BERGEN, Norway—Treatment with folic acid plus vitamin B12 was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease, according to a recent Norwegian study (JAMA 2009;302(19):2119-2126); however, nutrition scientists questioned the validity of the combined analysis protocol and results. The study used a combined analysis and extended follow-up of participants from two randomized, double blind, placebo-controlled clinical trials (Norwegian Vitamin Trial (NAT) and Western Norway B Vitamin Intervention Trial (NORVIT)). A total of 6,837 patients with ischemic heart disease were treated with B vitamins or placebo between 1998 and 2005, and were followed up through Dec. 31, 2007.Oral treatment administered 0.8 mg/d of folic acid plus 0.4 mg/d of vitamin B12 and 40 mg/d of vitamin B6 (n=1708); 0.8 mg/d of folic acid plus 0.4 mg/d of vitamin B12 (n=1703); 40 mg/d of vitamin B6 alone (n=1705); or placebo (n=1721).
During study treatment, median serum folate concentration increased more than six-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 (10.0 percent) who received folic acid plus vitamin B12 versus 288 participants (8.4 percent) who did not receive such treatment were diagnosed with cancer. A total of 136 (4.0 percent) who received folic acid plus vitamin B12 versus 100 (2.9 percent) who did not receive such treatment died from cancer. A total of 548 patients (16.1 percent) who received folic acid plus vitamin B12 versus 473 (13.8 percent) who did not receive such treatment died from any cause. 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.
Andrew Shao, Ph.D., vice president, scientific and regulatory affairs at the Council for Responsible Nutrition (CRN) commented on the study results, stating: ““The real headline of this study should be that smoking increases the risk of lung cancer—the study found 94 percent of the subjects who developed lung cancer were either current or former smokers. It is puzzling why patients who were given high-doses of folic acid were more likely to develop lung cancer than those subjects in the control group; however, it is important to point out that these results 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.’”
Additionally, Daniel Fabricant, Ph.D., vice president of scientific and regulatory affairs for the Natural Products Association (NPA), commented: “This is an analysis of two studies—the NORVIT and WENBIT. 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.”
