Chapter 7 164 supplementation in an unhealthier population 35, prompted us to examine the effect of magnesium in several subgroups, such as older and obese individuals and individuals with more severe arterial stiffness at baseline. In a subgroup with higher baseline arterial stiffness, we observed a beneficial effect of magnesium sulfate supplementation on arterial stiffness. Magnesium citrate and magnesium oxide supplementation tended to decrease arterial stiffness in this subgroup as well, albeit without reaching statistical significance. Although the subgroup analyses should be interpreted with caution as it was not prespecified in the study protocol, this result suggests that magnesium might be effective in a population with more severe prevalent arterial stiffness. Moreover, extending the treatment duration might also be effective, as several meta-analyses found a more pronounced effect of magnesium supplementation on vascular function markers and blood pressure in studies with longer treatment durations 28,35. Individuals with increased arterial stiffness include, but are not limited to, patients with T2D and CKD 36–38. Increased arterial stiffness is generally considered a marker of vascular calcification 39. As T2D and CKD patients are prone to vascular calcification, they may be better populations to study effects of magnesium supplementation on vascular calcification. Vascular calcification naturally develops with advancing age, but develops earlier and slightly differently in T2D and CKD patients compared to the general population 40. In T2D patients, hyperglycemia and formation of advanced glycation end products likely add to the progressive increase in arterial stiffness 41. In CKD patients, high levels of phosphate and calcium are strongly associated with vascular calcification 42. Preclinical studies have described several mechanisms by which magnesiummay play a role in the prevention of vascular calcification in CKD 23,43,44. First, magnesium is able to bind phosphate in the intestine and thereby reducing phosphate uptake 45. However, the extent to which magnesium is able to bind phosphate is suggested to be quite low. Second, magnesium is able to inhibit the formation of calciprotein particles (CPPs), which are potent inducers of vascular calcification and are formed by phosphate and calcium particles 46. However, magnesium seems to be incapable of reversing vascular calcification once CPPs are formed, suggesting that magnesium is particularly effective in halting the calcification process. Third, magnesium may inhibit differentiation of vascular smooth muscle cells into osteoblast-like cells and thereby protecting against vascular calcification 47.Whether these specific effects can be translated towards patients as well as towards the general population, must be further examined. In addition, RCTs with longer follow-ups are needed to closely monitor changes in vascular calcification and the potential inhibiting effect of magnesium supplementation. Finally, we assessed arterial remodelling by means of c-fPWV, which measures arterial stiffness, but does not
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