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J Clin Endocrinol Metab. 2015 Aug;100(8):3032-40. doi: 10.1210/jc.2015-2196. Epub 2015 Jun 5.

IGFBP-4 Fragments as Markers of Cardiovascular Mortality in Type 1 Diabetes Patients With and Without Nephropathy.

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Medical Research Laboratory (R.H., M.B., J.F.), Department of Clinical Medicine, Faculty of Health, and Faculty of Health (L.T., H.-H.P., P.R.), Aarhus University, and Departments of Heart Diseases (A.J.) and Endocrinology and Internal Medicine (J.F.), Aarhus University Hospital, DK-8000 Aarhus, Denmark; The Danish Diabetes Academy (R.H.), DK-5000 Odense, Denmark; Steno Diabetes Center (L.T., A.J., P.R.), Gentofte, DK-2820 Copenhagen, Denmark; Nordsjællands Hospital (L.T.), DK-3400 Hillerød, Denmark; Department of Medical Endocrinology (H.-H.P.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; and The Novo Nordisk Foundation Center for Basic Metabolic Research (P.R.), University of Copenhagen, DK-2300 Copenhagen, Denmark.



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.


The objective of the study was to investigate the prognostic value of IGFBP-4 fragments in a cohort of T1D 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.


Levels of IGF-1, IGF-2, IGFBP-1-4, NT- and CT-IGFBP-4, and PAPP-A at baseline.


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.


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

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