Coronary heart disease (CHD) is one of the most prevalent and high-impact complications related to type 2 diabetes mellitus (T2D) [1
]. In the general population, magnesium (Mg) deficiency might be associated with a greater risk of CHD; however, data on the inverse associations between Mg status and intake and CHD are inconsistent [3
]. In T2D, the prevalence of hypomagnesemia is increased 14–48%, compared with 3–15% in those without T2D [10
]. This could partly be due to increased urinary Mg excretion caused by insulin resistance, and partly due to poor dietary Mg intake [10
]. However, surprisingly few studies report on the association between Mg and CHD in patients with established T2D [14
In the DIAbetes and LifEstyle Cohort Twente (DIALECT), we collected extensive data on dietary Mg intake, 24 h urinary Mg excretion, and plasma Mg concentration. We aimed to study the association between the parameters of Mg (i.e., dietary Mg intake, 24 h urinary Mg excretion, and serum Mg concentration) and CHD. When we found that dietary Mg intake was inversely associated with CHD risk, we also explored whether there was an association between Mg intake from specific dietary sources (i.e., cereals, potatoes, etc.) and CHD risk.
In total, 450 patients with T2D were included in DIALECT-1. Baseline characteristics are shown in Table 1
. In short, patients were 63 ± 9 years old, and the majority of the population was male (57%). The population represents T2D in secondary health care, with a median diabetes duration of 11 (7–18) years, and a high prevalence of diabetic nephropathy (42%).
There were 100 (22%) CHD cases diagnosed in our population (Table 1
). T2D patients with CHD were older (66 ± 7 vs. 62 ± 9 years, p
< 0.001), were more often men (71% vs. 54%, p
= 0.003), and more often had peripheral artery disease (44% vs. 20%, p
< 0.001), and nephropathy (58% vs. 38%, p
< 0.001) than patients without CHD. There were no differences in lifestyle parameters between those with and without CHD. Regarding pharmacological treatment, those with CHD more often used beta-blockers (77% vs. 37%, p
< 0.001), and loop diuretics (33% vs. 14%, p
< 0.001) than those without CHD. This was paralleled by a lower diastolic blood pressure (72 ± 10 mmHg vs. 75 ± 9 mmHg, p
= 0.01) and heart rate (69 ± 11 beats/min vs. 75 ± 13 beats/min, p
< 0.001) in patients with CHD. Systolic blood pressure was 136 ± 16 mmHg, and did not differ between the groups. Although patients with CHD more often used statins (86% vs. 73%, p
= 0.006), serum LDL was similar in the groups (2.0 ± 0.7 mmol/L), and serum HDL cholesterol was lower in those with CHD (1.0 ± 0.3 mmol/L vs. 1.2 ± 0.4 mmol/L, p
< 0.001) compared to those without CHD.
Mean energy-adjusted dietary Mg intake was 305 ± 46 mg/day, and was lower in those with CHD (adjusted standardized beta = −0.14, p
= 0.003). Mean 24 h urinary Mg excretion was 3.94 ± 2.05 mmol/24 h, and mean plasma Mg concentration was 0.77 ± 0.09 mmol/L; neither differed statistically significantly between those with and without CHD (Table 1
). Hypomagnesemia (plasma Mg < 0.7 mmol/L) was present in 73 patients (17%), of which 11 patients (3%) had a plasma Mg of <0.6 mmol/L.
Dietary Mg intake was significantly correlated with 24 h urinary Mg excretion (Pearson R = 0.24, p < 0.001), but not with plasma Mg (R = 0.02, p = 0.64). 24 h urinary Mg excretion was significantly correlated with plasma Mg (R = 0.13, p < 0.008).
Systolic blood pressure was lowest in the highest gender-specific quartile of energy-adjusted magnesium intake (4th quartile 133 ± 13 vs. 1st quartile 137 ± 17 mmHg; Supplementary Table S2
), and the number of antihypertensive drugs used was lowest in this quartile as well (4th quartile 2 (0–3) vs. 2 (1–3) in other quartiles, p
= 0.008). Serum HbA1c and cholesterol levels were similar in all Mg intake quartiles. There was a trend towards higher urinary potassium excretion, dietary calcium, fiber, protein, and carbohydrate intake, as well as a lower dietary intake of fat in each of the higher quartiles of magnesium intake.
3.1. Association between Dietary Magnesium Intake, 24 h Urinary Magnesium Excretion, Plasma Magnesium Concentration, and the Prevalence of Coronary Heart Disease
The highest quartile of Mg intake was significantly associated with a lower prevalence ratio (PR) of CHD than the lowest quartile of Mg intake (0.40 (0.20, 0.77); Table 2
). When adjusting for age and lifestyle parameters (BMI, smoking, alcohol, and physical activity), the PR remained largely unchanged (0.42 (0.22, 0.82)). After adjustment for dietary intake of other micronutrients (total energy intake, sodium, and potassium), the PR became (0.40 (0.20, 0.79)), and the p
-trend was 0.01.
There was a similar trend towards a lower prevalence of CHD in the highest quartile of 24 h urinary Mg excretion, which was not statistically significant (PR 0.63 (0.33, 1.19)). After adjustment for lifestyle and nutritional factors, the PR remained similar (0.63 (0.32, 1.26)). Also, the highest quartile of plasma Mg concentration had a non-significant trend towards a lower prevalence of CHD (unadjusted PR 0.60 (0.31, 1.14), adjusted PR 0.62 (0.32, 1.20)). The PR ratios for dietary Mg intake, urinary Mg excretion and plasma Mg concentration did not change after further adjustment for other classic CHD risk factors, namely systolic blood pressure and LDL cholesterol (data not shown).
3.2. Analysis on Source of Magnesium Intake and Prevalence of CHD
We performed an explorative analysis whether there was an association between Mg intake from specific dietary sources and CHD. The largest dietary contributors to total dietary Mg intake for patients with T2D (Figure 1
) were cereals at 22% (16–26%), dairy at 14% (10–20%), coffee at 9% (6–13%), potatoes at 7% (4–10%), meat at 6% (5–8%), legumes and nuts at 6% (4–11%), fruit at 5% (3–8%), and vegetables with 3% (2–5%). We found no statistically significant association between Mg intake from specific food groups and CHD (Table 3
). However, there was a non-significant trend towards a lower prevalence of CHD for every 10 mg increase of dietary Mg intake derived from vegetables (PR 0.75 (0.52, 1.08)).
We found inverse associations for dietary Mg intake, 24 h urinary Mg excretion, and plasma Mg concentration with the prevalence of CHD in patients with T2D. As far as we know, this is the first study in T2D patients which simultaneously reports on these three Mg parameters in relation to CHD. The inverse association between dietary Mg intake and the prevalence of CHD we found was strongest for Mg intake derived from vegetables, albeit not statistically significant.
The mean dietary Mg intake we report (305 ± 46 mg/day) was somewhat lower than the median Mg intake in the general Dutch population, which is around 350 mg/day [22
], but was comparable to median Mg intake of population studies in the U.S. (308 mg/day) [4
]. We found that in the Dutch population, cereals, dairy, and coffee intake were the largest contributors to total Mg intake, at 22%, 14%, and 9% respectively. This was somewhat different from the U.K. population, where cereals (34%), meat (19%), and dairy (18%) intake were the most important contributors [23
]. In contrast, in the U.S. population the most important food groups were vegetables (13%), milk (8%), and meat (7%) [24
]. It should be noted that different groupings of food products renders a head-to-head comparison between these percentages difficult. The 24 h urinary Mg excretion we report (4.0 ± 2.1 mmol/24 h) was in line with the general population the Netherlands (4.2 ± 1.7 mmol/24 h for men and 3.5 ± 1.4 mmol/24 h for women) [5
]. Plasma Mg concentration (0.77 ± 0.09 mmol/L) was similar to an earlier report about Dutch diabetes patients (0.74 ± 0.10 mmol/L) [25
]. The prevalence of hypomagnesemia we found (17%) was in the range of the reported prevalence of hypomagnesemia in patients with T2D, between 14% and 48% [10
], and emphasizes that clinical vigilance for hypomagnesemia is warranted in T2D, because it is associated with increased insulin resistance and faster renal function decline [26
We are the first to report an inverse association between dietary Mg intake and the prevalence of CHD in T2D. In contrast, a large meta-analysis in non-T2D patients demonstrated no association between dietary Mg intake and incident CHD [9
]. However, low dietary Mg intake was associated with a higher risk of stroke, heart failure, new-onset diabetes, and all-cause mortality [9
]. It is known that in T2D renal wasting of Mg occurs [27
]. Additionally, Mg supplementation in T2D can improve insulin sensitivity and metabolic control [28
]. Possibly, an adequate Mg intake in patients with T2D is even more important than in those without T2D, in order to maintain an adequate Mg status and prevent diabetes-related complications. These data fuel the hypothesis that magnesium intake is beneficial in T2D patients.
In addition, when investigating Mg intake from specific food sources, we found the strongest inverse association between Mg derived from vegetables and CHD, albeit not quite reaching statistical significance. To our knowledge, the association with vegetable-derived Mg intake and CHD has not been described before. When studying Mg intake and Mg status, it is important to consider bioavailability of ingested Mg for intestinal uptake, as this might vary considerably depending on the source of Mg intake [29
]. Possibly, bioavailability from Mg in vegetables is greater than from other food sources; however, this issue would have to be addressed an in-depth mechanistic study. Nevertheless, our data illustrate that when studying the association between micronutrients and outcomes, intake of different food groups is also important. As vegetable intake in our population was low [30
], and vegetable intake only accounted for 3% of total Mg intake in this population, increasing vegetable intake is a good opportunity to not only increase Mg intake, but also to improve overall diet quality. It should be noted that in our study, it is difficult to distinguish between the protective effects of overall vegetable intake and those from vegetable-derived Mg intake. Other vegetable-derived components like antioxidants, but also potassium and vitamin K, might contribute to or interact with Mg in the eventual association with CHD [31
]. Maybe the possible cohort effect from these micronutrients and Mg could amplify such protection. Since such an analysis is beyond the scope and available data of the current study, future studies are necessary to further investigate mechanisms behind vegetable intake and risk of coronary heart disease.
Additionally, we found that lower 24 h urinary Mg excretion was associated with more prevalent CHD. In line with this finding, in the general population an inverse association between Mg excretion and CHD was reported [5
]. Potential renal Mg wasting in T2D renders the interpretation of urinary Mg excretion difficult. High urinary Mg excretion could, on the one hand, reflect a high dietary Mg intake; on the other hand, though, it could reflect the hypermagnesuria found in T2D [10
]. This could explain why, in our cohort, dietary Mg intake is more strongly associated with CHD than 24 h urinary excretion.
In parallel, lower plasma Mg concentration was also associated with prevalent CHD. In T2D, the association between plasma Mg concentration and CHD was investigated previously, and conflicting results were reported [14
]. In non-T2D subjects, conflicting results on the association between plasma Mg have been reported as well; however, a meta-analysis demonstrated an inverse association between plasma Mg and incident CHD [8
]. As Mg is mainly an intracellular cation, and therefore plasma Mg only reflects 1% of bodily Mg stores, the validity of using plasma Mg as a marker for Mg status has been questioned; Mg deficiency has been reported in patients without overt hypomagnesemia [11
Our paper was not designed to unravel mechanisms behind the inverse associations between Mg intake, Mg status, and CHD. However, several mechanisms have been proposed that could underlie this association. First, animal studies have consistently shown that higher Mg status inhibits vascular calcification [36
]. In human subjects, serum Mg and dietary Mg intake were inversely associated with the degree of coronary calcification [4
]. Second, low Mg status might be associated with cardiac arrhythmias [38
]. Lastly, increased CHD risk might be mediated through the association between low Mg status or intake and increased traditional CHD risk factors, such as blood pressure [39
] and insulin resistance [12
Our paper is the first to simultaneously report the association between dietary Mg intake, factors of Mg status (24 h urinary Mg excretion and plasma Mg), and CHD in patients with established T2D. The robustness of our findings is established through the fact that all three Mg parameters were inversely associated with CHD. The main limitation of our paper is the cross-sectional design, which only allowed us to study associations and not causality, and therefore there is a risk of reverse causality bias. Another limitation is that the FFQ we used in our study was not validated to estimate magnesium intake. However, because there was a moderate correlation between dietary Mg intake and urinary Mg excretion, we deemed the results sufficiently valid.
Our study has several clinical implications. First, we show that Mg intake is of the utmost importance with relation to T2D. Patients with T2D are at risk of developing hypomagnesemia, as Mg intake in our population was somewhat lower in comparison to the general population. Additionally, patients with T2D have increased renal Mg excretion [27
]. We show that Mg intake and Mg status is reduced in those with CHD, possibly indicating that higher Mg intake is associated with a lower risk of CHD. The best opportunity to increase Mg intake is to increase intake of Mg-rich vegetables. As Mg intake in the highest quartile is approximately 100 mg/day higher than in the lowest quartile, in clinical practice this could correspond with increasing vegetable intake by, for example, 200 g spinach, or 100 g rucola lettuce and two avocados per day. Alternatively, previous research has shown that several dietary patterns might reduce CHD risk or improve cardiac function, such as the Mediterranean diet; the Dietary Approaches to Stop Hypertension diet; or a high-protein, intermittent fasting, low-calorie diet [40
]. We add to these findings by illustrating that Mg is an important component in such diets. For future studies, it would be of interest to investigate how Mg and other beneficial nutritional approaches could reinforce each other in the pursuit of the reduction of CHD in diabetes patients. Additionally, future mechanistic studies should be done to investigate how vegetable-derived nutrients, particularly Mg, might reduce CHD risk.