Vitamin B6, B9 and B12 in Diabetic Nephropathy—Beware

Paul J. Thornalley; Naila Rabbani

Disclosures

Abstract and Introduction

Abstract

Combination therapy with vitamins B6, B9 and B12 is a therapeutic intervention to decrease levels of plasma homocysteine and the risk of cardiovascular disease. However, a recent trial found that cosupplementation with these vitamins exacerbated the decline in renal function and increased the risk of vascular disease in patients with diabetic nephropathy. Confidence in this high-dose vitamin supplement is shaken.

Introduction

High concentrations of plasma total homocysteine are known to be associated with the risk of developing diabetes-related cardiovascular disease, nephropathy and proliferative retinopathy. Cosupplementation of pyridoxine (vitamin B6), folic acid (vitamin B9) and vitamin B12 has been used to decrease levels of plasma homocysteine and the risk of cardiovascular disease. A study by House et al.[1] has now shown substantial adverse outcomes associated with high-dose vitamin B6, B9 and B12 cosupplementation in patients with advanced diabetic nephropathy. Unless other explanations come to light in further analyses of this study, these findings make repetition of a similar trial in this high-risk patient group unethical.

In a randomized controlled trial—the Diabetic Intervention with Vitamins to Improve Nephropathy (DIVINe) study—238 patients with type 1 or type 2 diabetes mellitus and advanced diabetic nephropathy were treated with supplements of 25.0 mg pyridoxine, 2.5 mg folic acid and 1.0 mg vitamin B12 per day or placebo for a mean follow-up period of 32 months. Compared to placebo, the high-dose vitamin B6, B9 and B12 cosupplementation produced an expected decrease in plasma homocysteine concentration (−2.2 μmol/l versus +2.6 μmol/l; P <0.001), but produced an unexpected accelerated decline in renal function, as determined by a decrease of the glomerular filtration rate (16.5 ml/min versus 10.7 ml/min per 1.73 m2; P = 0.02). Vitamin B6, B9 and B12 therapy also resulted in an increased number of vascular disease events, defined as a composite of myocardial infarction, stroke, revascularization and all-cause mortality (risk of outcome: 23.5% versus 14.4%, P = 0.04).

The DIVINe study can be criticized for its relatively small size (118 patients remained in the study at 36 months for the primary outcome) and the low level of statistical significance on primary and secondary adverse outcomes. Nonetheless, the study was well beyond pilot scale, and the primary outcome was assessed by the gold standard measurement of the radionuclide glomerular filtration rate. The adverse effects of high-dose B6, B9 and B12 supplements on glomerular filtration rate and vascular disease events cannot, therefore, be dismissed.

Another trial, the Heart Outcomes Prevention Evaluation (HOPE-2) study,[2] involved 5,522 patients with vascular disease or diabetes mellitus and found no effect of high-dose B6, B9 and B12 cosupplementation on death from cardiovascular disease, whereas the risk of stroke was decreased and the risk of unstable angina requiring hospitalization was increased. The Homocysteinemia in Kidney and End Stage Renal Disease (HOST) study[3] involved 2,056 patients with advanced kidney disease and found no effect of high-dose vitamin B6, B9 and B12 supplements on survival or risk of cardiovascular disease-related events. Taken together with the disappointing outcomes of these related trials, the DIVINe study provides a strong note of caution for further intervention trials on high-dose vitamin B6, B9 and B12 therapy in patients with diabetic nephropathy. Plausible explanations for the adverse effects of these supplements and other therapeutic strategies to decrease plasma homocysteine in diabetic nephropathy are now required.

Given the lack of precedent for the decline in glomerular filtration rate in the HOPE-2 study,[2] and the absence of a precedent for increased vascular disease events in the HOPE-22 and HOST[3] studies, the adverse effects found in the DIVINe study are probably the result of an interaction of the treatment with the background of advanced diabetic nephropathy. Previous studies with high-dose pyridoxine treatment of patients with ischemic heart disease[4] and high-dose treatment with the related compound pyridoxamine—a so-called vitamer as it fulfills the same specific vitamin function—in patients with advanced diabetic nephropathy[5] gave no evidence of acceleration of decline in glomerular filtration rate or increased cardiovascular disease events and mortality. House et al. speculate that the adverse effects observed in the DIVINe study may be due to accumulation of folate and vitamin B12 to toxic levels owing to the low glomerular filtration rate in patients with diabetic nephropathy. This accumulation might stimulate methylation of arginine leading to buildup of the nitric oxide synthase inhibitor asymmetric di-methylarginine (ADMA)—a predictor of accelerated decline in glomerular filtration rate and increased cardiovascular disease events in diabetic nephropathy.[6] Studies in patients requiring hemodialysis, however, suggest that cosupplementation with folate and methylcobalamin (a vitamin B12 vitamer) tends to decrease both levels of plasma homocysteine and ADMA.[7]

A further factor underlying the association of high-dose vitamin B6, B9 and B12 supplements and metabolic dysfunction in diabetic nephropathy could be the effect of high-dose folic acid on metabolite transport via the folate transporter 1 (RFC-1). In addition to facilitating transport of folate, RFC-1 is also a transporter of thiamine monophosphate (TMP) and thiamine pyrophosphate (TPP).[8] Diabetic nephropathy occurs within a background of thiamine (vitamin B1) deficiency owing to impaired renal reuptake of thiamine. Plasma thiamine concentrations were inversely linked to plasma soluble vascular cell adhesion protein 1 (sVCAM-1)—a risk marker of cardiovascular disease.[9] Folate binds to and is transported into cells by the RFC-1 transporter.[8] High-dose folic acid supplementation might exacerbate thiamine deficiency at susceptible sites, such as the kidney and vascular cells in diabetic nephropathy, by competing with TMP and TPP and impairing their uptake into tissues, thereby inhibiting sharing of thiamine metabolites between tissues rich in thiamine and those deficient in it.[9] This mechanism could be a further factor underlying the accelerated decline in glomerular filtration rate and increased vascular disease reported in the DIVINe study. Preclinical investigations are now required to test this and other plausible mechanisms underlying adverse effects of high dose vitamin B6, B9 and B12 supplementation.

Finally, clear discrimination of treatment with vitamin B6, B9 and B12 from other B-vitamins in titles, headlines, presentations and press releases, as well as in text of scientific reports, is required for clarity. 'B-vitamin therapy' is a catch-all, convenient phrase for a report title but can be misleading and lead to unnecessary concern in patients taking other B-vitamin supplements and in their carers. Of course, not all B-vitamins are the same. In a pilot–scale, placebo-controlled intervention trial, high-dose thiamine supplementation of patients with type 2 diabetes mellitus and early-stage diabetic nephropathy (microalbuminuria) improved renal function in all patients treated and produced regression of microalbuminuria for some individuals.[10] High-dose thiamine therapy holds promise as a novel additional treatment for early-stage diabetic nephropathy.

In summary, the recent DIVINe study provided evidence of adverse effects of high-dose vitamin B6, B9 and B12 supplementation in advanced stage diabetic nephropathy. Following this, supplementation at high therapeutic doses with this particular vitamin combination should preferably be avoided in advanced stage diabetic nephropathy, whereas research on the biochemical basis for the adverse effects needs to be initiated and alternative interventions to decrease plasma homocysteine levels must be explored.

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