Understanding Vitamin D: To D or not to D? Anastassios G Pittas, MD MS Tufts Medical Center

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1 Understanding Vitamin D: To D or not to D? Anastassios G Pittas, MD MS Tufts Medical Center D2dstudy.org pittas@d2dstudy.org Disclosure: NIH funding

2 Popularity of vitamin D RESEARCH CONSUMERS Publications in PubMed with term found in title or abstract

3 Please, raise your hand if you take a specific vitamin D supplement (outside of a multivitamin) Keep your hand raised if you take more than 4000 IU/day

4 Trends in use of high-dose vitamin D supplements Proportion of U.S. adults reporting use 1000 IU OR MORE 4000 IU OR MORE Rooney et al JAMA 2017

5 Panacea (Greek goddess of healing)

Is Vitamin D the Bipartisan Solution to U.S. Health Care Reform?

Europeans had 25(OH)D > 40 ng/ml 18% Due to low

used best-case scenario data; method of economic

6 Is Vitamin D the Bipartisan Solution to U.S. Health Care Reform? * Total Health Care Expenditures saved, if all Europeans had 25(OH)D > 40 ng/ml 18% Due to low vitamin D Other 82% *Caveats (small print): analyses used best-case scenario data; method of economic burden calculations not provided. Grant et al 2009, Grant 2011

8 A typical day in the clinic 44-yr old healthy woman, except for being at risk for diabetes (BMI 27, +FH), receives a letter shortly after her physical in April, with the following advice: You are deficient in Vitamin D. It is important to take units of Vitamin D every day to prevent diabetes.

9 A typical day in the clinic 44-yr old healthy woman, except for being at risk for diabetes (BMI 27, +FH), receives a letter shortly after her physical in April, with the following advice: You are deficient in vitamin D. It is important to take units of Vitamin D every day to prevent diabetes.

10 A typical day in the clinic 44-yr old healthy woman, except for being at risk for diabetes (BMI 27, +FH), receives a letter shortly after her physical in April, with the following advice: What do you mean by deficient? You are deficient in vitamin D. It is important to take units of Vitamin D every day to prevent diabetes.

11 Vitamin D Dietary Sources are Limited Natural resources Cod liver oil Oily fish (e.g. swordfish, salmon, tuna) Egg yolks Fortified foods Milk, orange juice Some yogurt Many cereal Dietary supplements * Disclaimer : There is no fruit in Fruity Pebbles

12 Evolutionary appropriate source of vitamin D Cutaneous biosynthesis upon solar UVB exposure Skin

13 Deficient? Deficiency Avoid specific syndromes Rickets Osteomalacia Suboptimal Delay chronic disease Osteoporosis, diabetes, cancer, multiple sclerosis etc. Optimal Maximize physiologic function to optimize wellbeing AND confer a minimum risk of disease By Deficiency, we really mean insufficiency or suboptimal status

14 A typical day in the clinic 44-yr old healthy woman, except for being at risk for diabetes (BMI 27, +FH), receives a letter shortly after her physical in April, with the following advice: What does in vitamin D mean? You are deficient in vitamin D. It is important to take units of Vitamin D every day to prevent diabetes.

15 Rosen NEJM 2011 in Vitamin D = blood 25(OH)D concentration 25(OH)D a biomarker of vitamin D status

16 25(OH)D, a wildly popular blood test Arch Pathol Lab Med Feb; 138(2):

17 Please, raise your hand if you know your vitamin D level Keep your hand know if you know what that level means

18 25(OH)D, a biomarker of vitamin D status o Biomarker of exposure Validated measure to reflect intake or biosynthesis

19 25(OH)D (a biomarker of exposure) after infrequent, very high-dose vitamin D supplementation 500,000 units of cholecalciferol (D 3 ) yearly Sanders et al 2010 JAMA

20 25(OH)D, a biomarker of vitamin D status o Biomarker of exposure Validated measure to reflect intake or biosynthesis o Biomarker of effect (= causal association) Causally related to and predictive of important health outcomes High LDL => CVD Low 25(OH)D => rickets Biomarker of Exposure Biomarker of Effect

21 Prerequisites for Causal Association of 25(OH)D with a condition (e.g., Diabetes) Plausible mechanism Specificity (not required) Temporal relationship [longitudinal studies] Strength of the association [high relative risk] Dose response o Consideration of alternative explanations o Experimental evidence o Cessation/removal of exposure (i.e., clinical trials) o Coherence [consistency among studies] Bradford Hill s Guidelines, Howick et al JRSocMe 2009

22 Vitamin D: A Bedroom Boost? Barassi A et al. Vitamin D and erectile dysfunction. J Sex Med 2014

23 Risk decreases by 35% for 25OHD (ng/ml) >25 vs. <15 (approx.) Association of 25OHD with Incident Diabetes Meta-analysis of longitudinal Observational Studies Song et al Diabetes Care 2013

24 44-yr old healthy woman, except for being at risk for diabetes (BMI 27, +FH), receives a letter shortly after her physical in April, with the following advice: Is it REALLY important to take vitamin D to prevent diabetes? You are deficient in vitamin D. It is important to take units of Vitamin D every day to prevent diabetes.

25 Prerequisites for Causal Association of 25(OH)D with a condition (e.g., Diabetes) Plausible mechanism Specificity (not required) Temporal relationship [longitudinal studies] Strength of the association [high relative risk] Dose response o Consideration of alternative explanations o Experimental evidence o Cessation/removal of exposure (i.e., clinical trials) Coherence [consistency among studies] Bradford Hill s Guidelines, Howick et al JRSocMe 2009

26 Factors that contribute to low 25(OH)D level Genetics Dietary pattern Food group Food Nutrient Intake Malabsorption Aging Lactose intolerance Gluten enteropathy Gastric surgery Biliary disease Medit diet Dairy Milk Vit D Skin (dark) Pigmentation UVB Exposure Cutaneous synthesis >90% Vitamin D Smoking Low intake of fish, alcohol Season, latitude > 43 o ; altitude; duration of sunlight; cloud cover; ozone cover; air pollution; time of day; protective clothing; sunscreen; physical inactivity; homebound; indoor lifestyle; Aging Genetics Baseline 25OHD Bioavailability ( in obesity) Illness (acute phase reactant) Diabetes AG Pittas

27 Factors that contribute to Diabetes risk Genetics Dietary pattern Food group Food Nutrient Intake Malabsorption Aging Lactose intolerance Gluten enteropathy Gastric surgery Biliary disease Medit diet Dairy Milk Vit D Skin (dark) Pigmentation Cutaneous synthesis >90% UVB Exposure Vitamin D Smoking Low intake of fish, alcohol Season, latitude > 43 o ; altitude; duration of sunlight; cloud cover; ozone cover; air pollution; time of day; protective clothing; sunscreen; physical inactivity; homebound; indoor lifestyle Aging Genetics Baseline 25OHD Bioavailability ( in obesity) Illness (acute phase reactant) Diabetes AG Pittas

28 Confounding, a major pitfall of observational studies with Vitamin D Is vitamin D status [i.e., low blood 25(OH)D] simply a marker of diabetes risk? A strong association supplementation would be beneficial

Hopkinson and Hopkinson 2013 Does vitamin D contribute

The Hobbit, an unexpected deficiency Vitamin D score

exposure (3p) and diet (1p) Outcomes: good vs.

29 Hopkinson and Hopkinson 2013 Does vitamin D contribute to the triumph of good over evil? The Hobbit, an unexpected deficiency Vitamin D score (0-4 points) based on diurnal habits, dwelling, light exposure (3p) and diet (1p) Outcomes: good vs. evil or victorious vs. defeated Vitamin D score good 3.4 vs. evil 0.4 (p<0.001) Conclusion: triumph of good over evil correlates with vitamin D score. Supplementation may be of benefit in achieving goodness.

30 Prerequisites for Effect (Causal Association) of Vitamin D [biomarker] with Diabetes [outcome] Plausible mechanism Specificity [not required] Temporal relationship [longitudinal studies] Strength of the association [high relative risk] Dose response Consideration of alternative explanations o Experimental evidence o Cessation/removal of exposure (i.e., clinical trials) Coherence [consistency among studies] Bradford Hill s Guidelines, Howick et al JRSocMe 2009

31 Vitamin D supplementation in young, healthy people with normal glucose tolerance Mitchell et al AJCN 2015

32 If your glucose (cholesterol etc.) is normal vitamin D will not make the level more normal

33 A diabetes prevention trial to determine whether vitamin D supplementation delays the onset of diabetes in people at risk for diabetes.

34 A diabetes prevention trial to determine whether vitamin D supplementation delays the onset of diabetes in people at risk for diabetes units vitamin D 3 2,423 patients with Pre-Diabetes Randomized (1:1) All participants receive current recommendations for pre-diabetes, vitamin D and calcium intake Follow-up ~4 years Incident Diabetes Placebo Pittas et al Diabetes Care 2014 Rationale and Design of D2d

35 Where is?

36 D2dstudy.org

37 Recently published large trials with vitamin D D (2000 IU/d) vs. 400 IU/d; 4 months; viral URI; n=703; age 27y; baseline 25OHD 36 ng/ml D (100,000 IU/m); CVD (ICD codes); n=5,110 New Zealand; age 50-84y; baseline 25OHD 26 ng/ml

38 Vitamin D 3 (2000 units/day) and calcium (1500 mg/day) and incidence cancer Incident cancer: 4.2 vs. 6.0% HR: 0.70 [0.47, 1.02] N=2,303 US White women (>55 y) Baseline 25OHD 33 ng/ml

39 44-yr old healthy woman, except for being at risk for diabetes (BMI 27, +FH), receives a letter shortly after her physical in April, with the following advice: So it does not really matter whether I take 1000 or 2000 units? Is more better? You are deficient in Vitamin D. It is important to take units of Vitamin D every day to prevent diabetes.

40 Vitamin D Recommended Intake Institute of Medicine (U.S.) 2011 Report RDA 1 Upper Limit 2 70 years 600 IU 4,000 IU > 70 years 800 IU 4,000 IU Under conditions of minimal sun exposure Applicable to normal healthy population groups 1 Recommended Dietary Allowance, intake that meets needs of 97.5% of healthy population for skeletal outcomes only 2 Tolerable Upper Intake Level, above which potential risk of adverse effects may increase with chronic use.

41 Association of 25OHD with Incident Diabetes Meta-analysis of Longitudinal Observational Studies Relative Risk (OH)D concentration, nmol/l Song et al Diabetes Care March 2013

42 More vitamin D may not be better Intake-Response Relationship for Nutrients = specific dose of vitamin D (e.g units) Morris and Tangney JAMA 2011

43 More vitamin D may not be better Longitudinal Observational Studies Cardiovascular disease Coronary Hearth Disease Pancreatic cancer Mortality Mortality Mortality (hospital)

44 More vitamin D has a diminishing effect on raising 25O(H)D Healthy, white post-menopausal women (n=163; baseline 25OHD 16 ng/ml), 1-year Gallagher et al Ann Intern Med 2012

45 44-yr old healthy woman, except for being at risk for diabetes (BMI 27, +FH), receives a letter shortly after her physical in April, with the following advice: You are deficient in Vitamin D. It is important to take units of Vitamin D every day to prevent diabetes. Can I take infrequent large doses, e.g. once a year?

46 Vitamin D 3 supplementation: Daily, weekly or monthly? Effective dose: 1,500 IU/day Ish-Shalom et al JCEM 2008

47 Infrequent, very high-dose vitamin D supplementation. Why not? 500,000 units of cholecalciferol (D 3 ) yearly Sanders et al 2010 JAMA

48 Infrequent, very high-dose vitamin D supplementation. Not a good idea. 500,000 units of cholecalciferol (D 3 ) yearly High infrequent (non-daily) doses of vitamin D may be metabolized differently and may have an unfavorable benefit/risk profile

49 44-yr old healthy woman, except for being at risk for diabetes (BMI 27, +FH), receives a letter shortly after her physical in April, with the following advice: Should I come back to re-check in 3 months? You are deficient in Vitamin D. It is important to take units of Vitamin D every day to prevent diabetes.

50 Seasonal variability of blood 25(OH)D level 22 ng/ml 30 ng/ml Measure 25(OH)D in April or October de Boer et al Ann Intern Med. 2012;156(9):

51 44-yr old healthy woman, except for being at risk for diabetes (BMI 27, +FH), receives a letter shortly after her physical in April, with the following advice: Your blood vitamin D level predicts risk of diabetes. In addition to following a plant-based diet, take 1000 units of vitamin D 3 every day, especially in the winter, until we have more information from ongoing studies. You are deficient in Vitamin D. It is important to take units of Vitamin D every day to prevent diabetes. Weather permitting, aim for 10 minutes of daily sun exposure without sunscreen. We don t need to check your vitamin D level every year.

52 Optimal 25OHD Concentration Institute of Medicine (U.S.) vs. Endocrine Society c ng/ml Deficiency < 12 Rickets, Osteomalacia Inadequacy Sufficiency Skeletal Outcomes ONLY IOM Sufficiency > 30 Skeletal & Non-skeletal Outcomes Endo Society

53 Which 25OHD threshold to follow, Institute of Medicine vs. Endocrine Society 100% 25 Insufficiency 77 80% Sufficiency 60% ~100 million US adults 40% 20% 0% IOM Endo Society

Vitamin D Replacement ROCKY MOUNTAIN MEETING NOV 2013 BANFF W.COKE UNIVERSITY OF TORONTO

Vitamin D Replacement ROCKY MOUNTAIN MEETING NOV 2013 BANFF W.COKE UNIVERSITY OF TORONTO Disclosures: (Academic Mea Culpa) No financial conflicts I have no expertise re: Vitamin D. OBJECTIVES: 1) Review