The homocysteine hypothesis: Still relevant to the prevention and treatment of cardiovascular disease?
ABSTRACTAlthough evidence suggests that the homocysteine hypothesis is still relevant as a predictor of cardiovascular risk, we cannot conclude that measuring the homocysteine level is useful in guiding treatment. Furthermore, studies of primary and secondary prevention show no evidence that taking folic acid or other B vitamins lowers the risk of cardiovascular events.
KEY POINTS
- Factors that can cause the plasma homocysteine concentration to be high include deficiencies of vitamin B6, vitamin B12, and folic acid; renal insufficiency; and genetic variants in enzymes responsible for homocysteine metabolism.
- Higher plasma homocysteine levels are associated with a higher risk of cardiovascular, cerebrovascular, and peripheral arterial disease.
- Supplementation of B vitamins and folic acid can lower plasma homocysteine levels.
- Randomized controlled trials of supplementation to prevent cardiovascular events and other adverse outcomes have had mostly negative results. However, most patients in these trials had normal baseline plasma homocysteine levels.
- Needed are randomized trials to see if supplementation improves outcomes in patients with high homocysteine levels.
Cerebrovascular and peripheral arterial disease
The evidence is also mixed for using folic acid and other B vitamins to prevent cerebrovascular disease and peripheral vascular disease. Although a 2007 meta-analysis found that folic acid supplementation decreased the risk of a first stroke by 18% (P = .045),50 a later meta-analysis contradicts this finding.51
A 2009 meta-analysis found that patients with peripheral arterial disease had higher homocysteine levels than controls, but it did not find any benefit from supplementation, owing to heterogeneity of the clinical end points used.52 Indeed, a 2009 Cochrane Database Systematic Review found that there were no adequate trials of the treatment of patients with peripheral vascular disease who have elevated plasma homocysteine.53
However, immediately after the Cochrane review was published, Khandanpour et al36 published the results of a trial of the effect of folic acid and 5-methyltetrahydrofolate (an active form of folic acid) supplementation on the ankle-brachial pressure index and the pulse-wave velocity in patients with peripheral arterial disease. These measures improved with 16 weeks of treatment. For the ankle-brachial pressure index, the P value was less than .01 for folic acid and .009 for 5-methyltetrahydrofolate; for the pulse-wave velocity, the P value was .051 for folic acid and .011 for 5-methyltetrahydrofolate.
Kidney disease
One could postulate that patients with end-stage renal disease or chronic kidney disease might benefit the most from folic acid supplementation, given the correlation of elevations in homocysteine levels with decline in glomerular filtration rate.
However, only one study found a lower rate of cardiovascular events with folic acid supplementation in dialysis patients, and the difference was not statistically significant (25% vs 36%, P < .08).31 Further, several studies found no benefit of folic acid supplementation in patients with chronic kidney disease.11,12,37
FUTURE DIRECTIONS AND RECOMMENDATIONS
Many experts have suggested that the existing evidence indicates that the homocysteine-lowering therapies folic acid, vitamin B6, and vitamin B12 do not lower the risk of cardiovascular disease.38,54–59 Indeed, the American Heart Association guidelines for cardiovascular disease prevention in women do not recommend folic acid supplementation to prevent cardiovascular disease.60 (Recommendations for men are the same as for women.) However, most of the clinical trials have not selected and treated patients with elevated homocysteine levels, but have instead included all patients regardless of homocysteine level.
At least two large ongoing trials are currently evaluating B-vitamin therapy for secondary prevention, but neither trial is looking specifically at patients with elevated homocysteine levels.61,62
Thus, instead of concluding that no patients could benefit from homocysteine-lowering treatment, future studies need to clarify:
- Whether patients with elevated homocysteine would benefit from such treatment
- At what level it would be appropriate to start treatment
- The appropriate target homocysteine level with treatment.
Particularly given the recent finding that folic acid supplementation may increase cancer risk,63 these questions need closer scrutiny.
