I read with great interest the article by Maddaloni et al. (1), which was recently published in Diabetes Care. In this study, the authors analyzed data from the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial, a large cardiovascular outcomes study, to investigate the relationship between bone metabolism biomarkers and major adverse cardiovascular events in individuals with type 2 diabetes. They found that higher levels of osteoprotegerin and osteopontin were independently associated with increased cardiovascular risk, while osteocalcin exhibited a nonlinear relationship with mortality. I commend the authors for their significant contributions and offer the following suggestions for future research.
First, while the study identifies an association between osteoprotegerin and osteopontin with cardiovascular events, the observational design of the study precludes the establishment of causality. Future research should include randomized controlled trials or Mendelian randomization studies to validate the causal role of these biomarkers in cardiovascular events. Second, the study population was predominantly individuals with type 2 diabetes, 72.4% of whom had a history of prior cardiovascular events. This limits the generalizability of the findings. Consequently, the findings of the study cannot be directly applied to individuals with diabetes without a history of cardiovascular disease or those with other forms of diabetes, such as type 1 diabetes. It is recommended that further studies be conducted in diverse populations to better assess the role of these biomarkers across different risk groups. Third, the study used the SomaScan platform to measure biomarker concentrations. Despite the high sensitivity and specificity demonstrated by this platform, it is important to note that differences in measurement methods across different platforms, as well as variations in biomarker concentrations influenced by experimental error or platform limitations, may occur (2). Future research should therefore aim to standardize biomarker measurement techniques across different platforms to enhance the robustness of the results.
Given the well-established interplay between diabetes, bone metabolism, and cardiovascular disease, further research is crucial to determine whether these biomarkers play a causal role in cardiovascular pathology or merely serve as indicators of underlying processes. Establishing their clinical relevance across diverse patient populations could enhance cardiovascular risk stratification in individuals with type 2 diabetes. Moreover, standardizing biomarker measurement methods across platforms would improve reproducibility and facilitate their potential integration into clinical practice. Such advancements could ultimately lead to novel therapeutic targets and more precise cardiovascular risk assessment strategies for patients with diabetes.
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Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Handling Editors. The journal editors responsible for overseeing the review of the manuscript were Steven E. Kahn and Vanita R. Aroda.
