A systematic review and meta-analysis published in Frontiers in Nutrition assessed the impact of magnesium and either vitamin D or vitamin E co-supplementation on inflammation and markers of lipid metabolism among people with overweight or obesity. Nine randomized and controlled trials (RCTs) and roughly 500 study participants were included. Four RCTs evaluated co-supplementation with magnesium and vitamin D (228 total participants), and five evaluated magnesium with vitamin E (272 participants). Subgroup analysis found that magnesium combined with vitamin D significantly reduced high-sensitivity C-reactive protein (hs-CRP) (pooled MD (mean difference) of −0.66), and tumor necrosis factor-α (TNF-α, MD of −0.87), but not interleukin-6 (IL-6) levels. No significant effects were observed for co-supplementation of vitamin E with magnesium on hs-CRP, triglycerides, LDL-cholesterol, or HDL-cholesterol, and no evidence of publication bias was detected in the RCTs.
The doses between the included RCTs also varied widely and were associated with some of the measured outcomes. In the two studies that used a higher dose of vitamin D (50,000 IU given once per week orally), serum 25-hydroxy vitamin D (25(OH)D) levels increased significantly compared to controls, while at the lower doses used in the other two trials (400 to 1000 IU per day), serum levels did not significantly change.
Although this systematic review did not compare magnesium or vitamin D alone to their combined use (i.e., the placebo groups did not contain magnesium or vitamin D), previous studies have done so, and there is some reason to think that there are advantages to using them in combination for some patients. Magnesium status affects the concentration of cytochrome P450 enzymes, including those involved in vitamin D metabolism (e.g., 5-hydroxylase (CYP2R1), 1α-hydroxylase (CYP27B1), 24-hydroxylases (CYP24A1 and CYP3A4). These magnesium-dependent enzymes activate vitamin D to its more biologically active form and also degrade active vitamin D in the liver and kidneys; vitamin D metabolism is thus dependent on adequate magnesium status.
For example, the American Journal of Clinical Nutrition published a 2x2 factorial RCT in 2018 with 180 participants (not included in the systematic review), funded by the National Cancer Institute, which found that magnesium supplementation interacted with baseline serum 25(OH)D status. Specifically, magnesium supplementation significantly altered plasma 25(OH)D3 concentrations, depending on baseline plasma 25(OH)D levels. In this study, magnesium lowered 25(OH)D3 and 24,25(OH)2D3 when 25(OH)D was higher (30 to 50 ng/mL) but increased 25(OH)D3 when 25(OH)D was lower (< 30 ng/mL). Magnesium supplementation also increased 25(OH)D2 as baseline 25(OH)D concentrations increased, with the authors of this study concluding that “optimal magnesium status may be important for optimizing 25(OH)D status”.
In another example, the journal Nutrition published an RCT in 2022 (included in the systematic review) with three treatment arms: a placebo group, a vitamin D-only group (1000 IU D3 per day), and a combination group receiving magnesium (glycinate, 360 mg per day) and vitamin D (1000 IU D3). The 12-week trial included 95 participants with overweight or obesity, with 25(OH)D and parathyroid hormone levels as the primary outcomes, and secondary outcomes related to cardiometabolic profiles, including multiple inflammatory markers and blood pressure. In this study, the participants who received the combination of vitamin D and magnesium had the largest increase in 25(OH)D. Additionally, participants in the combination group with systolic blood pressure > 132 mmHg had a significant decrease of 7.5 mmHg. No significant effects on inflammatory markers or parathyroid hormone levels were observed.
Older studies suggest that among people with magnesium deficiency, levels of biologically active vitamin D (1,25-(OH)2D) are frequently low, as are serum levels of vitamin D binding protein (aka GC-globulin). NHANES data also indicate that a high total intake of magnesium (including dietary or supplemental intake) is independently associated with a lower risk of both vitamin D deficiency and insufficiency, and this inverse association is particularly prominent among people at higher risk for vitamin D insufficiency. Importantly, NHANES data suggest that the inverse association between 25(OH)D and mortality (primarily because of cardiovascular disease and colorectal cancer) was modified by magnesium intake, but this was true mostly among people with magnesium intakes above the median. More recent NHANES data found that higher magnesium intake was associated with better cognitive function, as assessed by the Digit Symbol Substitution Test, and that this association was stronger among people with sufficient vitamin D status. An interaction between vitamin D status and magnesium was also observed in relation to handgrip strength among older adults. Per this NHANES analysis, low magnesium intake was associated with low handgrip strength, but only among people with deficient vitamin D status.
These studies strongly suggest that magnesium plays a critical role in vitamin D metabolism, with implications for important clinical risk factors, including associations with inflammatory markers, 25(OH)D status, blood pressure, handgrip strength, cognitive function, and even mortality risk. It’s also worth noting that insufficiencies of either or both of these nutrients are very common, with NHANES data indicating that nearly 80% of people in the U.S. have magnesium intakes below the RDA, and 65% have either vitamin D insufficiency or deficiency. Patients with cardiometabolic risk, overweight, or obesity have amplified risk, and co-supplementation of these complementary nutrients should be considered.
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