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

Four randomized, placebo-controlled human studies were conducted in healthy Dutch adults without cardiovascular disease. Two studies were parallel-group trials in adults aged 30 to 50 years, one was a crossover study in adults aged 50 to 70 years, and one crossover study enrolled healthy men aged 50 to 71 years.

The active regimens were oral betaine, folic acid, and phosphatidylcholine given against placebo in four randomized studies. Betaine was tested at 6 g/d for 6 weeks in studies 1 and 3, and at 3 g/d and 1.5 g/d for 6 weeks in study 2; folic acid was 0.8 mg/d for 6 weeks in studies 1 and 3. Phosphatidylcholine was provided as 34.0 g/d of PhosChol, supplying about 2.6 g/d choline, for 2 weeks in a crossover study.

Overall, high-dose betaine worsened the lipid profile, phosphatidylcholine increased triglycerides, and folic acid was lipid-neutral. Across studies 1 to 3, betaine 6 g/d increased total cholesterol by 0.42 (0.30; 0.55), LDL cholesterol by 0.36 (0.25; 0.46), and triacylglycerols by 0.14 (0.04; 0.23) relative to placebo, while HDL cholesterol did not change. Folic acid 0.8 mg/d showed no meaningful combined effect on total cholesterol, HDL cholesterol, LDL cholesterol, triacylglycerols, or the total/HDL ratio. In study 4, phosphatidylcholine increased triacylglycerols by 0.14 mmol/l (8%) and did not affect total or LDL cholesterol. The authors concluded that betaine is less suitable as a homocysteine-lowering agent in healthy humans, whereas phosphatidylcholine may be more suitable and folic acid remains lipid-neutral.

The studies were short term, so they do not address long-term lipid or cardiovascular outcomes. Sample sizes were modest, some per-arm sample sizes were not reported in the provided text, and several dose-specific betaine effects did not reach statistical significance. The findings were limited to healthy adults in the Netherlands, which reduces generalizability to other populations.