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ABSTRACT & COMMENTARY
By David Kiefer, MD
SYNOPSIS: A meta-analysis and systematic review found vitamin C supplementation improved endothelial function in patients with diabetes, atherosclerosis, and heart failure.
SOURCE: Ashor AW, et al. Effect of vitamin C on endothelial function in health and disease: A systematic review and meta-analysis of randomised controlled trials. Atherosclerosis 2014;235:9-20.
This meta-analysis and systematic review was undertaken to investigate the clinical effects of supplemental vitamin C on endothelial function. Vitamin C’s effect as a free radical scavenger and, through its activity as an enzyme co-factor, maintaining the vasodilator nitric oxide’s blood levels, created a compelling mechanistic connection to vascular health and disease, underpinning the rationale for this analysis.
The authors used Cochrane’s methodology to review four major databases (PubMed, Embase, Scopus, and Cochrane Library) up to May 2013 for randomized, controlled trials in adults that examined the effect of vitamin C on a variety of search terms to capture cardiovascular effects and endothelial function. To assess endothelial function, this meta-analysis analyzed parameters from the clinical trials including flow-mediated dilation, forearm blood flow, and pulse wave analysis. All told, 9685 studies were located from the database searches plus four from other sources, though 9458 were excluded after title and abstract screening. Of the remaining 231 studies, 179 did not meet the inclusion criteria of adult subjects, randomized controlled trial, vitamin C as the intervention, and an endothelial functional measurement using ultrasound, venous occlusion plethysmography, pulse wave velocity, iontophoresis, or pulse amplitude tonometry. The remaining 52 studies were included in the qualitative analysis of the systematic review. Seven of these studies did not have endothelial measurements that were applied appropriately, so only 44 trials were included in the quantitative aspect of the meta-analysis.
The 52 studies (27 orally dosed vitamin C, 18 intravenous, and 7 not detailed) represented 1324 research subjects (75% male, median age 51.1 years). Qualitatively, two-thirds of the studies reported a significant improvement in endothelial function with the administration of vitamin C; one-third did not. The quantitative analysis of the 44 studies corroborated the significant improvement in endothelial function with a standardized mean difference of 0.50 (95% confidence interval [CI], 0.34-0.66; P < 0.001), though there was a moderate amount of heterogeneity between the studies. Subgroup analyses showed no effect of vitamin C supplementation in studies on healthy volunteers (smokers and non-smokers) or people with hypertension. However, supplementation benefited people with diabetes, atherosclerosis, heart failure, and those who underwent experimentally induced endothelial dysfunction using glucose, lipids, endotoxins, organic nitrite, insulin, and methionine.
With respect to doses, lower doses (90-500 mg daily) of vitamin C supplementation did not affect endothelial function (P < 0.1), whereas higher doses (501-4000 mg daily) did lead to a statistically significant improvement in endothelial function (P < 0.01-0.001), a correlation that was also seen in the regression analysis on vitamin C dose and magnitude of effect. With respect to safety, none of the studies analyzed that used a vitamin C dose > 2 g daily (the Institute of Medicine upper limit) reported any adverse effects. In the discussion, the authors tie their results into known mechanisms of action, namely the lessening of oxidative damage and vascular inflammation that leads to healthy endothelial function and a lowering of the risk of cardiovascular disease.
This is an important analysis, extending the findings from observational studies showing a connection between vitamin C intake and improved cardiovascular health;1 for example, the authors quote results affirming that 700 mg of vitamin C daily is associated with a 25% decrease in the risk of coronary heart disease, likely by affecting the inflammatory process and the pathophysiology of atherosclerotic plaque disruption. However, also quoted is the fact that randomized controlled trials generally have been negative, possibly due to genetic effects, vitamin C status, and confounding effects that were unaccounted for. The results here — a dose-dependent effect on the vessels themselves — adds to mechanistic data and begins the process of trying to determine who might benefit most from vitamin C therapy.
What can we conclude from who might benefit most from vitamin C therapy? The results presented here point toward those with experimentally induced endothelial dysfunction, not usually the demographic seen in most clinics. In those studies, supraphysiologic dosing (240-2600 mg) was used short-term, another uncommon intervention. Healthy individuals, presumably with normal endothelial function and/or adequate vitamin C status, did not benefit from supplementation. The authors suggest a focus on vitamin C dosing of 500 mg daily or more in people with endothelial dysfunction, low vitamin C status, or increased oxidative stress; again, clinically it may be difficult to know definitively who falls into that category. Also, this meta-analysis focused on randomized controlled trials of supplemental, not dietary, vitamin C. As with other vitamins, the clinical results seen for supplementation can differ significantly from a reliance of vitamins and minerals in food as shown in dietary studies. Interestingly, in this study, studies involving healthy smokers did not show an endothelial benefit, even given the oxidative stress imparted by tobacco smoke. It is true, as the authors conclude, that teasing out all of these effects would require a well-designed, randomized, controlled trial, but, until then, given its relative safety and affordability, there seems to be little reason not to recommend this well-known nutrient to most, if not all, of the population.