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Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans.

Olthof MR, van Vliet T, Verhoef P, Zock PL, Katan MB - PLoS Med. (2005)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Wageningen Centre for Food Sciences, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands. margreet.olthof@wur.nl

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.

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Flow Diagram of Participant Progress through Study 4
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pmed-0020135-g005: Flow Diagram of Participant Progress through Study 4

Mentions: The primary endpoint of study 4 was plasma homocysteine concentrations. Blood lipid measurements were planned before the study took place, but power analysis was based on changes in the primary endpoint homocysteine concentrations, and not on changes in blood lipids. The original study protocol of this study can be found in Protocols S2–S4, and the trial was registered at clinicaltrials.gov under identifier NCT00102232. This study was conducted according to Good Clinical Practice guidelines at TNO Quality of Life (Zeist, the Netherlands). The local medical ethics committee approved the protocol, and all volunteers gave their written informed consent. Volunteers were recruited from March to May 2003. Eligible volunteers were healthy as assessed by physical examination, a general health and lifestyle questionnaire, blood pressure measurement, routine clinical laboratory tests, and blood analyses of homocysteine and B vitamins. Plasma homocysteine concentrations were below 26 μmol/l. Volunteers had no history of CVD, and had not used vitamin B supplements, lecithin, or supplements containing choline, choline derivatives, or betaine more than once a week during the 1 mo before screening. Out of the eligible men, the 26 men between 50–71 y of age with the highest plasma homocysteine concentrations (range 11.0 to 23.1 μmol/l) were included in this placebo-controlled, double-blind cross-over trial (Figure 5). Participants were stratified by plasma homocysteine concentrations at screening and by smoking habits and then randomly assigned to one of two treatment orders; they received each of the following supplements for 2 wk, with a 2-wk wash out in between: (a) 34.0 g of a soybean lecithin preparation, in which phosphatidylcholine is the only phospholipid (PhosChol Nutrasal, Oxford, Connecticut, United States) and (b) placebo oil, which consisted of 25.5 g of a mixture of edible oils that mimicked the fatty acid composition of the phosphatidylcholine supplement (provided by Unilever Research Laboratory, Vlaardingen, the Netherlands) (Table 2). A person not further involved in the study assigned codes to the study treatments and provided the key in a sealed envelope to the principal investigator at TNO. The statistician randomly allocated the selected participants to one of the two treatment orders. Randomization was done using a computerized procedure that produced combinations based on random seed numbers. The statistician supplied the principal investigator with sealed envelopes with the treatment allocation per participant. The participants and all others involved in this study were unaware of treatment allocation. The statistician performed unblinding of the treatment allocation after the study had ended, laboratory analyses were complete, and datasets were locked. Phosphatidylcholine and placebo supplements were matched for fat content and fatty acid composition (Table 2). The amount of choline in 34 g of the phosphatidylcholine supplement was 2.6 g, as measured by Koc et al. [21] and by TNO. The daily dose of 2.6 g of choline is well below the current tolerable upper intake level of 3.5 g of choline per day for adults [22]. Participants ingested half of the daily supplement dose two times per day (i.e., at breakfast and at dinner). The individual portions of half the daily dose of the supplements were mixed with 200 ml of custard. Participants returned 99.5% of the bowls empty, which indicated good compliance. From 2 wk before the start of the study until the end of the study participants were not allowed to consume food products rich in lecithin or betaine.


Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans.

Olthof MR, van Vliet T, Verhoef P, Zock PL, Katan MB - PLoS Med. (2005)

Flow Diagram of Participant Progress through Study 4
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1140947&req=5

pmed-0020135-g005: Flow Diagram of Participant Progress through Study 4
Mentions: The primary endpoint of study 4 was plasma homocysteine concentrations. Blood lipid measurements were planned before the study took place, but power analysis was based on changes in the primary endpoint homocysteine concentrations, and not on changes in blood lipids. The original study protocol of this study can be found in Protocols S2–S4, and the trial was registered at clinicaltrials.gov under identifier NCT00102232. This study was conducted according to Good Clinical Practice guidelines at TNO Quality of Life (Zeist, the Netherlands). The local medical ethics committee approved the protocol, and all volunteers gave their written informed consent. Volunteers were recruited from March to May 2003. Eligible volunteers were healthy as assessed by physical examination, a general health and lifestyle questionnaire, blood pressure measurement, routine clinical laboratory tests, and blood analyses of homocysteine and B vitamins. Plasma homocysteine concentrations were below 26 μmol/l. Volunteers had no history of CVD, and had not used vitamin B supplements, lecithin, or supplements containing choline, choline derivatives, or betaine more than once a week during the 1 mo before screening. Out of the eligible men, the 26 men between 50–71 y of age with the highest plasma homocysteine concentrations (range 11.0 to 23.1 μmol/l) were included in this placebo-controlled, double-blind cross-over trial (Figure 5). Participants were stratified by plasma homocysteine concentrations at screening and by smoking habits and then randomly assigned to one of two treatment orders; they received each of the following supplements for 2 wk, with a 2-wk wash out in between: (a) 34.0 g of a soybean lecithin preparation, in which phosphatidylcholine is the only phospholipid (PhosChol Nutrasal, Oxford, Connecticut, United States) and (b) placebo oil, which consisted of 25.5 g of a mixture of edible oils that mimicked the fatty acid composition of the phosphatidylcholine supplement (provided by Unilever Research Laboratory, Vlaardingen, the Netherlands) (Table 2). A person not further involved in the study assigned codes to the study treatments and provided the key in a sealed envelope to the principal investigator at TNO. The statistician randomly allocated the selected participants to one of the two treatment orders. Randomization was done using a computerized procedure that produced combinations based on random seed numbers. The statistician supplied the principal investigator with sealed envelopes with the treatment allocation per participant. The participants and all others involved in this study were unaware of treatment allocation. The statistician performed unblinding of the treatment allocation after the study had ended, laboratory analyses were complete, and datasets were locked. Phosphatidylcholine and placebo supplements were matched for fat content and fatty acid composition (Table 2). The amount of choline in 34 g of the phosphatidylcholine supplement was 2.6 g, as measured by Koc et al. [21] and by TNO. The daily dose of 2.6 g of choline is well below the current tolerable upper intake level of 3.5 g of choline per day for adults [22]. Participants ingested half of the daily supplement dose two times per day (i.e., at breakfast and at dinner). The individual portions of half the daily dose of the supplements were mixed with 200 ml of custard. Participants returned 99.5% of the bowls empty, which indicated good compliance. From 2 wk before the start of the study until the end of the study participants were not allowed to consume food products rich in lecithin or betaine.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Wageningen Centre for Food Sciences, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands. margreet.olthof@wur.nl

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 MeSH
Related in: MedlinePlus