I HAVE NO CONFLICTS OF INTEREST Page 1 Vitamins / supplements to be - PDF document

Updates in Nutrition and Exercise: New Trials and New Guidelines for the Average Adult Jeffrey A. Tice, MD Professor of Medicine Division of General Internal Medicine University of California, San Francisco I HAVE NO CONFLICTS OF INTEREST Page 1

Vitamins / supplements to be covered • Antioxidants briefly • Folate / Homocysteine briefly • Vitamin D / Calcium – USPSTF, New trial • Fish oil / Omega-3 – CVD: New Trials and MA • 2018 Exercise Guidelines Page 2

Audience Question #1 • Are you currently taking: a. Vitamins? b. Other supplements? c. Both? d. Neither Vitamin Use in the U.S.A. “To improve or maintain overall health.” • 52% of Americans and increasing – More than doubled since 1970s • $41 billion on supplements in 2016 • Reports from observational studies of diet are very popular with patients and are always in the news • MVI, Vitamins C & D, calcium, omega-3s Dickinson, JACN, 2014 Page 3

Why antioxidants? • Antioxidants prevent the free radical damage that is associated with cancer, heart disease, and aging • Antioxidants are provided by a healthy diet that includes a variety of fruits and vegetables • Observational studies consistently show higher intake / blood levels associated with less cancer, heart disease, and death ß Carotene and Retinol Efficacy Trial (CARET) • Subjects – 18,000 smokers – Ages 45 – 74 • RCT ß-carotene 30 mg • Outcome: Lung CA, Death, CVD death Page 4

CARET Randomized Trial Results > 18,000 participants followed for 4+ years on beta-carotene or placebo Omenn, NEJM, 1996 Vitamin E • The primary fat soluble anti-oxidants • US RDA 22 IU in men and women • Deficiency: Rare • Observational studies: dose response reduction in CVD events up to daily intake > 200 IU per day Page 5

The answer! • Meta-analysis of 47 high quality randomized trials of antioxidants • 181,000 individuals • 25,000 deaths Bjelakovic, JAMA, 2007. Death from any cause • Vitamin A 16% increase • Beta-carotene 7% increase • 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. Page 6

Folate, Homocysteine, and Heart Disease Homocysteine and Risk of Death Homocysteine RR < 9 1.0 9-14.9 3.3 15-19.9 6.3 ≥ 20 9.9 p<0.001 Observational study! Nygard, NEJM, 1997 Page 7

The Answer! • Pooled meta-analysis of 8 large, high quality randomized trials • 37,485 individuals • 5,125 deaths • 9,326 major vascular events • 3,010 cancers Clarke, Archives IM, 2010. Folate / Homocysteine RCTs • Homocysteine 25% decrease • Death No effect: 1.02 (.97-1.08) • CVD events No effect: 1.01 (.97-1.05) • Cancer No effect: 1.05 (.98-1.13) Folate does not prevent cancer or heart disease Clarke, Archives IM, 2010. Page 8

Folate And Neural Tube Defects (NTD) • 70% reduction in 2 nd occurrences – 4 mg of folate • 63% reduction in 1 st occurrence – 0.4 mg of folate • Since flour fortification – 46% reduction in NTD Meta-analysis, Blencowe, IJE, 2010. That is the question! TO D OR NOT TO D...? Page 9

Audience Question #2 • The 2018 US Preventive Services Task Force updates recommend Vitamin D for: a. Prevention of falls b. Prevention of fractures c. Both d. Neither Institute of Medicine Report Panel reviewed 1000 studies on 25 health outcomes to update previous 1997 recommendations Page 10

Vitamin D: Adult Dietary Reference Intake* (U.S.) • Age • 1-70 years 600 IU / day • > 70 years 800 IU / day *Institute of Medicine, 2010: Sufficient to meet the needs of virtually all people. Vitamin D levels in Americans Prevalence of inadequate 25(OH) vitamin D among American women ≥14 years old by IOM definitions < 12 ng/ml 10 to 12% At risk of deficiency < 20 ng/ml 34 to 39% At risk of inadequacy < 30 ng/ml ~80% Why so little D? NHANES 2003-2006 Page 11

Vitamin D: The New Panacea • Reduces the following diseases... – Cancer (Colon, Breast, Prostate, Pancreatic, ...) – Cardiovascular disease – Multiple sclerosis, Type 1 DM, RA – Influenza and URIs – Chronic pain – Total Mortality! RCT: VIDARIS Trial, JAMA, October 2012 • 322 healthy adults in New Zealand • 100,000 IU D3 monthly • 18 months follow-up 25(OH) D URI incidence Vitamin D 48 ng/mL 3.7 infections/person Placebo 25 ng/mL 3.7 infections/person Page 12

VITAL (VIT D and OmegA-3 TriaL) • RCT n = 25,871 • Vitamin D3 2000 IU daily; adherence 80% • Follow-up: Median 5.3 years (3.8-6.1) • Participants – 67.1 years old – 51% female – 20% Black, 4% Hispanic, 71% NHW Manson et al, NEJM, 2018 VITAL: Vitamin D Results Outcome Hazard Ratio (95% CI) Cancer* 0.96 (0.88-1.06) Breast Cancer 1.02 (0.79-1.31) 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) Myocardial Infarction 0.96 (0.78-1.19) Death from Any Cause 0.99 (0.87-1.12) * Co-Primary Endpoints ; 24 endpoints reported in Table 2 Manson et al, NEJM, 2018 Page 13

Vitamin D and Bone Strength • RCT n = 311 • Vitamin D3 400 vs. 4,000 vs 10,000 IU daily • Follow-up: 3 years • Dose response: higher 25(OH)D, lower PTH • Unexpected dose response : lower bone density, greater loss of bone Burt et al, JAMA, 2019 US Preventive Services Task Force • 2018 – Vitamin D for fracture prevention (I) – Vitamin D for fall prevention (D) I = Insufficient evidence: the balance of benefits and harms cannot be determined D = The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Page 14

What About Calcium? IOM Report 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 2500 mg/day Tolerable Upper Intake Level: Page 15

Meta-analysis Annals IM 10/25/2016 • Calcium intake in RDA range is not associated with CVD in health adults • Editorial – Imperfect evidence – Diet is safer (fewer kidney stones) – Low fat dairy, tofu, canned fish with bones: 2-3 servings/day Vitamin D and Calcium Take Home Points • Target frail, older patients for fracture prevention • 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 Page 16

A fishy story… OMEGA 3 FATTY ACIDS Omega-3 Fatty Acids • Oily, cold water fish = best sources of Ω -3 fatty acids – EPA = eicosapentanoic acid – DHA = docosahexanoic acid • People who consume fish rich in EPA and DHA have fewer fatal and non fatal CV events Page 17

Randomized trials of Ω -3s in heart disease • GISSI-Prevention: Lancet 1999 – Only positive trial • 2010: 5 studies. NEJM, Circ, JAMA, BMJ – Not even a trend towards benefit for post-MI, CVD or atrial fibrillation • Intubated with acute lung injury: JAMA 2011 – Harm: 3 extra days in ICU, trend - more death (p=0.054) • 2018: RCT in >15,000 patients w/ diabetes, new MA – No benefit VITAL (VIT D and OmegA-3 TriaL) • RCT n = 25,871 without CVD or cancer • Murine omega-3 FA 1 g daily; adherence 80% • Follow-up: Median 5.3 years (3.8-6.1) • Participants – 67.1 years old – 51% female – 20% Black, 4% Hispanic, 71% NHW Manson et al, NEJM, 2018 Page 18

VITAL: Omega-3 FA Results Outcome Hazard Ratio (95% CI) Cancer* 1.03 (0.93-1.13) Breast Cancer 0.90 (0.70-1.16) Death from Cancer 0.97 (0.79-1.20) Major CVD Event* 0.92 (0.80-1.06) Death from CVD 0.96 (0.76-1.21) Myocardial Infarction 0.72 (0.59-0.90) Death from Any Cause 1.02 (0.90-1.15) * Co-Primary Endpoints; 24 endpoints reported in Table 2 Manson et al, NEJM, 2018 REDUCE-IT • RCT n = 8,179 with CVD or DM on statin with LDL <100 and TG 135-499 mg/dL • Icosapent ethyl (EPA) 2 gm BID (Vascepa) • Follow-up: Median 4.9 years • Participants – 64 years old – 29% female – 90% White Bhatt NEJM 2019 Page 19

REDUCE-IT Bhatt NEJM 2019 New Meta-Analysis this month • N = 127,477 followed for 5 years • Small benefit: total CVD ARR 0.622 = NNT 161 • Dose response for outcomes • Total mortality not reported Hu JAHA 2019 Page 20

Summary Omega-3 FA / Fish oil • Minimal to no benefit for supplements in modern era of medical therapy for vascular disease • Pharmaceutical: Vascepa – 4 gm daily – Lowers TG – Appears to lower CVD event rates General principles • Eat enough to avoid deficiency • Doses significantly above RDAs are unhelpful and may be harmful ≠ Page 21

Summary • Beta-carotene Discourage - harmful • Vitamin E Discourage - harmful • Folate For child-bearing age to prevent neural tube defects • Vit D + calcium Older, frail patients to prevent fractures • Fish oil / Omega Discourage – minimal 3 FA to no benefit Michael Pollan ’ s Recommendations • Eat real food • Not too much • Mostly plants • Some fish • Mediterranean Diet Page 22