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

Research output: Contribution to journalJournal articleResearchpeer-review


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.

Original languageEnglish
JournalJournal of Clinical Endocrinology and Metabolism
Issue number8
Pages (from-to)3032-3040
Number of pages8
Publication statusPublished - 1. Aug 2015


  • Adult
  • Biomarkers/blood
  • Cardiovascular Diseases/blood
  • Cause of Death
  • Diabetes Mellitus, Type 1/blood
  • Diabetic Nephropathies/blood
  • Female
  • Follow-Up Studies
  • Humans
  • Insulin-Like Growth Factor Binding Protein 4/blood
  • Male
  • Middle Aged
  • Peptide Fragments/blood
  • Pregnancy
  • Prognosis
  • Risk Factors


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