS The design of the DIAbetes and LifEstyle Cohort Twente (DIALECT) prospective cohort study has been described in detail previously (6). The study has been approved by the

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Section: Discussionsupporting

confidence: 89%

Fibroblast Growth Factor 23 and Mortality in Patients With Type 2 Diabetes and Normal or Mildly Impaired Kidney Function

et al. 2019

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“…This is consistent with the findings from our study that showed that the duration of diabetes morbidity, HbA1c, CRP, and systolic blood pressure was a risk factor for DR in patients with type 2 diabetes. In line with a previous study ( 28 ), we also found that the plasma levels of GDF-15 were significantly associated with renal damage and could predict the development of diabetic retinopathy in patients with type 2 diabetes. Importantly, the association between circulating plasma GDF-15 concentrations and the progression of DR in type 2 diabetic patients in our study was independent of the traditional DR risk factors mentioned above.…”

Section: Discussionsupporting

confidence: 92%

The Relationship Between Circulating Growth Differentiation Factor 15 Levels and Diabetic Retinopathy in Patients With Type 2 Diabetes

et al. 2021

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ObjectiveGrowth differentiation factor 15 (GDF-15) is a member of the TGF-β superfamily that has anti-inflammatory properties. The objective of this study was to evaluate the relationship between circulating GDF-15 levels and diabetic retinopathy (DR) in patients with type 2 diabetes.Materials/MethodsA case–control study was performed in which 402 patients with type 2 diabetes were enrolled. Of these, 171 patients had DR and the remaining 231 patients without DR acted as controls. The plasma GDF-15 levels were measured using ELISA, while DR was diagnosed using the canon ophthalmic digital imaging system and the Canon EOS 10D digital camera (Canon, Tokyo, Japan) through a non-pharmacologically dilated pupil.ResultsThe levels of GDF-15 were significantly higher in patients with DR [168.9 (112.9–228.3) pg/ml vs. 127.8 (96.1–202.8) pg/ml, P < 0.001] compared to controls. Results of the Spearman correlation analysis showed that the GDF-15 levels were positively associated with the duration of diabetes morbidity, fasting plasma glucose, systolic blood pressure, albumin/creatinine ratio, creatinine, and liver enzymes, but negatively associated with eGFR (both P < 0.001). The participants in the highest GDF-15 quartile had a significantly increased risk for DR (OR = 2.15, 95% CI 1.53–3.02) after adjusting for potential cofounders.ConclusionsThe circulating GDF-15 levels are positively associated with DR independent of potential cofounders.

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“…Higher levels of circulating GDF-15 have been linked to an increased risk for several adverse outcomes, including a recent study showing an association with incident type 2 diabetes (27), deteriorating microalbuminuria (28), progression of albuminuria in persons with type 2 diabetes (28), kidney function decline and cardiovascular risk in persons with type 1 diabetes (29), early death in patients undergoing haemodialysis (30), as well as incident heart failure and cardiovascular events in the general population (31). The fact that GDF-15 was the only biomarker that was associated with incident cardiovascular events is interesting and also supported by several studies showing associations between GDF-15 levels and both cardiovascular morbidity and mortality (32)(33)(34)(35).…”

Section: Gdf-15mentioning

confidence: 89%

Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes: a proteomics approach

Carlsson

Nowak

Lind

et al. 2019

Upsala Journal of Medical Sciences

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Background: Diabetic kidney disease (DKD) is a leading risk factor for end-stage renal disease and is one of the most important risk factors for cardiovascular disease in patients with diabetes. It is possible that novel markers portraying the pathophysiological underpinning processes may be useful. Aim: To investigate the associations between 80 circulating proteins, measured by a proximity extension assay, and prevalent DKD and major adverse cardiovascular events (MACE) in type 2 diabetes. Methods: We randomly divided individuals with type 2 diabetes from three cohorts into a two-thirds discovery and one-third replication set (total n ¼ 813, of whom 231 had DKD defined by estimated glomerular filtration rate <60 mg/mL/1.73 m 2 and/or urinary albumin-creatinine ratio !3 g/mol). Proteins associated with DKD were also assessed as predictors for incident major adverse cardiovascular events (MACE) in persons with DKD at baseline. Results: Four proteins were positively associated with DKD in models adjusted for age, sex, cardiovascular risk factors, glucose control, and diabetes medication: kidney injury molecule-1 (KIM-1, odds ratio [OR] per standard deviation increment, 1.65, 95% confidence interval [CI] 1.27-2.14); growth differentiation factor 15 (GDF-15, OR 1.40, 95% CI 1.16-1.69); myoglobin (OR 1.57, 95% CI 1.30-1.91), and matrix metalloproteinase 10 (MMP-10, OR 1.43, 95% CI 1.17-1.74). In patients with DKD, GDF-15 was significantly associated with increased risk of MACE after adjustments for baseline age, sex, microalbuminuria, and kidney function and (59 MACE events during 7 years follow-up, hazard ratio per standard deviation increase 1.43 [95% CI 1.03-1.98]) but not after further adjustments for cardiovascular risk factors. Conclusion: Our proteomics approach confirms and extends previous associations of higher circulating levels of GDF-15 with both micro-and macrovascular disease in patients with type 2 diabetes. Our data encourage additional studies evaluating the clinical utility of our findings.

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Growth differentiation factor-15 and fibroblast growth factor-23 are associated with mortality in type 2 diabetes – An observational follow-up study

Cited by 37 publications

References 40 publications

Fibroblast Growth Factor 23 and Mortality in Patients With Type 2 Diabetes and Normal or Mildly Impaired Kidney Function

Fibroblast Growth Factor 23 and Mortality in Patients With Type 2 Diabetes and Normal or Mildly Impaired Kidney Function

The Relationship Between Circulating Growth Differentiation Factor 15 Levels and Diabetic Retinopathy in Patients With Type 2 Diabetes

Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes: a proteomics approach

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