Take it to Heart: Exploring the Role of High-Dose B-Vitamin Therapy in CVD Risk Reduction

Worrying Trends

Over 17 million patients die annually of cardiovascular disease (CVD), representing 31% of all deaths and making CVD the leading cause of global morbidity and mortality by a significant margin.¹ Stroke, a component of CVD, is the most common cause of disability-adjusted life years (DALYs) lost globally, with overall burden projected to rise from 38 million DALYs in 1990, to 61 million in 2020.² The preponderance of evidence continues to suggest that CV risk profiles vary considerably across different demographics including, but not limited to, age, sex, race and nationality (e.g. developing versus developed nations), further complicating generalized treatment efforts and necessitating patient-centered treatment approaches.^3,4 Clinical outcomes also vary according to patient- and population-specific risk factors and comorbidities such as tobacco use, diet, physical inactivity, family history, hypertension, dyslipidemia, diabetes mellitus, and obesity.^5,6

Mechanisms At Play

Cardiovascular disease etiologies remain complex and multifactorial. With respect to mechanisms concerning the B-vitamin complex, it has long been established that folate deficiency leads to increased plasma homocysteine (hyperhomocysteinemia), an independent risk factor for coronary artery disease, stroke, peripheral vascular atherosclerosis, and both arterial and venous thromboembolism.^7,8 In fact, epidemiologic studies and clinical trials have consistently demonstrated that a 20% to 25% relative reduction in homocysteine levels is associated with a significant reduction in cardiovascular events.⁹ Both folate and vitamin B₁₂ are potent regulators of homocysteine metabolism through the modulation of the vitamin B₁₂-dependent enzyme methionine synthase, which – in most tissues and cells – is the major (or only) pathway for the conversion of homocysteine to methionine, a critical component of the folate cycle.^10,11

Recent research has also highlighted folate’s role in improving vascular outcomes via increased NOS (nitric oxide synthase) coupling and NO (nitric oxide) bioavailability. In vitro analyses suggest that this mechanism may be independent of – and additive to – folate’s homocysteine-lowering effect, and certainly represents an area of opportunity for further research. The critical role of NO bioavailability in vascular biology is well documented, and endothelial dysfunction – the reduced ability of the endothelium to produce NO – is a hallmark of cardiovascular disease.¹²

B-Vitamins and Cardiovascular Outcomes

It is vitally important to distinguish between B-vitamin fortification and therapeutic interventions with high-dose therapy. For example, although the general population of North America – where fortification of foods is mandated – on average achieves the RDA (recommended dietary allowance) of 400 mg/d for folate, clinical studies of folate in the restoration of endothelial function suggest that higher doses of folic acid are required to confer benefits on cardiovascular endpoints.^Ibid

While evidence for the prophylactic use of B-vitamins for primary or secondary stroke prevention is generally mixed, a recent follow-up analysis of the Vitamin Intervention for Stroke Prevention (VISP) study demonstrated that Vitamin B significantly reduced the recurrence of stroke relative to placebo intervention (OR 0.86; 95% CI: 0.76-0.97). In a Kaplan–Meier survival analysis comparing 4 groups, patients with a baseline B₁₂ level at the median or higher randomized to high-dose therapy (2.5 mg folate, 25 mg B6, and 400 mcg B₁₂ daily) had the best overall outcome, and those with B₁₂ less than the median and assigned to low-dose therapy (20 mcg folate, 200 mcg B6, and 6 mcg B₁₂ daily) had the worst (P=0.02 for combined stroke, death, and coronary events; P=0.03 for stroke and coronary events).¹³

In the HOPE 2 trial, the benefit of homocysteine-lowering therapy (HLT), comprising a daily combination of 2.5 mg of folate, 50 mg of vitamin B6, and 1 mg of vitamin B₁₂, remained after adjusting for concomitant antithrombotics, lipid-lowering, and antihypertensive treatment at study entry (HR 0.71; 95% CI: 0.56-0.91).¹⁴ Moreover, the PACIFIC study – a double-blind, placebo-controlled, factorial randomized trial assessing the effects of two doses of folic acid versus placebo on plasma homocysteine levels – clearly demonstrated the beneficial effects of high-dose folic acid therapy in high-risk patients. In this trial, a 2 mg daily dose of folic acid resulted in a 33% greater effect on homocysteine reduction compared to the 20 mcg dose.¹⁵

Finally, although no human trials have specifically conducted dose–response studies of supplemental folic acid and endothelial function, a review of the available literature suggests that – in patients with compromised endothelial function – daily doses 5 mg or greater can effectively restore endothelium-dependent vasodilation and reduce cardiovascular risk in specific patient subgroups.¹²

What Lies Ahead?

While the current evidence continues to build in favor of high-dose B-vitamin therapy, there are a number of critical future considerations. The current body of literature reinforces the importance of gaining a better understanding of B-vitamin therapy in subgroups who may benefit, while avoiding subgroups who may not.^11,12,16 Future clinical trials should focus particular attention on appropriate patient segmentation and study-powering, adjusting for variables such as baseline renal function, age, sex, country-specific dietary standards (e.g. folate fortification), therapeutic dosing/administration, and present comorbidities.