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Background Arterial stiffness is closely related to the process of atherosclerosis, an independent cardiovascular risk factor, and predictive of future cardiovascular events and mortality. Recently, we showed that magnesium citrate supplementation results in a clinically relevant improvement of arterial stiffness. It remained unclear whether the observed effect was due to magnesium or citrate, and whether other magnesium compounds may have similar effects. Therefore, we aim to study the long-term effects of magnesium citrate, magnesium oxide and magnesium sulfate on arterial stiffness. In addition, we aim to investigate possible underlying mechanisms, including changes in blood pressure and changes in gut microbiota diversity. Methods In this randomized, double-blind, placebo-controlled trial, a total of 162 healthy overweight and slightly obese men and women will be recruited. During a 24-week intervention, individuals will be randomized to receive: magnesium citrate; magnesium oxide; magnesium sulfate (total daily dose of magnesium for each active treatment 450 mg); or placebo. The primary outcome of the study is arterial stiffness measured by the carotid–femoral pulse wave velocity (PWV c–f ), which is the gold standard for quantifying arterial stiffness. Secondary outcomes are office blood pressure, measured by a continuous blood pressure monitoring device, and gut microbiota, measured in fecal samples. Measurements will be performed at baseline and at weeks 2, 12 and 24. Discussion The present study is expected to provide evidence for the effects of different available magnesium formulations (organic and inorganic) on well-established cardiovascular risk markers, including arterial stiffness and blood pressure, as well as on the human gut microbiota. As such, the study may contribute to the primary prevention of cardiovascular disease in slightly obese, but otherwise healthy, individuals. Trial registration ClinicalTrials.gov, NCT03632590 . Retrospectively registered on 15 August 2018.

Background: Low circulating magnesium (Mg) is associated with an increased risk of developing type 2 diabetes mellitus (T2DM). We aimed to study the performance of a nuclear magnetic resonance (NMR)-based assay that quantifies ionized Mg in EDTA plasma samples and prospectively investigate the association of Mg with the risk of T2DM. Methods: The analytic performance of an NMR-based assay for measuring plasma Mg was evaluated. We studied 5747 subjects free of T2DM at baseline in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study. Results: Passing–Bablok regression analysis, comparing NMR-measured ionized Mg with total Mg measured by the Roche colorimetric assay, produced a correlation of r = 0.90, with a slope of 1.08 (95% CI: 1.00–1.13) and an intercept of 0.02 (95% CI: −0.02–0.08). During a median follow-up period of 11.2 (IQR: 7.7–12.0) years, 289 (5.0%) participants developed T2DM. The association of NMR-measured ionized Mg with T2DM risk was modified by sex (Pinteraction = 0.007). In women, we found an inverse association between Mg and the risk of developing T2DM, independent of adjustment for potential confounders (HR: 1.80; 95% CI: 1.20–2.70). In men, we found no association between Mg and the risk of developing T2DM (HR: 0.90; 95%: 0.67–1.21). Conclusion: Lower NMR-measured plasma ionized Mg was independently associated with a higher risk of developing T2DM in women, but not in men.