IGFBP-4 Fragments as Markers of Cardiovascular Mortality in Type 1 Diabetes Patients With and Without Nephropathy
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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 language | English |
|---|---|
| Journal | The Journal of Clinical Endocrinology & Metabolism |
| Volume | 100 |
| Issue number | 8 |
| Pages (from-to) | 3032-40 |
| Number of pages | 9 |
| ISSN | 0021-972X |
| DOIs | |
| Publication status | Published - Aug 2015 |
- Adult, Biological Markers, Cardiovascular Diseases, Cause of Death, Diabetes Mellitus, Type 1, Diabetic Nephropathies, Female, Follow-Up Studies, Humans, Insulin-Like Growth Factor Binding Protein 4, Male, Middle Aged, Peptide Fragments, Pregnancy, Prognosis, Risk Factors
Research areas
ID: 150710509