IGFBP-4 Fragments as Markers of Cardiovascular Mortality in Type 1 Diabetes Patients With and Without Nephropathy
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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.
In: The Journal of Clinical Endocrinology & Metabolism, Vol. 100, No. 8, 08.2015, p. 3032-40.Research output: Contribution to journal › Journal article › Research › peer-review
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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
Y1 - 2015/8
N2 - CONTEXT: Type 1 diabetes (T1D) is characterized by an increased risk of macrovascular complications. Pregnancy-associated plasma protein-A (PAPP-A) generated N- and C-terminal fragments of IGF binding protein-4 (NT-IGFBP-4 and CT-IGFBP-4) have been suggested as cardiac biomarkers.OBJECTIVE: The objective of the study was to investigate the prognostic value of IGFBP-4 fragments in a cohort of T1D patients.DESIGN AND PATIENTS: We prospectively followed up 178 T1D patients with diabetic nephropathy and 152 T1D patients with normoalbuminuria for 12.6 (range 0.2-12.9) years.MAIN OUTCOME MEASURES: Levels of IGF-1, IGF-2, 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, 8 and 45 were due to fatal cardiovascular events, respectively. Using receiver-operating characteristic curve analyses, patients were divided into subgroups using cutoff values of 261 μg/L NT-IGFBP-4, 81 μg/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 < .001) and CT-IGFBP-4 levels (44% vs 15%, P < .001) above vs below cutoffs. Similarly, cardiovascular mortality was elevated in patients with high NT-IGFBP-4 levels (40% vs 7.8%, P < .001) and high CT-IGFBP-4 levels (30% vs 7.4%, P < .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 [95% confidence interval (CI)] of 5.81 (95% CI 2.62-12.86) (P < .001) and 2.58 (95% CI 1.10-6.10) (P = .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 < .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 macrovascular complications. Pregnancy-associated plasma protein-A (PAPP-A) generated N- and C-terminal fragments of IGF binding protein-4 (NT-IGFBP-4 and CT-IGFBP-4) have been suggested as cardiac biomarkers.OBJECTIVE: The objective of the study was to investigate the prognostic value of IGFBP-4 fragments in a cohort of T1D patients.DESIGN AND PATIENTS: We prospectively followed up 178 T1D patients with diabetic nephropathy and 152 T1D patients with normoalbuminuria for 12.6 (range 0.2-12.9) years.MAIN OUTCOME MEASURES: Levels of IGF-1, IGF-2, 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, 8 and 45 were due to fatal cardiovascular events, respectively. Using receiver-operating characteristic curve analyses, patients were divided into subgroups using cutoff values of 261 μg/L NT-IGFBP-4, 81 μg/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 < .001) and CT-IGFBP-4 levels (44% vs 15%, P < .001) above vs below cutoffs. Similarly, cardiovascular mortality was elevated in patients with high NT-IGFBP-4 levels (40% vs 7.8%, P < .001) and high CT-IGFBP-4 levels (30% vs 7.4%, P < .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 [95% confidence interval (CI)] of 5.81 (95% CI 2.62-12.86) (P < .001) and 2.58 (95% CI 1.10-6.10) (P = .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 < .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.
KW - Adult
KW - Biological Markers
KW - Cardiovascular Diseases
KW - Cause of Death
KW - Diabetes Mellitus, Type 1
KW - Diabetic Nephropathies
KW - Female
KW - Follow-Up Studies
KW - Humans
KW - Insulin-Like Growth Factor Binding Protein 4
KW - Male
KW - Middle Aged
KW - Peptide Fragments
KW - Pregnancy
KW - Prognosis
KW - Risk Factors
U2 - 10.1210/jc.2015-2196
DO - 10.1210/jc.2015-2196
M3 - Journal article
C2 - 26046968
VL - 100
SP - 3032
EP - 3040
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 8
ER -
ID: 150710509