A study testing the hypothesis that vitamin B therapy would slow the progression of diabetic nephropathy and prevent vascular events instead showed just the opposite: Use of high-dose B vitamins worsened renal function and raised the rates of MI and stroke, according to Dr. Andrew A. House of the University of Western Ontario, London, and his associates.
“Our trial is the first study to our knowledge to show significant detrimental effects from pharmacological doses of B vitamins,” they said.
Vitamin B therapy lowers plasma concentrations of homocysteine and improves endothelial function, but most clinical trials in which high-dose B vitamins have been used to decrease homocysteine have failed to demonstrate improved cardiovascular outcomes, according to the researchers (JAMA 2010;303:1603-9).
“Given the recent large-scale clinical trials showing no treatment benefit, and our trial demonstrating harm, it would be prudent to discourage the use of high-dose B vitamins as a homocysteine-lowering strategy outside the framework of properly conducted clinical research,” Dr. House and his colleagues concluded.
The investigators tested their hypothesis that vitamin B therapy would improve nephropathy and vascular events in a study of 238 adults with type 1 or 2 diabetes and stages 1-3 chronic kidney disease who were treated at five university medical centers in Canada.
The participants were randomly assigned in equal numbers to receive either a daily tablet containing folic acid (2.5 mg/day), vitamin B6 (25 mg/day), and vitamin B12 (1 mg/day) or a matching placebo. They were followed every 6 months for up to 3 years (mean follow-up, 32 months).
As expected, plasma homocysteine levels decreased in the group taking vitamin B therapy but increased in those taking placebo, resulting in a significant mean difference of 4.8 micromol/L between the two groups.
Nevertheless, compared with patients assigned to placebo, those assigned to the B vitamin group had a much greater decrease in renal function, as assessed by one direct and two indirect methods: radionuclide glomerular filtration rate (GFR), estimated GFR using creatinine clearance, and estimated GFR using the Modification of Diet in Renal Disease (MDRD) formula.
“Over 36 months, the GFR decreased by a mean of 16.5 mL/min/1.73 m
There were no differences between the two groups in measures of proteinuria or in need for dialysis.
Participants who received vitamin B therapy also had approximately twice as many cardiovascular and cerebrovascular events as those who received placebo. The 3-year risk of a composite outcome that included MI, stroke, revascularization, and all-cause mortality was 23.5% in the vitamin B group and 14.4% in the placebo group.
The two groups did not differ in rates of all-cause mortality, amputation, or cognitive decline.
The rates of adverse events (88%-90%) and severe adverse events (32%-33%) were not significantly different between the two groups. The rate of serious adverse events was slightly higher in the placebo group (40%) than in the active treatment group (34%).
The study findings suggest that vitamin B therapy is associated with both renal and vascular toxicity. Possible explanations are that folic acid may promote cell proliferation through its role in thymidine synthesis; that folic acid and B12 might alter the methylation potential in vascular cells; or that all the components of vitamin B therapy might increase the methylation of l-arginine to asymmetric dimethylarginine, a nitric oxide synthase inhibitor.
It also is possible that the decrease in homocysteine is actually protective, but that this benefit may be offset by the treatment's toxicity, Dr. House and his associates said.
The study was supported by the Canadian Institutes of Health Research and the Kidney Foundation of Canada. Pan American Laboratories provided the B vitamins and placebos. Dr. House and an associate reported having a patent pending on the use of mesna to reduce homocysteine levels in patients on dialysis. The same associate reported receiving fees from Pan American Laboratories and Medice Arzneimittel Ptter GmbH.