The main goal of our study is to test the association of baseline and time-varying serum magnesium (SMg) levels with major cardiovascular disease (CVD) events in the Systolic Pressure Intervention Trial (SPRINT) participants with and without chronic kidney disease (CKD). Hypomagnesemia has been recognized as a risk factor for CV morbidity and mortality in the general population and in patients with advanced CKD. Low extracellular Mg concentration has also been associated with endothelial cell dysfunction and vascular calcification, pathways that could contribute to CVD burden. Low SMg associates with incidence and progression of CKD via mechanisms that may include increased inflammation, insulin resistance, hypertension, and/or nephrotoxicity. Our study will be the first to specifically assess the association of longitudinal changes in SMg with CVD events in a large US cohort of patients with or without CKD. CVD events (primary outcome) consist of fatal or non-fatal myocardial infarction (MI), stroke, heart failure, non-MI acute coronary syndrome, or death attributable to CVD. A secondary renal outcome will be rate of change in eGFR (eGFR slope) from 6-month post-randomization until the end of follow-up. We expect low SMg to be associated with a higher risk for CV death and events, and a greater longitudinal decrease in eGFR in the SPRINT cohort, particularly in patients with CKD based on the higher prevalence of underlying endothelial dysfunction and comorbidity in this prespecified high-risk subgroup.
We aim to test this association with multivariable Cox proportional hazards regression models using baseline and time-varying Mg measurements, and incorporating known and putative confounders. Our study will provide new and important information including data on within-person SMg variability over time, that is critical for the design of cost-effective pragmatic interventional studies of Mg supplementation as an inexpensive therapy to mitigate CVD in high-risk CKD patients.
Compared to our knowledge on calcium and phosphate metabolism in patients with chronic kidney disease (CKD), our knowledge of how the mineral, magnesium (Mg), is regulated in the general population is poorly understood, and there are no specific guidelines for management or Mg supplementation. Low serum Mg (SMg) levels can have direct and indirect detrimental effects on the heart, blood vessels, and kidney. The examination of the utility of changes in SMg levels to evaluate patients with CKD at high risk of cardiovascular events and kidney disease progression is of paramount importance to provide solid basis for the design of prospective interventional studies, and open the possibility for Mg supplementation to become an inexpensive therapy in CKD patients.
