Literature Review and Commentary

By Alan R. Gaby, MD

Potassium May Improve Glucose Metabolism

Twenty-seven mostly obese African American adults (mean age, 55 years; mean body mass index, 34.7 kg/m²) with prediabetes and a serum potassium level of 3.3-4.0 mEq/L were randomly assigned to receive, in double-blind fashion, 1,564 mg per day of potassium (as potassium chloride) in capsule form in two divided doses per day or placebo (maltodextrin) for three months. Participants in both groups gained weight during the study, with an overall mean weight gain of 1.24 kg. At the end of the study, compared with baseline, the mean fasting blood glucose level fell by 1.1 mg/dl in the potassium group and increased by 6.1 mg/dl in the placebo group (p = 0.03 for the difference in the change between groups). There was a trend (p = 0.086) toward greater insulin sensitivity in the potassium chloride group than in the placebo group during an oral glucose tolerance test.

Comment: Potassium is known to play a role in glucose metabolism. The typical American diet contains suboptimal amounts of this mineral, which is found mainly in fruits and vegetables. A dietary survey of 12,581 adults in the United States revealed that less than 2% consumed at least 4.7 g per day of potassium (the current Adequate Intake level).¹ Population groups that tend to have relatively low potassium intake include teenage girls and young women, African Americans, and the elderly.

The results of the present study suggest that consuming adequate amounts of potassium could help prevent type 2 diabetes. Potassium supplementation might also improve glycemic control in some people with type 2 diabetes. However, potassium should be used with caution in diabetics, because hyperkalemia is common in this patient population, being observed in one study in 15% of patients attending a diabetes clinic.² Therefore, renal function and serum potassium should be determined in diabetic patients before recommending an increase in potassium intake through diet or supplements.

Chatterjee R, et al. Effects of potassium supplements on glucose metabolism in African Americans with prediabetes: a pilot trial. Am J Clin Nutr. 2017;106:1431-1438.

Potassium and Magnesium May Enhance Recovery After a Stroke

Two hundred ninety-one Taiwanese patients who had recently been discharged from the hospital after a stroke were studied. Exclusion criteria included poor renal function (glomerular filtration rate less than 60 ml per minute) and the use of potassium-sparing medicines. The patients were randomly assigned to receive, in double-blind fashion, regular salt, potassium-enriched salt (K salt: 50% NaCl, 50% KCl), or potassium- and magnesium-enriched salt (K/Mg salt: 42.85% NaCl, 42.85% KCl, and 14.3% magnesium sulfate heptahydrate) for six months. It was assumed that patients would consume about 6.5 g per day of table salt (in addition to soy sauce and other salt-containing condiments). At that level of intake, the daily amounts provided would be: regular salt, 2,555 mg of sodium; K salt, 1,278 mg of sodium and 1,701 mg of potassium; K/Mg salt, 1,094 mg of sodium, 1,752 mg of potassium, and 92 mg of magnesium. After adjustment for baseline neurologic status, as compared with the group consuming regular salt, the odds ratio of having good neurologic performance at six months was 1.60 for K salt (p = 0.26) and 2.21 for K/Mg salt (p = 0.052).

Comment: This study suggests that increasing potassium and magnesium intake while decreasing sodium intake may aid in the neurologic recovery of stroke patients. The results were only of borderline statistical significance, so a larger study should be conducted to confirm the findings. The extent to which each of these dietary changes (more potassium, more magnesium, and less sodium) contributed to the observed benefit is not clear. In Taiwan, as in the United States, a large proportion of the population consumes suboptimal amounts of potassium and magnesium and excessive amounts of sodium.

Pan WH, et al. Intake of potassium- and magnesium-enriched salt improves functional outcome after stroke: a randomized, multicenter, double-blind controlled trial. Am J Clin Nutr. 2017;106:1267-1273.

Metformin Can Cause Vitamin B12 Deficiency

Three hundred ninety insulin-treated patients with type 2 diabetes were treated with metformin or placebo for 52 months. Compared with placebo, metformin significantly increased the mean serum concentration of methylmalonic acid. The increase in methylmalonic acid levels was associated with a significant increase in the severity of polyneuropathy.

Comment: Metformin is widely used to treat type 2 diabetes and polycystic ovary syndrome. This drug has been reported to inhibit the absorption of vitamin B12 in a dose-dependent manner. Discontinuation of the drug corrected vitamin B12 malabsorption in only about half of cases. In an earlier study of 390 patients with type 2 diabetes, the prevalence of vitamin B12 deficiency was significantly higher in patients treated with 850 mg of metformin three times per day for 4.3 years than in those given placebo (9.9% vs. 2.7%; p = 0.004).³ In the new study, treatment with metformin increased serum concentrations of methylmalonic acid, which indicates a worsening of functional vitamin B12 status. The association between methylmalonic levels and severity of polyneuropathy suggests that metformin-induced vitamin B12 deficiency can increase the severity of diabetic neuropathy. Patients taking metformin should therefore have their vitamin B12 status monitored periodically or be treated prophylactically with vitamin B12 supplements.

Out M, et al. Long-term treatment with metformin in type 2 diabetes and methylmalonic acid: Post hoc analysis of a randomized controlled 4.3 year trial. J Diabetes Complications. 2018;32:171-178.

Anthocyanins Inhibit Platelet Aggregation

Sixteen healthy sedentary non-overweight Australian volunteers (mean age, 38 years) were randomly assigned to receive, in double-blind fashion, 320 mg per day of purified anthocyanins extract (from bilberry and black currant) or placebo for four weeks. After a two-week washout period, each person received the alternate treatment for an additional four weeks. Compared with baseline, anthocyanins significantly decreased ADP-induced platelet aggregation, whereas placebo had no effect.

Comment: Excessive platelet activity plays a role in the pathogenesis of cardiovascular disease, and drugs that inhibit platelet aggregation are frequently prescribed for patients who have or are at risk of developing heart disease. Several food-derived flavonoids, including anthocyanins and quercetin, have been shown to inhibit platelet aggregation. Other nutrients that inhibit platelet aggregation include omega-3 and omega-6 fatty acids, magnesium, vitamin B6, vitamin E, and vitamin C.⁴ Many of these nutrients are present in relatively large amounts in a whole-foods plant-based diet. The cardioprotective effect of such a diet might be explained in part by inhibition of platelet aggregation, although a number of other mechanisms are likely involved as well.

Thompson K, et al. The effect of anthocyanin supplementation in modulating platelet function in sedentary population: a randomised, double-blind, placebo-controlled, cross-over trial. Br J Nutr. 2017;118:368-374.

Folic acid vs. 5-Methyltetrahyrofolate (5-MTHF)

Thirty-nine healthy volunteers (mean age, 56 years) were randomly assigned to receive, in double-blind fashion, 400 µg per day of folic acid or an equimolar amount of 5-methyltetrahydrofolate (5-MTHF; 416 µg/day) in two divided doses per day for four weeks. The mean increase in the serum folate level from baseline was significantly greater in the folic acid group than in the 5-MTHF group (66.5 vs. 41.8 nmol/L; p < 0.04). The mean serum homocysteine concentration decreased to a nonsignificantly greater extent in the folic acid group than in the 5-MTHF group (13.4% vs. 7.8%; p = 0.24). There were too few participants homozygous for the MTHFR 677C→T genotype (2 in each group) to evaluate that subgroup separately.

Comment: A number of practitioners and supplement companies have argued, largely on theoretical grounds, that 5-MTHF is preferable to folic acid as a nutritional supplement.

Some manufacturers have replaced folic acid with 5-MTHF in their multivitamin products, and some practitioners are of the opinion that products containing folic acid should not be used. I have previously reviewed this controversy⁵ and concluded that the evidence is not sufficient to justify routinely switching from folic acid to 5-MTHF. Specifically, folic acid appears to be at least as effective as, and may be more effective than, 5-MTHF for lowering homocysteine levels and for treating depression, including among people homozygous for the MTHFR 677C→T genotype.⁵ The results of the new study support previous research regarding homocysteine-lowering and also suggest that folic acid is more effective than 5-MTHF for raising serum folate levels.

Sicinska E, et al. Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces serum homocysteine concentrations in older adults. Int J Food Sci Nutr. 2018;69:64-73.

High-Dose Multivitamins and Minerals Effective for Heart Patients

Some 1,708 patients aged 50 years or older (median age, 65 years) who had had a myocardial infarction at least six weeks (median, 4.6 years) previously were randomly assigned to receive, in double-blind fashion, in a 2 x 2 factorial design, a high-dose 28-component multivitamin-multimineral supplement (vitamins), EDTA chelation therapy, both treatments, or placebo. The vitamins were taken in two divided doses per day, and included (daily doses) 100 mg thiamine, 200 mg niacin/niacinamide, 50 mg pyridoxine, 800 µg folic acid, 100 µg cyanocobalamin, 400 mg pantothenic acid, 1,200 mg vitamin C, 400 IU alpha-tocopherol, 60 µg vitamin K1, 100 mg citrus bioflavonoids, 500 mg calcium, 500 mg magnesium, 20 mg zinc, 2 mg copper, 20 mg manganese, 150 µg iodine, 200 µg selenium, 200 µg chromium, and other nutrients. Intravenous treatment consisted of 40 infusions of disodium EDTA-based chelation therapy or placebo (normal saline).

The primary outcome measure was the time to first occurrence of any component of the composite endpoint of all-cause mortality, myocardial infarction, stroke, coronary revascularization, or hospitalization for angina. The results of the EDTA chelation component of the trial have been reported previously.⁶ With respect to the vitamins component of the trial, in intent-to-treat analysis, the incidence of the primary endpoint was nonsignificantly lower by 10% in the vitamins group than in the placebo group (27% vs. 30%; p = 0.21).⁷ In a pre-specified subgroup analysis of the 27% of patients who were not taking statins at baseline, the incidence of the primary endpoint was significantly lower by 37.5% in the vitamins group than in the placebo group (22.76% vs. 36.44%; p = 0.006). The incidence of the secondary endpoint of a combination of cardiovascular mortality, stroke, or recurrent myocardial infarction was 54% lower in the vitamins group than in the placebo group (p = 0.002).

Comment: In this study, administration of a high-dose multivitamin-multimineral supplement substantially decreased cardiovascular disease-related morbidity and mortality in patients with a history of a myocardial infarction who were not taking a statin drug. The compliance rate was relatively low in this study, but all patients who were enrolled were included in the analysis, regardless of whether they adhered to the treatment recommendations. The results may have been even better if only the compliant patients were included in the analysis. The benefits of this multivitamin-multimineral supplement are similar to those reported in randomized controlled trials of statin drugs. However, that finding does not prove that vitamins and minerals can be used as an effective alternative to statin drugs. A randomized controlled trial that compares these two treatments would be needed to investigate that possibility.

Issa OM, et al. Effect of high-dose oral multivitamins and minerals in participants not treated with statins in the randomized Trial to Assess Chelation Therapy (TACT). Am Heart J. 2018;195:70-77.

Magnesium for Depression

One hundred twenty-six adults (mean age, 52 years) living in Vermont with mild-to-moderate depression were randomly assigned to receive, in open-label fashion, 248 mg per day of magnesium (from 500 mg of magnesium chloride) or no treatment (control) for six weeks, and then the alternate treatment assignment for an additional six weeks. Compared with no treatment, magnesium supplementation was associated with significant improvements in measures of both depression and anxiety (p < 0.001 for each). The mean degree of improvement relative to the control period was approximately 40% for depression. Similar effects were observed regardless of age, gender, baseline severity of depression, baseline magnesium level, or use of antidepressants. Effects were observed within two weeks.

Comment: Depression is one of the known manifestations of magnesium deficiency. A previous double-blind trial found that magnesium supplementation can improve symptoms of depression in people with a low serum magnesium level.⁸ The results of the present study suggest that the beneficial effect of magnesium is not limited to people with hypomagnesemia. Serum magnesium is an unreliable indicator of magnesium nutritional status. Therefore, some people with normal serum magnesium might have depression as a result of intracellular magnesium depletion. It is also possible that magnesium improves depression through a pharmacological effect. Because magnesium is safe and inexpensive, it should be considered for adjunctive treatment of depression. In some cases, magnesium supplementation might obviate the need for antidepressant medication.

Tarleton EK, et al. Role of magnesium supplementation in the treatment of depression: A randomized clinical trial. PLoS One. 2017;12:e0180067.

Intermittent High-Dose Vitamin D Dosing Not Recommended

One hundred seven elderly individuals (mean age, 81 years) living in a long-term care facility in Colorado were randomly assigned to receive, in double-blind fashion, high-dose vitamin D3 (100,000 once a month; equivalent to about 3,300 IU per day) or standard-dose vitamin D3 (monthly placebo for those taking 400-1,000 IU per day as part of usual care, or 12,000 IU once a month for those taking less than 400 IU per day as part of usual care; thus, equivalent to approximately 400-1,000 IU per day for the standard dose) for one year. The mean serum 25-hydroxyvitamin D level at baseline was 23 ng/ml. The incidence of acute respiratory infections was significantly lower by 40% in the high-dose group than in the standard-dose group (0.67 vs. 1.11 per person-year; p = 0.02). The incidence of falls was significantly higher by 133% in the high-dose group than in the standard-dose group (1.47 vs. 0.63 per person-year; p < 0.001).

Comment: In this study, monthly high-dose vitamin D3 supplementation reduced the incidence of acute respiratory infections but increased the incidence of falls in elderly long-term care residents. At baseline, the mean vitamin D supplement dose was 229 IU per day, which suggests that many participants were consuming less than Recommended Dietary Allowance for their age group (800 IU per day). Previous studies have found that vitamin D in doses of 800 IU per day can decrease the risk of falls. In several studies, however, intermittent administration of large bolus doses of vitamin D3 significantly increased the incidence of falls. In a study in which participants received 500,000 IU as a single dose once a year for three to five years (equivalent to 1,370 IU per day) the excess falls occurred mainly in the three months after the annual vitamin D doses.⁹ That finding supports the hypothesis that subtle toxicity occurs transiently after large bolus doses of vitamin D, and results in impaired strength or balance.

Based on the available evidence, more frequent administration of lower vitamin D doses seems preferable to less frequent administration of higher doses. There is no obvious reason to expect that more frequent vitamin D dosing would attenuate the protective effect against infections that was observed in the present study.

Ginde AA, et al. High-dose monthly vitamin D for prevention of acute respiratory infection in older long-term care residents: a randomized clinical trial. J Am Geriatr Soc. 2017;65:496-503.