High-Dose B Vitamin Therapy May Not Be Helpful in Diabetic Nephropathy

June 3, 2010 — High-dose B vitamin therapy may not be helpful in diabetic nephropathy, according to the results of a multicenter, randomized, double-blind, controlled trial reported in the April 28 issue of the Journal of the American Medical Association. Compared with placebo, high doses of B vitamins were actually associated with a greater decrease in glomerular filtration rate (GFR) and an increase in vascular events.

"Hyperhomocysteinemia is frequently observed in patients with diabetic nephropathy," write Andrew A. House, MD, from University of Western Ontario in London, Ontario, Canada, and colleagues. "B-vitamin therapy (folic acid, vitamin B₆, and vitamin B₁₂) has been shown to lower the plasma concentration of homocysteine."

The goal of the study was to examine whether B vitamin supplementation would slow progression of diabetic nephropathy and reduce the risk for vascular complications. Between May 2001 and July 2007, a total of 238 patients with type 1 or type 2 diabetes and clinically diagnosed diabetic nephropathy were enrolled and observed in the Diabetic Intervention with Vitamins to Improve Nephropathy trial at 5 university medical centers in Canada.

"This is a rather large, very well-designed, randomized double-blind study with a reasonable follow-up time," Troels Krarup Hansen, MD, PhD, associate professor of endocrinology and internal medicine at Aarhus University Hospital in Denmark, told Medscape Diabetes & Endocrinology when asked for independent comment. "The patient cohort is homogenous and includes only patients with diabetic nephropathy."

Participants were randomly assigned to receive a single tablet daily of B vitamins containing folic acid (2.5 mg/day), vitamin B₆ (25 mg/day), and vitamin B₁₂ (1 mg/day), or matching placebo. The primary study endpoint was change from baseline to 36 months in radionuclide GFR. Secondary endpoints were dialysis; a composite of myocardial infarction, stroke, revascularization, and all-cause mortality; and total plasma homocysteine levels.

During the trial, mean follow-up was 31.9 ± 14.4 months. Mean decrease in radionuclide GFR at 36 months was 16.5 ± 1.7 mL/minute/1.73 m² in the B vitamin group and 10.7 ± 1.7 mL/minute/1.73 m² in the placebo group (mean difference, −5.8; 95% confidence interval [CI], −10.6 to −1.1; P = .02).

The need for dialysis did not differ between groups (hazard ratio [HR], 1.1; 95% CI, 0.4 - 2.6; P = .88). Rate of the composite outcome in the B vitamin group was twice that in the placebo group (HR, 2.0; 95% CI, 1.0 - 4.0; P = .04).

At 36 months, mean (SE) plasma total homocysteine levels decreased by 2.2 (0.4) μmol/L in the B vitamin group and increased by 2.6 (0.4) μmol/L in the placebo group (mean difference, −4.8; 95% CI, −6.1 to −3.7; P < .001, favoring B vitamins).

"The decline in renal function in the control group was as expected which support the assumptions used in the sample size calculation," Dr. Hansen said. "There is an expected decline in homocysteine levels in the treatment group compared to the placebo group, but despite this the active treatment turns out to have detrimental effects on both renal function and vascular complications."

On the basis of these findings, the study authors concluded that among patients with diabetic nephropathy, high doses of B vitamins vs placebo resulted in a greater decrease in GFR and an increase in vascular events.

"Clearly, the results call for caution in using high dose B vitamins (pharmacological doses) in high risk patients like diabetes patients with diabetic nephropathy," Dr. Hansen said. "On the other hand it is important to stress that the results do not imply that multivitamins containing usual low doses of B vitamins are harmful."

Limitations of this study noted by Dr. Hansen include use of a highly selected patient group, namely diabetes patients with diabetic nephropathy, preventing extrapolation of the detrimental effects of the active treatment to other patient groups at high risk for vascular complications.

"As this is the first large scale randomized study to show significant detrimental effects of high dose B vitamins, one would wish to see the findings reproduced in another setting before judging this treatment principle dangerous," Dr. Hansen concluded. "It may, however, be unethical to duplicate the study, and other ways to manipulate homocysteine levels may be more attractive to investigate."

The Canadian Institutes of Health Research and the Kidney Foundation of Canada supported this study. Pan American Laboratories (Covington, Louisiana) provided in-kind the B vitamins and matching placebo. The senior author (J. David Spence, MD) has received consulting fees from Pan American Laboratories in the United States and from Medice Arzneimittel Pütter GmbH & Co in Germany. Drs. House and Spence have a patent pending on the use of mesna, a thiol, to reduce homocysteine levels in patients receiving dialysis. The other study authors have disclosed no relevant financial relationships.

Dr. Hansen has disclosed no relevant financial relationships.

JAMA. 2010;303:1603-1609.