Osteoprotegerin, Osteopontin, and Osteocalcin Are Associated With Cardiovascular Events in Type 2 Diabetes: Insights From EXSCEL

OBJECTIVE To evaluate the association of four bone metabolism biomarkers (osteoprotegerin, osteopontin, sclerostin, and osteocalcin) with cardiovascular events in people with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) was a randomized clinical trial evaluating the cardiovascular (CV) safety and efficacy of once-weekly exenatide for patients with T2D. Candidate biomarker data were selected from proteomic profiling performed at baseline and 12 months after randomization samples by SomaScan assay in 5,473 trial participants. The primary composite outcome was the first occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke (major cardiovascular events [MACE]). Cox proportional hazards models controlling for confounders were used for time-to-event analyses to calculate hazard ratios (HRs) with 95% CI for a 1 SD increase in the biomarker concentrations. RESULTS The primary outcome occurred in 813 participants (14.9%). Higher levels of osteoprotegerin (HR 1.11; 95% CI 1.03-1.20; P = 0.0047) and osteopontin (HR 1.10; 95% CI 1.02-1.18; P = 0.0095) were associated with an increased risk of MACE. The addition of osteoprotegerin and osteopontin to a clinical predictive model containing traditional CV risk factors provided minimal incremental value for MACE prediction (C-index 0.629 vs. 0.638; likelihood ratio test P < 0.001). Osteocalcin and sclerostin were not associated with MACE. Osteocalcin had a nonlinear association with all-cause death and with CV death. CONCLUSIONS Higher levels of osteoprotegerin and osteopontin are associated with an increased risk of CV events in people with T2D, supporting the hypothesis that pathways involved in bone metabolism play a role in CV disease.