Treatment with folic acid plus vitamin B12 was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway, according to a recent study published in JAMA.

The objective of this study was to evaluate effects of treatment with B vitamins on cancer outcomes and all-cause mortality in two randomized controlled trials.

Combined analysis and extended follow-up of participants from these randomized, double-blind, placebo-controlled clinical trials (Norwegian Vitamin Trial and Western Norway B Vitamin Intervention Trial). A total of 6837 patients with ischemic heart disease were treated with B vitamins or placebo between 1998 and 2005, and were followed up through December 31, 2007.

Subjects received oral treatment with folic acid (0.8 mg/d) plus vitamin B12 (0.4 mg/d) and vitamin B6 (40 mg/d) (n = 1708); folic acid (0.8 mg/d) plus vitamin B12 (0.4 mg/d) (n = 1703); vitamin B6 alone (40 mg/d) (n = 1705); or placebo (n = 1721).

During study treatment, median serum folate concentration increased more than 6-fold among participants given folic acid. After a median 39 months of treatment and an additional 38 months of post-trial observational follow-up, 341 participants (10%) who received folic acid plus vitamin B12 vs. 288 participants (8.4%) who did not receive such treatment were diagnosed with cancer (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.03-1.41; P = .02).

A total of 136 (4%) who received folic acid plus vitamin B12 vs. 100 (2.9%) who did not receive such treatment died from cancer (HR, 1.38; 95% CI, 1.07-1.79; P = .01). A total of 548 patients (16.1%) who received folic acid plus vitamin B12 vs. 473 (13.8%) who did not receive such treatment died from any cause (HR, 1.18; 95% CI, 1.04-1.33; P = .01). Results were mainly driven by increased lung cancer incidence in participants who received folic acid plus vitamin B12. Vitamin B6 treatment was not associated with any significant effects.

Researchers concluded that treatment with folic acid plus vitamin B12 was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway, where there is no folic acid fortification of foods.

Responding to the study’s release, Daniel Fabricant, PhD, vice president of scientific and regulatory affairs for the Natural Products Association (NPA), Washington, D.C., said “Despite the authors’ justification for the analysis, previous review has indicated the NORVIT might not have been adequately powered and the factorial design might have been too complex, thus rendering the trial incapable of isolating the effect of folate per se. Being combined with the WENBIT, which was terminated early, and which wasn’t without its design flaws, either, creates a scenario in which two flawed studies are combined to yield one larger flawed study. This does not seem to be in the best interest of medical science or public health.”

He went on to say that that most of the subjects in both trials were also being treated with beta-blockers and statins, and some were also being treated with ACE inhibitors and diuretics, “yet there are no numbers, no analysis on the effects these interventions may have on the incidence of cancer. There is no adjustment of the baseline effect for these interventions, yet the authors adjusted the baseline for smoking, age and sex, which are all factors in the development of cancer. We have no way of determining these factors’ impact on this study as they just decided to leave that out, like ordering off of an a la carte menu.”

Andrew Shao, PhD, vice president, scientific and regulatory affairs, Council for Responsible Nutrition (CRN), Washington, D.C. said it is important to note that the results from this study “are inconsistent with the larger body of data and that this effect has not been observed previously. In fact, as the authors themselves point out, ‘Epidemiological studies have demonstrated no associations between intakes of folate or folic acid and lung cancer risk’.”

He added: “Consumers, as well as researchers and healthcare professionals, must not lose sight of the safe, well-established benefits of folic acid supplementation and fortification for women of childbearing age to prevent neural tube defects, as well as other potential benefits of folic acid supplementation, such as for cardiovascular health and cognitive function in the general population.”