In a contrasting recent cross-sectional study, plasma concentrations of trimethylamine N-oxide, choline and betaine are all reported to be associated with an increased number of vascular events in an at-risk population. It is proposed that the causal agent is trimethylamine or its N-oxide; trimethylamine is produced in the gut by CID44216842 bacterial metabolism of choline and oxidized in the liver to its N-oxide. This cannot account for the betaine results because betaine is not converted to trimethylamine in the gut. Betaine concentrations in tissues, where it functions as an osmolyte, are orders of magnitude higher than in plasma therefore elevated betaine concentrations themselves are unlikely to cause damage. Our preliminary prospective results could reconcile these inconsistencies: although low plasma betaine concentrations were a more significant risk factor for myocardial infarction, there was also an increased risk associated with the highest concentrations, and we speculate that there were some patients whose control of betaine efflux from tissues is compromised, and this subgroup is prone to early events. Cross-sectional studies do not demonstrate causality, but generate hypotheses. This is also illustrated by the effects of lipid lowering drugs on plasma betaine concentrations and urinary betaine excretion. Are the differences caused by the drug treatment, or do they reflect differences in the patients that are prescribed those drugs? In the case of statins, there is no reason to suspect that the patients treated with statins differed significantly from the minority who were not receiving statins, and it is likely that an increase in plasma betaine is another pleotropic effect of statins. Fibrates, however, almost certainly cause increased betaine PKI-166 excretion and since this is negatively correlated with the plasma betaine it is plausible to suggest that it is a cause of the lower plasma betaine in these patients. Fibrate treatment is therefore inducing a betaine deficiency, which may compromise the benefits of fibrate. Subjects being prescribed fibrate would be expected to have elevated triglyceride and low-density lipoprotein, so finding a difference in these in fibrate-treated patients is a trivial result that has no necessary connection with the differences in plasma betaine.