Page 1 Vitamins / supplements to be covered Audience Question #1 - PDF document

Updates in Nutrition and Exercise: New Trials and New Guidelines for the Average Adult Jeffrey A. Tice, MD Professor of Medicine I HAVE NO CONFLICTS OF INTEREST Division of General Internal Medicine University of California, San Francisco In the news this week… • Annals of Internal Medicine – Conclusion: Use of dietary supplements is not associated with mortality benefits among U.S. adults • Canadian Medical Association Journal – Use of vitamin D drops leading to kidney failure in a 54-year-old man Page 1

Vitamins / supplements to be covered Audience Question #1 • Antioxidants briefly • Are you currently taking: • Folate / Homocysteine briefly a. Vitamins? • Vitamin D / Calcium b. Other supplements? – USPSTF, New trial c. Both? • Fish oil / Omega-3 d. Neither – CVD, Diabetes, New Trial • 2018 Exercise Guidelines Vitamin Use in the U.S.A. “To improve or maintain overall health.” Why antioxidants? • Antioxidants prevent the free radical damage • 52% of Americans and increasing that is associated with cancer, heart disease, – More than doubled since 1970s and aging • $41 billion on supplements in 2016 • Antioxidants are provided by a healthy diet that includes a variety of fruits and • Reports from observational studies of diet vegetables are very popular with patients and are • Observational studies consistently show always in the news higher intake / blood levels associated with • MVI, Vitamins C & D, calcium, omega-3s less cancer, heart disease, and death Dickinson, JACN, 2014 Page 2

ß Carotene and Retinol Efficacy Trial (CARET) CARET Randomized Trial Results > 18,000 participants followed for 4+ years on beta-carotene or placebo • Subjects –18,000 smokers –Ages 45 – 74 • RCT ß-carotene 30 mg • Outcome: Lung CA, Death, CVD death Omenn, NEJM, 1996 Vitamin E The answer! • The primary fat soluble anti-oxidants • Meta-analysis of 47 high quality • US RDA 22 IU in men and women randomized trials of antioxidants • Deficiency: Rare • 181,000 individuals • Observational studies: dose response • 25,000 deaths reduction in CVD events up to daily intake > 200 IU per day Bjelakovic, JAMA, 2007. Page 3

Death from any cause • Vitamin A 16% increase Folate, Homocysteine, and Heart • Beta-carotene 7% increase Disease • Vitamin E 4% increase • Vitamin C Trend towards increase (6%) All p << 0.05 except vitamin C Bottom line: actively discourage anti-oxidant use Bjelakovic, JAMA, 2007. Homocysteine and Risk of Death The Answer! Homocysteine RR • Pooled meta-analysis of 8 large, high < 9 1.0 quality randomized trials 9-14.9 3.3 15-19.9 6.3 • 37,485 individuals ≥ 20 9.9 p<0.001 • 5,125 deaths • 9,326 major vascular events Observational study! • 3,010 cancers Nygard, NEJM, 1997 Clarke, Archives IM, 2010. Page 4

Folate / Homocysteine RCTs Folate And Neural Tube Defects (NTD) • 70% reduction in 2 nd occurrences • Homocysteine 25% decrease – 4 mg of folate • Death No effect: 1.02 (.97-1.08) • 63% reduction in 1 st occurrence • CVD events No effect: 1.01 (.97-1.05) – 0.4 mg of folate • Since flour fortification • Cancer No effect: 1.05 (.98-1.13) – 46% reduction in NTD Meta-analysis, Blencowe, IJE, 2010. Folate does not prevent cancer or heart disease Clarke, Archives IM, 2010. Audience Question #2 • The 2018 US Preventive Services Task Force updates recommend Vitamin D for: a. Prevention of falls That is the question! b. Prevention of fractures TO D OR NOT TO D...? c. Both d. Neither Page 5

Vitamin D: Institute of Medicine Report Adult Dietary Reference Intake* (U.S.) • Age • 1-70 years 600 IU / day • > 70 years 800 IU / day Panel reviewed 1000 studies on 25 health outcomes to update *Institute of Medicine, 2010: Sufficient to meet the needs of virtually previous 1997 recommendations all people. Vitamin D levels in Americans Vitamin D: The New Panacea • Reduces the following diseases... Prevalence of inadequate 25(OH) vitamin D – Cancer (Colon, Breast, Prostate, Pancreatic, ...) among American women ≥ 14 years old by – Cardiovascular disease IOM definitions – Multiple sclerosis, Type 1 DM, RA < 12 ng/ml 10 to 12% At risk of deficiency – Influenza and URIs < 20 ng/ml 34 to 39% At risk of inadequacy < 30 ng/ml ~80% – Chronic pain – Total Mortality! Why so little D? NHANES 2003-2006 Page 6

RCT: VIDARIS Trial, JAMA, October 2012 VITAL (VIT D and OmegA-3 TriaL) • RCT n = 25,871 • 322 healthy adults in New Zealand • Vitamin D3 2000 IU daily; adherence 80% • 100,000 IU D3 monthly • Follow-up: Median 5.3 years (3.8-6.1) • 18 months follow-up • Participants 25(OH) D URI incidence – 67.1 years old – 51% female Vitamin D 48 ng/mL 3.7 infections/person – 20% Black, 4% Hispanic, 71% NHW Placebo 25 ng/mL 3.7 infections/person Manson et al, NEJM, 2018 VITAL: Vitamin D Results US Preventive Services Task Force Outcome Hazard Ratio (95% CI) • 2018 Cancer* 0.96 (0.88-1.06) – Vitamin D for fracture prevention (I) Breast Cancer 1.02 (0.79-1.31) – Vitamin D for fall prevention (D) Death from Cancer 0.83 (0.67-1.02) Major CVD Event* 0.97 (0.85-1.12) Death from CVD 1.11 (0.88-1.40) I = Insufficient evidence: the balance of benefits and Myocardial Infarction 0.96 (0.78-1.19) harms cannot be determined D = The USPSTF recommends against the service. There Death from Any Cause 0.99 (0.87-1.12) is moderate or high certainty that the service has no net * Co-Primary Endpoints ; 24 endpoints reported in Table 2 benefit or that the harms outweigh the benefits. Manson et al, NEJM, 2018 Page 7

IOM Report Calcium What About Calcium? Recommendations DRI – Adequate Intake Adolescents: 1300 mg/day Women and men (19-50 years): 1000 mg/day Women and men (>50 years): 1200 mg/day Current intake levels: Women: ~1/3 of their recommended intake Men: ~3/4 of their recommended intake Tolerable Upper Intake Level: 2500 mg/day Vitamin D and Calcium Take Home Points • Target frail, older patients • 800 IU of vitamin D3 per day is sufficient – Ensure adequate calcium intake – Dietary calcium preferred • Evidence is strong: no benefit for other diseases • Avoid large doses of either supplement A fishy story… OMEGA 3 FATTY ACIDS Page 8

Omega-3 Fatty Acids Randomized trials of Ω -3s in heart disease • Oily, cold water fish = best sources of Ω - • GISSI-Prevention: Lancet 1999 3 fatty acids – Only positive trial –EPA = eicosapentanoic acid • 2010: 5 studies. NEJM, Circ, JAMA, BMJ –DHA = docosahexanoic acid – Not even a trend towards benefit for post-MI, CVD or atrial • People who consume fish rich in EPA fibrillation and DHA have fewer fatal and non fatal CV events • Intubated with acute lung injury: JAMA 2011 • 1-2 servings/week fish associated with – Harm: 3 extra days in ICU, trend - more death (p=0.054) 36% less risk of CV death and 17% less • 2018: RCT in >15,000 patients w/ diabetes, new MA total mortality – No benefit VITAL (VIT D and OmegA-3 TriaL) VITAL: Omega-3 FA Results • RCT n = 25,871 Outcome Hazard Ratio (95% CI) Cancer* 1.03 (0.93-1.13) • Murine omega-3 FA 1 g daily; adherence 80% Breast Cancer 0.90 (0.70-1.16) • Follow-up: Median 5.3 years (3.8-6.1) Death from Cancer 0.97 (0.79-1.20) • Participants Major CVD Event* 0.92 (0.80-1.06) Death from CVD 0.96 (0.76-1.21) – 67.1 years old Myocardial Infarction 0.72 (0.59-0.90) – 51% female Death from Any Cause 1.02 (0.90-1.15) – 20% Black, 4% Hispanic, 71% NHW * Co-Primary Endpoints; 24 endpoints reported in Table 2 Manson et al, NEJM, 2018 Manson et al, NEJM, 2018 Page 9

General principles Summary Omega-3 FA / Fish oil • Eat enough to avoid deficiency • No benefit in modern era of medical therapy for vascular disease • Doses significantly above RDAs are unhelpful and may be harmful • No significant harms: trend towards fewer deaths in most trials, though not VITAL � • Discourage use Michael Pollan � s Recommendations Summary • Beta-carotene Discourage - harmful • Eat real food • Vitamin E Discourage - harmful • Not too much • Folate For child-bearing age to prevent neural tube • Mostly plants defects • Vit D + calcium Older, frail patients to prevent fractures • Some fish • Mediterranean Diet • Fish oil / Omega Discourage – no benefit 3 FA Page 10

Physical Activity and Health ? Move 2018 Physical Activity Guidelines SO WHAT ELSE CAN WE DO? Advisory Committee Scientific Report, 2 nd Edition US Dept of Health and Human Services Key Evidence Based Benefits Impact of Limited Physical Activity (RCT) of Exercise • Improves sleep quality • Inadequate physical activity (not meeting the physical activity guideline) • Improves cognitive function –$117 billion in annual health costs • Reduces depression and anxiety –10% of premature mortality • Improves quality of life • Prevent falls, fractures, obesity, diabetes, cancer, CAD, dementia … 2018 Physical Activity Guidelines Carlson, Prev Chron Dis, 2018; Carlson, PCD, 2015. Page 11