What are proven clinical antioxidants?

Proven Clinical Antioxidants

Based on the strongest available evidence, no antioxidant supplements are proven to reduce morbidity or mortality in the general population, and some may cause harm. The Institute of Medicine concluded that consuming antioxidants has not been demonstrated to protect against cardiovascular disease, diabetes, or cancer 1. Large placebo-controlled trials have consistently failed to show benefit and in some cases demonstrated adverse effects 1.

Evidence Against Routine Antioxidant Supplementation

Vitamin E

• The Heart Outcomes Prevention Evaluation Trial (9,541 subjects, 38% with diabetes) found that vitamin E supplementation (400 IU/day) for 4.5 years resulted in no significant benefit 1
• High-dose vitamin E (400 IU/day) showed significantly increased risk of prostate cancer in healthy men (HR: 1.17; 99% CI: 1.004,1.36; P = 0.008) 1
• Increased risk of heart failure (RR: 1.13; 95% CI: 1.01,1.26; P = 0.03) 1
• Doses exceeding 400 IU/day associated with increased all-cause mortality 1

Beta-Carotene

• Two major trials (CARET and ATBC) found unexpected increases in lung cancer mortality among smokers taking beta-carotene supplements at doses of 20-30 mg/day 1
• The American Cancer Society explicitly warns that beta-carotene supplements may be harmful for cigarette smokers 1

Vitamin C

• Mixed evidence: Some studies show potential benefit for coronary heart disease at doses >600 mg/day (RR: 0.73; 95% CI: 0.57,0.94) 1
• However, systematic reviews conclude insufficient evidence to support routine supplementation for cardiovascular prevention 1
• The American College of Nutrition recommends against using high-dose vitamin C as monotherapy for infection prevention in healthy individuals (Grade B recommendation, 96% consensus) 2

Other Antioxidants

• Resveratrol, anthocyanins, and other polyphenols lack convincing clinical trial evidence 1
• Selenium, carotenoids, and other antioxidants have not demonstrated protection against chronic diseases 1

Context-Specific Exceptions Where Antioxidants May Be Beneficial

Critical Illness

• The American Society for Parenteral and Enteral Nutrition (ASPEN) recommends combined antioxidant micronutrients at 5-10 times dietary reference intakes for critically ill patients based on 15 RCTs showing significant reduction in infectious complications and mortality 3
• Enteral combination of vitamin C and vitamin E may reduce length of mechanical ventilation (though without mortality impact) 3
• Clinical effects demonstrated after just 5 days of administration in mechanically ventilated patients 3

Documented Deficiency States

• Supplementation is appropriate only when documented deficiency exists 1, 2, 3
• The Clinical Nutrition society recommends repletion therapy with appropriate doses for documented deficiency states, continuing until nutritional status is restored 2
• Malnourished patients should receive supplementation to maximize anti-infection nutritional defense 2

Specific Clinical Scenarios

• Vitamin E may improve ALT, AST, and histology in non-diabetic, non-cirrhotic NASH patients, though concerns about mortality risk remain 1
• Zinc supplementation may benefit diabetic patients with skin ulcerations (small studies only) 1

Critical Safety Warnings

Absolute Contraindications to High-Dose Vitamin C

• Hemochromatosis or iron overload conditions 2, 4
• G6PD deficiency 2, 4
• Renal dysfunction 2, 4
• History of oxalate kidney stones 2, 4

General Safety Concerns

• High dosages of antioxidants may lead to diarrhea, bleeding, and toxic reactions 1
• Antioxidants could theoretically repair oxidative damage to cancer cells, potentially reducing chemotherapy/radiotherapy effectiveness 3
• The Clinical Nutrition society states that doses exceeding 10 times the dietary reference intake should not be used without proven severe deficiency 2

Clinical Decision Algorithm

For healthy, well-nourished individuals:

• Do not recommend antioxidant supplements 1, 2, 3
• Ensure adequate dietary intake of 100-200 mg/day vitamin C from food sources 2
• Emphasize whole foods (fruits and vegetables) rather than isolated supplements 1

For diabetic patients:

• Do not recommend antioxidant supplements as replacement for dietary management 3
• Supplement only if documented deficiency exists 3
• Prioritize dietary sources of antioxidants 3

For critically ill patients requiring mechanical ventilation:

• Consider combination antioxidants at 5-10x DRI 3
• Use established protocols (e.g., vitamin C 1.5g every 6 hours for sepsis, or 2-3g/day for critical illness) 4

For at-risk populations (malnourished, physically active):

• Assess nutritional status and risk factors 2
• Provide daily allowances to ensure adequate intake 2
• Consider 200-500 mg/day vitamin C for those with documented increased requirements 2

Key Pitfalls to Avoid

• Never assume that because a compound is an antioxidant in vitro, it will provide clinical benefit at high doses 1
• Do not measure plasma vitamin C during acute illness, as inflammation makes interpretation unreliable 2
• Avoid mixing glutathione with vitamin C in IV infusions due to chemical incompatibility concerns 4
• Do not use antioxidant supplements during active cancer treatment 3
• The American Diabetes Association emphasizes that antioxidant supplements should not be recommended due to lack of efficacy and safety concerns 3