A critical review of the antioxidant controversy/safety issues for fatsoluble

Transcription

1 A critical review of the antioxidant controversy/safety issues for fatsoluble vitamins Hans K. Biesalski MD PhD Dept. Biological Chemistry and Nutrition University Stuttgart-Hohenheim

2 More than hundred studies exist describing beneficial effects of antioxidants on different diseases. A few large intervention studies could not confirm the results. Some of them even described harmful outcome Nevertheless bad news are good news antioxidants are claimed to be not even unnecessary but harmfull!

3 Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and metaanalysis. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. CONCLUSIONS: Treatment with beta carotene, vitamin A, and vitamin E may increase mortality.

4 Bjelkovic et al., 2007: No increase of mortality in all 68 RCT Low risk of bias: 5% in increase of mortality in 47 studies 13 Studies with less than 1000 participants: 1% risk reduction High risk of bias: signifcant decrease of mortality 21 out of 68 mentioned mortality Mean duration of vitamin intake: 2.7 years

5 Intervention effect of antioxidant supplements vs placebo on mortality in trials with low risk of bias (14 out of 47 with only one death!) 5% increase of mortality

6 Intervention effect of antioxidant supplements vs placebo or no intervention on mortality in trials with high risk of bias

7 Evaluation of the 68 studies of Bjelakovic according to the study goal: Total PP SP TT Positive outcome No effect Negative outcome

8 Vitamin deficiencies are not healthy! Treatment of the deficiency might result in a decrease of mortality. However, there is no evidence that vitamins can reduce mortality in the absence of a deficiency.

9

10

11 Method of evaluation: Questionnaire regarding multivitamin intake in the last twelve month in men with prostate cancer Result: Those who supplied multivitamins (>7/week) plus selenium were primarily affected. (RR 5.8 for fatal prostate cancer n=8) men with a genetic history in the family (RR n=3) Genetic?

12 All case mortality risk difference Meta Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality. Ann Intern. Med 2004 Miller et al participants in 19 clinical trials. 9 tested vitamin E alone 10 tested vitamin E combined with other vitamins and minerals Non-linear linear Vitamine E Harmful Vitamin E Beneficial IU Vitamin E

13 D. Vivekananthan et al., Lancet Vol 348 June Use of antioxidant vitamins for the prevention of cardiovascular disease: meta analysis of randomised trials. The lack of a salutary effect was seen consistently for various doses of vitamins in diverse populations. Our results combined with the lack of mechanistic data for efficacy of vitamin E, do not support the routine use of vitamine E.

14 Odds ratios (95% Cl) of the combined endpoint of cardiovascular death or non-fatal MI for individuals treated with vitamin E or control therapy. Source: Vivekananthan DP, The Lancet 361, 2003

15 Odds ratios (95% Cl) of all-cause mortality for individuals treated with vitamin E or control therapy. Source: Vivekananthan DP, The Lancet 361, 2003

16 Number of events in the CHAOS-Study P<0.001 P<0.015 α-tocopherol (800/400 IE) Placebo Stephens et al., Lancet 1996 Dosis? Mono? Non Fatal MI Major CV Events CV death All death

17 Six year effect of combined vitamin C and E supplementation on atherosclerotic progression. Salonen et al. Circulation 107: years supplementation with 136mg vitamin E and 250mg vitamin C twice daily slowed down progression of carotid atherosclerosis in men but not in women. Further slow down of progression in hypercholesteronemic persons.

18 Intima Media Durchmesser der Carotis bei supplementierten (3 Jahre 136mg Vitamin E und 250mg Vitamin C 2xtäglich) und Placebo Source: Salonen RM, Circulation, 2002 * Common-carotid artery-intima media thickness

19 What can vitamins (or essential micronutrients) in general really do? In physiological doses they can act within their usual homoeostatic control and can compensate an inadequate intake and not more! Consequence: If they work in physiological doses there must have been a deficiency or inadequate supply! The major question is: what was the reason for the deficiency?

20 Up to 50% of patients with chronic musculo-sceletal pain have an insufficient Vitamin D supply (NHANES III) Supplementation with moderate doses of vitamin D completely abolished pain Even vitamin D acts as a pain killer this effect is based on the compensation of a vitamin D-deficiency. Special risk groups: Elderly and Immigrants

21 Vitamin D-deficiency in healthy groups Vailed and non-vailed turkish women in Germany or Turkey (Erkal et al., 2006)

22 25(OH)D Plasmalevel and muscolo-sceletal pain (Erkal et al., 2006)

23 With increasing age the ability of the skin to synthesize vitamin D decreases. In elderly > 65 years the vitamin D ysynthesis drops to 25% of normal. Paradoxically the plasma vitamin D levels are higher in northern than southern Europe. Lips P. JSB 2007

24 If there is a deficiency the compensation works!! Low 25 hydroxyvitamin D and 1,25- dihydroxyvitamin D levels are independently associated with all cause (RR 2.08) and cardiovascular mortality (RR 2.22). (Dobnig et al., Arch Int Med. 2008) Women who are vitamin D-deficient have a 253% increased risk for developing colorectal cancer, and women who ingested 1500mg Ca/da and 1100 IU/d vitamin D3 for 4yr reduced risk for developing cancer by 60% (Holick MF JANS 2008)

25 If there is a deficiency the compensation works!! For a marginal or subclinical deficiency only a few marker if at all exist. To measure effectiveness of antioxidants it is not enough to look at an endpoint It is of importance to show that supplementaion with antioxidant has indeed an antioxidative effect! If there is an antioxidative effect, there was a need!

26 Time course of reduction in plasma concentration of F2-isoprostanes in participants supplemented with 3200 IU/day Vitamin E Plasma concentrations of vitamin E measured after 16 weeks of supplementation with variing doses of vitamin E or placebo Roberts LJ et al., FRBM 43: 2007

27 Change in F2-isoprostane by quintile of baseline F2 Isopro Vitamin C supplementation (1000mg/d 2 month) reduced F2Isopro 22% when F2 baseline levels were > 50µg/ml (Block G. FRBM 2008) One participant died due to a car accident if not mentioned antioxidants might have killed him!

28 Baseline F2 Isopro levels > 50µg/ml was strongly associated with BMI and was present in 42% of the sample (Block G et al., FRBM 2008) The activity depends on the underlying oxidative stress

29 Can Vitamins or antioxidants reduce mortality if supplied in higher doses? 28% risk reduction for mortality in trauma patients (2.272 vs control 2.022) exposed to high doses of antioxidants (Vit. C, E, Se) for 7 days (Collier et al., JPEN 32: 2008)

30 Plasma concentrations in a subset of patients receiving antioxidant supplementation and those receiving standard care AOX Risk of multiple organ failure among 301 patients receiving antioxidant supplementation and 294 pateints receiving standard care Nathens et al., Ann Surg 236:2002

31 Is there a need for aditional vitamins or should we follow the general paradigm: There is enough nutrition for all, additional vitamins are not needed!

32 100% 90 % not reaching the recommendations in the National Nutrition Survey male female VD FA VE Ca VA Mg Zn B1 B2

33 Main dietary sources for Vitamin E

34 Intake of vitamins in consumers of supplements from different sources: (usual and fortified food; fortified instant beverages; supplements) Sichert-Hellert et al., 2006

35 Mean intake in Germany: 12mg/day Recommendation 2006: 15mg/day 100% only with fortified food and beverages Sufficient Vitamin E intake cannot easily achieved via nutrition. What about prevention?

36 Plasma a-tocopherol concentration by tertile of a-tocopherol intake among all subjects (602) A or non-supplement users B (272) 75% of the USpopulation do not even meet the EAR for Vitamin E (NHANES III) Gao et al., J Nutr. 136; 2006

37 What can vitamins (or essentiel micronutrients) in general really do in secondary prevention? Diseases and xenobiotics have different impacts on micronutrient requirement and turnover. Consequently, the appropriate dosis to ensure the individual need in a disease state may vary. Consequently, in secondary prevention the doses needed to compensate an inadequate supply may be higher than the doses needed for primary prevention

38 Malnutrition increases complications (n=709) % patients Pulmonary infection Urinary infection Wound inf ection Sepsis Intraabdominal abscess Extraperitoneal abscess Septic coagulopathy Respiratory failure Cardiac arrest Cardiac arrythmia Cardiac failure Wound dehiscence Well nourished (SGA) Malnourished (SGA) Correia et al, Clin Nutrition 2003; 22:

39 Worsening in oxidative stress (Lipidperoxidation, protein-oxidation) according to intake of antioxidant vitamins prior ICU administration in critically ill % 89% Higher ox.stress Lower ox.stress 20 33% AOX intake between 66% to 100% of RDA 11% AOX intake below 66% of RDA Abiles et al. Crit Care 2006

40 Low intake of antioxidants may have an impact in the long term (CHD, Cancer, Neurological diseases) Risk groups for poor antioxidant status Elderly Strong vegetarians Smoker Chronic alcohol intake (more than moderate) Obesity Dieting (< kcal) Diabetes COPD Chronic imflammatory diseases Cancer Fat Malabsorption

41 What can vitamins (or essentiel micronutrients) in general really do in primary prevention? A diet rich in all essentiel micronutrients protects from a couple of diseases in later life. Consequently, in primary prevention micronutrients protect from deficiency in physiological doses.

42 What can vitamins (or essentiel micronutrients) in general really do? In pharmacological doses they can act as micronutrients and in addition by circumventing the homoeostatic control may also act in a different way! Consequence: If they work in pharmacological doses they may or should be treated like xenobiotics!

43 Conclusion The primary goal to supplement antioxidants is to ensure an adequate supply adapted to the life cycle. Normal intake achievable via nutrition (RDA) may be enough in a healthy status. However, diseases may result in a higher need. Antioxidants are not recommended to increse life span but to improve life quality in chronic diseases