General Discussion 163 7 a period of 24 weeks, 24-h urinary cortisol excretion was significantly reduced in the magnesium supplementation group, compared to the placebo group. Further analyses showed that in the magnesium group the cortisol/cortisone ratio was significantly lower compared to the placebo group, which indicates increased activity of the kidney enzyme 11β-HSD type 2, leading to increased inactivation of cortisol. These novel findings imply improved glucocorticoid metabolism after long-term magnesium citrate treatment, providing a potential mechanism underlying the beneficial effect of increased magnesium intake on cardiovascular health. Effects on arterial stiffness Arterial stiffness is strongly related to blood pressure and has been shown to be an independent predictor of cardiovascular morbidity and mortality 34. Arterial stiffness can be measured non-invasively by c-fPWV (directly) and augmentation index (indirectly). In Chapter 6, we performed a relatively large RCT in which we primary focused on effects of magnesium citrate supplementation on arterial stiffness, but now with a higher dose. As secondary aim we explored whether other inorganic magnesium formulations, including magnesium oxide and magnesium sulfate, are non-inferior to magnesium citrate in terms of effects on arterial stiffness. Secondary outcomes were blood pressure and plasma and urine magnesium. Our study is the first to perform a head-to-head comparison among various types of magnesium supplements and their effects on vascular function markers and blood pressure. We showed that supplementation with magnesium citrate for 24-wk had no effect on arterial stiffness and blood pressure and that magnesium oxide and magnesium sulfate had similar non-significant effects. Further subgroup analyses showed that in subjects with prevalent increased arterial stiffness at baseline (≥9.0 m/s) magnesium sulfate supplementation did significantly reduce arterial stiffness after 24-wk. Furthermore, magnesium citrate led to a more pronounced increase in 24-h urinary magnesium excretion than magnesium oxide and magnesium sulfate, while plasma magnesium was similar between the three groups. Our study was primarily designed to replicate a previously observed effect of magnesium supplementation on arterial stiffness in the general population 10, but now with a higher dose. Surprisingly, in contrast with the earlier trial, we found no effect of magnesium citrate on arterial stiffness. This inconsistency may be due to the differences among the study populations, with slightly healthier individuals in our study, as evident by lower mean BMI and lower total cholesterol levels. Furthermore, the current study included more women. Our non-significant findings in the total population, together with findings from a recent meta-analysis showing greater effects of magnesium
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