“After several randomized controlled trials and a meta-analysis indicated that lowering homocysteine levels with B vitamins (to reduce the negative effects of homocysteine on the blood vessel walls) did not result in cardiovascular benefit, the use of vitamin therapy to lower homocysteine levels was widely regarded as being ineffective. However, there is now evidence that the large trials showing no efficacy may have obscured the benefits of vitamin therapy. An analysis of data showed that grouping all patients together may have obscured important differences among patient (and perhaps population) subgroups.
For instance, the main results of the Vitamin Intervention for Stroke Prevention (VISP) trial (1) showed that B vitamins (folic acid, vitamin B6, vitamin B12) had no effect on the risk of recurrent stroke, death or myocardial infarction, whereas a subgroup analysis (2) of the trial showed the benefits of B vitamins in a defined subset of the population. The subgroup analysis excluded patients with B12 deficiency (because they were all receiving injections of vitamin B12 regardless of the treatment to which they were randomly assigned) and patients with significant renal impairment (because it was thought they would not respond to vitamin therapy). There was a significant reduction of stroke and myocardial infarction in the remaining participants who received B vitamins, and this finding was even more pronounced when patients were grouped by their serum vitamin B12 level at the beginning of the study. A 34% reduction of the risk of stroke, death or myocardial infarction was seen in patients who entered the study with a serum vitamin B12 level above the median (i.e., they could absorb the vitamin reasonably well) and received high-dose vitamins in comparison those who entered the study with a serum vitamin B12 level below the median and received low-dose vitamins. At the time, it seemed that the negative findings were explained mainly by excluding patients who had received vitamin B12 injections, and this seemed to be supported by the finding of the Heart Outcomes Prevention Evaluation 2 (HOPE-2) trial – the only large trial to use an adequate dose of B12 for elderly patients with coronary heart disease – that B vitamins significantly reduced the risk of stroke (3). In the VISP trial in 2011, researchers reported that a subgroup of patients with a genetic variation (poly-morphism) of a transport protein for vitamin B12 were responsive to high-dose vitamin therapy (4).
Vitamin B12 may thus play a key role in stroke prevention interventions that involve vitamin therapy for reducing high levels of homocysteine, which are linked to an increased risk of thrombosis and stroke (5). The prevalence of metabolic vitamin B12 deficiency (not necessarily reflected in serum B12 levels) increases steeply with age, as do plasma total homocysteine levels (6). As a result of the fortification of grains with folic acid, nearly all inhabitants of North America are folate-replete, which means that vitamin B12 is now the major determinant of total homocysteine levels. Some researchers have estimated that approximately 20% of older persons have vitamin B12 deficiency.
More recently, it has been reported that B vitamin therapy was shown to increase cardiovascular risk in a subgroup of patients with diabetic nephropathy (7). It seems that the benefit or harm from vitamin therapy for lowering homocysteine levels depends not only on an adequate dosage and absorption of vitamin B12, but also on renal function. Folate status, vitamin B12 status and renal function are all crucial for interpreting the results of clinical trials of vitamin therapy for lowering homocysteine levels. The clinical implications of these issues are that metabolic vitamin B12 deficiency needs to be better detected and treated, and that it would be advisable to substitute methylcobalamin for cyanocobalamin in patients with renal failure.
When subgroup analyses are biologically based, thoughtfully developed and pre-planned, their results can reinforce the findings from randomized controlled trials and may lead to insights that can help explain apparently divergent results. In clinical practice it may be reasonable to consider acting on such insights, pending results from subsequent clinical trials that focus on those particular subgroups.”
Based on: Spence J. D. and Stampfe M. J. Understanding the Complexity of Homocysteine Lowering With Vitamins: The Potential Role of Subgroup Analyses. JAMA. 2011; 306(23):2610–2611.