Effect of Homocysteine-Lowering Nutrients on Blood Lipids: Results from Four Randomised, Placebo-Controlled Studies in Healthy Humans

PLoS Medicine

May 2005

DOI: 10.1371/journal.pmed.0020135

Citations:101

Influential Citations:10

Interventional (Human) Studies

Enhanced Details

Methods

Four placebo-controlled, randomized studies in healthy adults. Study 1: double-blind, parallel design; 36 participants (15 men, 21 women), aged 30-50. Study 2: parallel design; participants healthy adults; sample size not specified. Study 3: double-blind, cross-over; 40 participants (23 men, 17 women), aged 50-70. Study 4: cross-over; 26 men aged 50-71. Studies measured homocysteine; lipid measurements were post-hoc in some studies; protocols followed CONSORT guidelines; randomization and blinding procedures described.

Intervention

Betaine: 6 g/day for 6 weeks; two daily doses (3 g after breakfast and 3 g after dinner) dissolved in water. Lower doses 1.5 g/day and 3 g/day for 6 weeks also tested (two daily portions). Folic acid: 0.8 mg/day for 6 weeks; two daily portions after breakfast and dinner; dissolved in water. Phosphatidylcholine: 2.6 g/day of choline from phosphatidylcholine for 2 weeks; two daily portions after meals; taken with custard. Phosphatidylcholine lecithin (PhosChol Nutrasal): 34.0 g/day lecithin providing ~2.6 g choline for 2 weeks; two half-doses per day; fat content matched with placebo; taken with custard.

Results

Betaine 6 g/day for 6 weeks increased LDL cholesterol by 0.36 mmol/L (~11%), total cholesterol by 0.42 mmol/L, and triglycerides by 0.14 mmol/L; HDL unchanged; LDL rise observed within 2 weeks. Lower betaine doses (1.5 g/d and 3 g/d) increased LDL but not significantly. Folic acid 0.8 mg/day for 6 weeks had no effect on lipid concentrations. Phosphatidylcholine 2.6 g/day for 2 weeks increased triglycerides by 0.14 mmol/L (~8%), with no change in cholesterol. Overall interpretation: betaine’s lipid-raising effects may offset its homocysteine-lowering benefits for cardiovascular health; phosphatidylcholine’s lipid effects are inconclusive but probably small; folic acid does not affect lipids and remains the preferred homocysteine-lowering option.

Limitations

Not originally powered to assess lipid outcomes; post-hoc lipid analyses; small-to-moderate sample sizes; cross-over designs with potential carryover; short study durations; different lipid measurement matrices across studies; generalizability limited to healthy adults.

Abstract

Background Betaine (trimethylglycine) lowers plasma homocysteine, a possible risk factor for cardiovascular disease. However, studies in renal patients and in obese individuals who are on a weight-loss diet suggest that betaine supplementation raises blood cholesterol; data in healthy individuals are lacking. Such an effect on cholesterol would counteract any favourable effect on homocysteine. We therefore investigated the effect of betaine, of its precursor choline in the form of phosphatidylcholine, and of the classical homocysteine-lowering vitamin folic acid on blood lipid concentrations in healthy humans. Methods and Findings We measured blood lipids in four placebo-controlled, randomised intervention studies that examined the effect of betaine (three studies, n = 151), folic acid (two studies, n = 75), and phosphatidylcholine (one study, n = 26) on plasma homocysteine concentrations. We combined blood lipid data from the individual studies and calculated a weighted mean change in blood lipid concentrations relative to placebo. Betaine supplementation (6 g/d) for 6 wk increased blood LDL cholesterol concentrations by 0.36 mmol/l (95% confidence interval: 0.25–0.46), and triacylglycerol concentrations by 0.14 mmol/l (0.04–0.23) relative to placebo. The ratio of total to HDL cholesterol increased by 0.23 (0.14–0.32). Concentrations of HDL cholesterol were not affected. Doses of betaine lower than 6 g/d also raised LDL cholesterol, but these changes were not statistically significant. Further, the effect of betaine on LDL cholesterol was already evident after 2 wk of intervention. Phosphatidylcholine supplementation (providing approximately 2.6 g/d of choline) for 2 wk increased triacylglycerol concentrations by 0.14 mmol/l (0.06–0.21), but did not affect cholesterol concentrations. Folic acid supplementation (0.8 mg/d) had no effect on lipid concentrations. Conclusions Betaine supplementation increased blood LDL cholesterol and triacylglycerol concentrations in healthy humans, which agrees with the limited previous data. The adverse effects on blood lipids may undo the potential benefits for cardiovascular health of betaine supplementation through homocysteine lowering. In our study phosphatidylcholine supplementation slightly increased triacylglycerol concentrations in healthy humans. Previous studies of phosphatidylcholine and blood lipids showed no clear effect. Thus the effect of phosphatidylcholine supplementation on blood lipids remains inconclusive, but is probably not large. Folic acid supplementation does not seem to affect blood lipids and therefore remains the preferred treatment for lowering of blood homocysteine concentrations. show less