Bone Metabolism Markers Linked to Increased Cardiovascular Risk in Type 2 Diabetes, EXSCEL Study Finds

Osteoprotegerin, a regulatory protein in bone remodeling, and osteopontin, a multifunctional molecule linked to inflammation and tissue repair, are strongly associated with major adverse cardiovascular events (MACE) in the study. Elevated levels of these proteins suggest they may serve as markers or mediators of vascular calcification and inflammatory processes contributing to CV disease in T2D. The dual roles of these molecules in bone and vascular biology further emphasize their importance in the context of diabetes-related complications.

Conversely, osteocalcin, a protein primarily linked to bone formation, did not significantly affect cardiovascular outcomes in this population. While some earlier studies have hinted at a potential protective effect of osteocalcin on CV health, its role remains unclear, particularly in the context of T2D. This disparity among bone-derived markers underlines the need for further research to clarify their distinct contributions to CV risk.

To fill this knowledge gap, Ernesto Maddaloni, Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK, and colleagues aimed to evaluate the association of four bone metabolism biomarkers—osteoprotegerin, osteopontin, sclerostin, and osteocalcin—with cardiovascular events in individuals with type 2 diabetes.

The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) was a randomized clinical trial designed to assess the CV safety and efficacy of once-weekly exenatide in patients with T2D. Data on candidate biomarkers were selected from proteomic profiling conducted at baseline and 12 months after randomization, using the SomaScan assay in 5,473 trial participants.

The primary composite outcome included the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, referred to as MACE. Time-to-event analyses were performed using Cox proportional hazards models, adjusting for potential confounders, to calculate hazard ratios (HRs) for a 1 standard deviation increase in biomarker concentrations.

The study led to the following findings:

• The primary outcome occurred in 14.9% of participants.
• Higher levels of osteoprotegerin (HR 1.11) and osteopontin (HR 1.10) were associated with an increased risk of MACE.
• Adding osteoprotegerin and osteopontin to a clinical predictive model containing traditional CV risk factors provided minimal incremental value for MACE prediction (C-index 0.629 versus 0.638).
• Osteocalcin and sclerostin were not associated with MACE.
• Osteocalcin had a nonlinear association with all-cause death and with CV death.

"The findings suggest that elevated levels of osteoprotegerin and osteopontin are linked to a higher risk of cardiovascular events in individuals with type 2 diabetes, reinforcing the idea that bone metabolism pathways may contribute to the development of cardiovascular disease," the researchers concluded.

Reference:

Ernesto Maddaloni, Maggie Nguyen, Svati H. Shah, Rury R. Holman; Osteoprotegerin, Osteopontin, and Osteocalcin Are Associated With Cardiovascular Events in Type 2 Diabetes: Insights From EXSCEL. Diabetes Care 2024; dc241455. https://doi.org/10.2337/dc24-1455