Osteoprotegerin, osteopontin and osteocalcin are associated with cardiovascular events in type 2 diabetes: insights from EXSCEL

Objective. To evaluate the association between four bone metabolism biomarkers (osteoprotegerin, osteopontin, sclerostin and osteocalcin) with cardiovascular events in people with type 2 diabetes.

Research Design and Methods. EXSCEL was a randomized clinical trial evaluating the cardiovascular safety and efficacy of once-weekly exenatide in type 2 diabetes. Candidate biomarker data was selected from proteomic profiling performed in baseline and 12 months after randomization samples by SomaScan assay in 5473 trial participants. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE). Cox proportional-hazards models controlling for confounders were used for time-to-event analyses to calculate hazard ratios (HR) with 95% confidence intervals (CI) for a 1 standard deviation increase in the biomarker concentrations.

Results. The primary outcome occurred in 813 (14.9%) participants. Higher levels of osteoprotegerin (HR 1.11, 95% CI 1.03–1.20, P=0.0047) and osteopontin (HR 1.10, 95% C 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 cardiovascular 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 showed a non-linear association with all-cause death and with cardiovascular death.

Conclusions. Higher levels of osteoprotegerin and osteopontin are associated with an increased risk of cardiovascular events in people with type 2 diabetes, supporting the hypothesis that pathways involved in bone metabolism play a role in cardiovascular disease.