What is the evidence for vitamin C (ascorbic acid) supplementation in preventing or treating diseases, particularly in patients with a history of cardiovascular disease or cancer?

Vitamin C Supplementation for Disease Prevention

Vitamin C supplementation should not be routinely recommended for the prevention of cardiovascular disease or cancer, as no primary prevention trials have demonstrated benefit, and observational studies show inconsistent results. 1

Evidence for Cardiovascular Disease Prevention

Primary Prevention - No Demonstrated Benefit

• No randomized controlled trial has examined vitamin C supplementation alone for primary prevention of cardiovascular disease. 1
• Observational cohort studies examining vitamin C effects on cardiovascular disease have produced inconsistent and conflicting results. 1
• The largest available trial (Physicians Health Study II with 14,641 participants) found no reduction in major cardiovascular events (HR 0.99,95% CI 0.89-1.10) over 8 years of follow-up. 2
• This same trial showed no benefit for total myocardial infarction (HR 1.04), total stroke (HR 0.89), cardiovascular mortality (HR 1.02), or procedures like CABG/PTCA (HR 0.96). 2

Quality of Evidence

• The evidence for cardiovascular outcomes was downgraded to low or very low quality due to indirectness, imprecision, and inconsistency. 2
• Current evidence is limited to one trial of middle-aged and older male physicians from the USA, limiting generalizability. 2

Evidence for Cancer Prevention

No Protective Effect Demonstrated

• No primary prevention trial of vitamin C supplementation alone on cancer has been reported. 1
• Observational studies have generally shown no statistically significant associations between vitamin C supplement use and risk for breast, prostate, colon, or lung cancer. 1
• A large randomized trial of 7,627 women found no effect on total cancer incidence (RR 1.11,95% CI 0.95-1.30) or cancer mortality (RR 1.28,95% CI 0.95-1.73) over 9.4 years. 3

Combination Antioxidant Trials

• Trials combining vitamin C with vitamin E and beta-carotene showed no statistically significant effect on cancer prevention. 1
• Duration and combined use of antioxidants had no effect on cancer incidence or cancer death. 3

Effects on Cardiovascular Risk Factors

Limited and Inconsistent Benefits

• There is limited evidence that vitamin C supplementation improves cardiovascular biomarkers, with high heterogeneity across studies (I² > 50%). 4
• Some systematic reviews reported improvements in blood pressure, glucose, LDL cholesterol, and triglycerides, but these findings are not consistent. 4
• No overall effects were demonstrated for arterial stiffness, insulin levels, total cholesterol, or HDL cholesterol. 4

Potential Subgroup Effects

• Subgroup analyses suggest possible benefits in specific populations: those with higher BMI, elevated glucose or cholesterol, low baseline vitamin C status, or higher cardiovascular risk. 4
• However, these subgroup findings require confirmation in prospective trials designed specifically for these populations. 4

All-Cause Mortality

Vitamin C supplementation does not reduce all-cause mortality (HR 1.07,95% CI 0.97-1.18), with very low-quality evidence supporting this conclusion. 2

Clinical Approach

What to Recommend Instead

• Emphasize dietary sources of vitamin C rather than supplementation, as the antioxidant benefits observed in epidemiological studies come from antioxidant-rich foods, not isolated supplements. 5
• Focus on dietary counseling promoting fruits, vegetables, whole grains, and legumes, which have more consistent evidence for health benefits. 5
• Diets naturally high in vitamin C-containing foods show inverse relationships with cardiovascular events in observational studies, even though supplementation trials do not replicate these benefits. 2, 6

Prevalence of Deficiency

• Vitamin C deficiency affects approximately 5% of the population in industrialized countries, with 13% having suboptimal status. 6
• Supplementation may be appropriate for documented deficiency, but not for disease prevention in adequately nourished individuals. 6

Important Caveats

Why Observational Studies Differ from Trials

• Observational studies consistently show associations between higher vitamin C intake and better health outcomes, but randomized trials do not confirm these benefits. 7, 2, 6
• This discrepancy likely reflects that people with higher dietary vitamin C intake have overall healthier lifestyles and dietary patterns that cannot be replicated by supplementation alone. 6
• Prevention may not be realized by supplementation in populations already adequately supplied through dietary sources. 6

Optimal Intake Considerations

• While some researchers argue that 200 mg per day represents the optimum intake based on pharmacokinetic and Phase II trial data, this has not translated to demonstrated benefits in Phase III prevention trials. 7
• The relationship between intake and systemic concentrations is saturable, meaning higher doses do not necessarily produce proportionally higher tissue levels. 7, 6

Genetic Factors

• Variations in genes participating in redox homeostasis and vitamin C transport may affect plasma concentrations, but impact sizes are generally low and primarily affect individuals with suboptimal dietary supply. 6