IGFBP-4 fragments as markers of cardiovascular mortality in type 1 diabetes patients with and without nephropathy

Rikke Hjortebjerg, Lise Tarnow, Anders Jorsal, Hans-Henrik Parving, Peter Rossing, Mette Bjerre, Jan Frystyk

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

CONTEXT: Type 1 diabetes (T1D) is characterized by an increased risk of macro-vascular complications. Pregnancy-associated plasma protein-A (PAPP-A) generated N- and C-terminal fragments of insulin-like growth factor binding protein-4 (NT-IGFBP-4/CT-IGFBP-4) have been suggested as cardiac biomarkers.

OBJECTIVE: To investigate the prognostic value of IGFBP-4 fragments in a cohort of T1D patients.

DESIGN AND PATIENTS: We prospectively followed 178 T1D patients with diabetic nephropathy and 152 T1D patients with normoalbuminuria for 12.6 (0.2-12.9) years.

MAIN OUTCOME MEASURES: Levels of IGF-I, IGF-II, IGFBP-1-4, NT- and CT-IGFBP-4, and PAPP-A at baseline.

RESULTS: During follow-up, 15 patients with normoalbuminuria and 71 patients with nephropathy died. Of these deaths, eight and 45 were due to fatal cardiovascular events, respectively. Using receiver operating characteristic curve analyses, patients were divided into subgroups using cut-off values of 261 μ g/L NT-IGFBP-4, 81 μ g/L CT-IGFBP-4 or 10 mIU/L PAPP-A. All-cause mortality was significantly higher in patients with NT-IGFBP-4 levels (55% vs. 16%, p<0.001) and CT-IGFBP-4 levels (44% vs. 15%, p<0.001) above vs. below cut-offs. Similarly, cardiovascular mortality was elevated in patients with high NT-IGFBP-4 levels (40% vs. 7.8%, p<0.001) and high CT-IGFBP-4 levels (30% vs. 7.4%, p<0.001). After adjustments for nephropathy and traditional cardiovascular risk factors, high NT- and CT-IGFBP-4 levels remained prognostic of cardiovascular mortality with hazard ratios (HR) (95% confidence interval) of 5.81 (2.62;12.86) (p<0.001) and 2.58 (1.10;6.10) (p=0.030), respectively. After adjustments, PAPP-A was not associated with overall or cardiovascular death. All IGF protein levels were higher in patients with diabetic nephropathy (p<0.001), but no variables associated with mortality.

CONCLUSION: High IGFBP-4 fragment levels were associated with increased all-cause and cardiovascular mortality rates in T1D patients with and without diabetic nephropathy.

OriginalsprogEngelsk
TidsskriftJournal of Clinical Endocrinology and Metabolism
Sider (fra-til)3032-40
Antal sider8
ISSN0021-972X
StatusUdgivet - 1. aug. 2015
Udgivet eksterntJa

Fingeraftryk

Insulin-Like Growth Factor Binding Protein 4
Medical problems
Pregnancy-Associated Plasma Protein-A
Diabetic Nephropathies
Insulin-Like Growth Factor Binding Protein 1
Insulin-Like Growth Factor II
Biomarkers
Insulin-Like Growth Factor I

Citer dette

Hjortebjerg, Rikke ; Tarnow, Lise ; Jorsal, Anders ; Parving, Hans-Henrik ; Rossing, Peter ; Bjerre, Mette ; Frystyk, Jan. / IGFBP-4 fragments as markers of cardiovascular mortality in type 1 diabetes patients with and without nephropathy. I: Journal of Clinical Endocrinology and Metabolism. 2015 ; s. 3032-40.
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title = "IGFBP-4 fragments as markers of cardiovascular mortality in type 1 diabetes patients with and without nephropathy",
abstract = "CONTEXT: Type 1 diabetes (T1D) is characterized by an increased risk of macro-vascular complications. Pregnancy-associated plasma protein-A (PAPP-A) generated N- and C-terminal fragments of insulin-like growth factor binding protein-4 (NT-IGFBP-4/CT-IGFBP-4) have been suggested as cardiac biomarkers.OBJECTIVE: To investigate the prognostic value of IGFBP-4 fragments in a cohort of T1D patients.DESIGN AND PATIENTS: We prospectively followed 178 T1D patients with diabetic nephropathy and 152 T1D patients with normoalbuminuria for 12.6 (0.2-12.9) years.MAIN OUTCOME MEASURES: Levels of IGF-I, IGF-II, IGFBP-1-4, NT- and CT-IGFBP-4, and PAPP-A at baseline.RESULTS: During follow-up, 15 patients with normoalbuminuria and 71 patients with nephropathy died. Of these deaths, eight and 45 were due to fatal cardiovascular events, respectively. Using receiver operating characteristic curve analyses, patients were divided into subgroups using cut-off values of 261 μ g/L NT-IGFBP-4, 81 μ g/L CT-IGFBP-4 or 10 mIU/L PAPP-A. All-cause mortality was significantly higher in patients with NT-IGFBP-4 levels (55{\%} vs. 16{\%}, p<0.001) and CT-IGFBP-4 levels (44{\%} vs. 15{\%}, p<0.001) above vs. below cut-offs. Similarly, cardiovascular mortality was elevated in patients with high NT-IGFBP-4 levels (40{\%} vs. 7.8{\%}, p<0.001) and high CT-IGFBP-4 levels (30{\%} vs. 7.4{\%}, p<0.001). After adjustments for nephropathy and traditional cardiovascular risk factors, high NT- and CT-IGFBP-4 levels remained prognostic of cardiovascular mortality with hazard ratios (HR) (95{\%} confidence interval) of 5.81 (2.62;12.86) (p<0.001) and 2.58 (1.10;6.10) (p=0.030), respectively. After adjustments, PAPP-A was not associated with overall or cardiovascular death. All IGF protein levels were higher in patients with diabetic nephropathy (p<0.001), but no variables associated with mortality.CONCLUSION: High IGFBP-4 fragment levels were associated with increased all-cause and cardiovascular mortality rates in T1D patients with and without diabetic nephropathy.",
author = "Rikke Hjortebjerg and Lise Tarnow and Anders Jorsal and Hans-Henrik Parving and Peter Rossing and Mette Bjerre and Jan Frystyk",
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journal = "Journal of Clinical Endocrinology and Metabolism",
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IGFBP-4 fragments as markers of cardiovascular mortality in type 1 diabetes patients with and without nephropathy. / Hjortebjerg, Rikke; Tarnow, Lise; Jorsal, Anders; Parving, Hans-Henrik; Rossing, Peter; Bjerre, Mette; Frystyk, Jan.

I: Journal of Clinical Endocrinology and Metabolism, 01.08.2015, s. 3032-40.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - IGFBP-4 fragments as markers of cardiovascular mortality in type 1 diabetes patients with and without nephropathy

AU - Hjortebjerg, Rikke

AU - Tarnow, Lise

AU - Jorsal, Anders

AU - Parving, Hans-Henrik

AU - Rossing, Peter

AU - Bjerre, Mette

AU - Frystyk, Jan

PY - 2015/8/1

Y1 - 2015/8/1

N2 - CONTEXT: Type 1 diabetes (T1D) is characterized by an increased risk of macro-vascular complications. Pregnancy-associated plasma protein-A (PAPP-A) generated N- and C-terminal fragments of insulin-like growth factor binding protein-4 (NT-IGFBP-4/CT-IGFBP-4) have been suggested as cardiac biomarkers.OBJECTIVE: To investigate the prognostic value of IGFBP-4 fragments in a cohort of T1D patients.DESIGN AND PATIENTS: We prospectively followed 178 T1D patients with diabetic nephropathy and 152 T1D patients with normoalbuminuria for 12.6 (0.2-12.9) years.MAIN OUTCOME MEASURES: Levels of IGF-I, IGF-II, IGFBP-1-4, NT- and CT-IGFBP-4, and PAPP-A at baseline.RESULTS: During follow-up, 15 patients with normoalbuminuria and 71 patients with nephropathy died. Of these deaths, eight and 45 were due to fatal cardiovascular events, respectively. Using receiver operating characteristic curve analyses, patients were divided into subgroups using cut-off values of 261 μ g/L NT-IGFBP-4, 81 μ g/L CT-IGFBP-4 or 10 mIU/L PAPP-A. All-cause mortality was significantly higher in patients with NT-IGFBP-4 levels (55% vs. 16%, p<0.001) and CT-IGFBP-4 levels (44% vs. 15%, p<0.001) above vs. below cut-offs. Similarly, cardiovascular mortality was elevated in patients with high NT-IGFBP-4 levels (40% vs. 7.8%, p<0.001) and high CT-IGFBP-4 levels (30% vs. 7.4%, p<0.001). After adjustments for nephropathy and traditional cardiovascular risk factors, high NT- and CT-IGFBP-4 levels remained prognostic of cardiovascular mortality with hazard ratios (HR) (95% confidence interval) of 5.81 (2.62;12.86) (p<0.001) and 2.58 (1.10;6.10) (p=0.030), respectively. After adjustments, PAPP-A was not associated with overall or cardiovascular death. All IGF protein levels were higher in patients with diabetic nephropathy (p<0.001), but no variables associated with mortality.CONCLUSION: High IGFBP-4 fragment levels were associated with increased all-cause and cardiovascular mortality rates in T1D patients with and without diabetic nephropathy.

AB - CONTEXT: Type 1 diabetes (T1D) is characterized by an increased risk of macro-vascular complications. Pregnancy-associated plasma protein-A (PAPP-A) generated N- and C-terminal fragments of insulin-like growth factor binding protein-4 (NT-IGFBP-4/CT-IGFBP-4) have been suggested as cardiac biomarkers.OBJECTIVE: To investigate the prognostic value of IGFBP-4 fragments in a cohort of T1D patients.DESIGN AND PATIENTS: We prospectively followed 178 T1D patients with diabetic nephropathy and 152 T1D patients with normoalbuminuria for 12.6 (0.2-12.9) years.MAIN OUTCOME MEASURES: Levels of IGF-I, IGF-II, IGFBP-1-4, NT- and CT-IGFBP-4, and PAPP-A at baseline.RESULTS: During follow-up, 15 patients with normoalbuminuria and 71 patients with nephropathy died. Of these deaths, eight and 45 were due to fatal cardiovascular events, respectively. Using receiver operating characteristic curve analyses, patients were divided into subgroups using cut-off values of 261 μ g/L NT-IGFBP-4, 81 μ g/L CT-IGFBP-4 or 10 mIU/L PAPP-A. All-cause mortality was significantly higher in patients with NT-IGFBP-4 levels (55% vs. 16%, p<0.001) and CT-IGFBP-4 levels (44% vs. 15%, p<0.001) above vs. below cut-offs. Similarly, cardiovascular mortality was elevated in patients with high NT-IGFBP-4 levels (40% vs. 7.8%, p<0.001) and high CT-IGFBP-4 levels (30% vs. 7.4%, p<0.001). After adjustments for nephropathy and traditional cardiovascular risk factors, high NT- and CT-IGFBP-4 levels remained prognostic of cardiovascular mortality with hazard ratios (HR) (95% confidence interval) of 5.81 (2.62;12.86) (p<0.001) and 2.58 (1.10;6.10) (p=0.030), respectively. After adjustments, PAPP-A was not associated with overall or cardiovascular death. All IGF protein levels were higher in patients with diabetic nephropathy (p<0.001), but no variables associated with mortality.CONCLUSION: High IGFBP-4 fragment levels were associated with increased all-cause and cardiovascular mortality rates in T1D patients with and without diabetic nephropathy.

M3 - Journal article

C2 - 26046968

SP - 3032

EP - 3040

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

ER -