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Anastassios G Pittas, MD MS Associate Professor of Medicine

Vitamin D for Diabetes To D or not to D ? “It isn’t so much the things we don’t know that get us in trouble. It’s the things we know that may not be so”. Anastassios G Pittas, MD MS Associate Professor of Medicine Division of Endocrinology, Diabetes and Metabolism Tufts Medical Center

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Anastassios G Pittas, MD MS Associate Professor of Medicine

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  1. Vitamin D for DiabetesTo D or not to D?“It isn’t so much the things we don’t know that get us in trouble. It’s the things we know that may not be so” Anastassios G Pittas, MD MS Associate Professor of Medicine Division of Endocrinology, Diabetes and Metabolism Tufts Medical Center apittas@tuftsmedicalcenter.org www.D2dstudy.org

  2. Pleaseraise your hand if you take a specific vitamin D supplement (outside of a multivitamin)

  3. Panacea (Greek goddess of healing)

  4. Vitamin D, the 21st century version of Panacea

  5. Vitamin D, the 21st century version of Panacea Low vitamin D predicts fatal cancer, Pilz et al Independent association of low vitamin D with all cause-and cardiovascular mortality, Dobnig et al Low vitamin D predicts stroke, Pilz et al Association of vitamin D deficiency with heart failure and sudden cardiac death, Pilz et al Vtamin D predicts breast cancer tumor size, Brouwers (abstract) Vitamin D supplementation might increase testosterone levels, Pilzet al

  6. Vitamin D is Big Business

  7. The Bipartisan Solution to U.S. Health Care Reform * Total Health Care Expenditures saved, if all Europeans had 25(OH)D > 40 ng/ml • *Caveats (small print): analyses used “best-case scenario”data; • method of economic burden calculations not provided Grant et al 2009, Grant 2011

  8. Summary and Conclusions • Population 25OHD is lower than it used to be… but, so what? • Promising findings from observational research need confirmation in trials. • Supplementation with vitamin D is unnatural and potentially dangerous.

  9. Vitamin D Dietary Sources are Limited Holick NEJM

  10. Solar UVB Exposure in Decline

  11. Vitamin D Homeostasis 25OHD, a biomarker of vitamin D status 25OHD (ng/mL) trend over time 1988-1994  2001-2006 ~28 ~24 Looker et al AJCN 2008:88:1519 Looker et al NCHS Data Brief, No 59, March 2011 Rosen NEJM 2011

  12. Summary and Conclusions • Population 25OHD is lower than it used to be… but, so what?

  13. Definition of Biomarker • Biomarker of exposure • Validated measure to reflect intake or exposure • Example: 25-hydroxyvitamin D

  14. 25OHD concentration (biomarker of exposure)after infrequent very high-dose vitamin D supplementation 500,000 IU of cholecalciferol (D3) yearly Sanders et al 2010 JAMA

  15. Definition of Biomarker • Biomarker of exposure • Validated measure to reflect intake or exposure • Example: 25-hydroxyvitamin D • Biomarker of effect (causal association) • Validated measure that is causally related to and predictive of health outcome of interest • Example: LDL Biomarker of Exposure≠ Biomarker of Effect

  16. Prerequisites for Causal Association of Vitamin D with Disease • Biological plausibility • Specificity [not required] • Temporal relationship: longitudinal studies • Strength of the association: high relative risk • Dose response (except in thresholds) • Experimental evidence • Cessation/removal of exposure, intervention [RCT] • Consideration of alternative explanations • Coherence [consistency among studies] Bradford Hill’s criteria

  17. Vitamin D and Cellular Function Implications for Health beyond Bone 1-hydroxylase Ca2+ 25(OH)D 1,25(OH)2D VDR expression All cells [Ca2+]i 1-hydroxylase 1-hydroxylase expression 25(OH)D 1,25(OH)2D Pancreas (beta cell) Vasculature Immune cells Skin Colon Prostate Breast Placenta Brain VDR RXR VDRE gene Gene Expression

  18. Prerequisites for Causal Association of vitamin D with Diabetes • Biological plausibility • Specificity [not required] • Temporal relationship: longitudinal studies • Strength of the association: high relative risk • Dose response (except in thresholds) • Experimental evidence • Cessation/removal of exposure, intervention [RCT] • Consideration of alternative explanations • Coherence [consistency among studies]  X Bradford Hill’s criteria

  19. Risk of Incident Type 2 Diabetes by Joint Categories of Vitamin D and Calcium Intake Prospective Observational; Nurses Health Study cohort Pittas et al Diabetes Care 2006 29:3:650

  20. Risk of Incident Type 2 Diabetes by Joint Categories of Vitamin D and Calcium Intake Prospective Observational; Nurses Health Study cohort Risk by 33% Risk by 33% Pittas et al Diabetes Care 2006 29:3:650

  21. Association of 25OHD with Incident Type 2 Diabetes Nested Case-Control; Nurses Health Study cohort Supported by NIDDK R21DK78867 Risk by 48% p for trend 0.008 >33 ng/ml Pittas et al, Diabetes Care 2010

  22. Association of 25OHD with Incident DiabetesMeta-analysis of LongitudinalObservational Studies • Risk by35% • for 25OHD (ng/mL) >25-30 vs. <8-20 Relative Risk Knekt_FMC_Men 0.49 (0.15-1.64) Knekt_FMC_Women 0.91 (0.37-2.23) Knekt_MFH_Men 0.17 (0.05-0.52) Knekt_MFH_Women 1.45 (0.58-3.62) Pittas_NHS_Women 0.52 (0.33-0.83) 1.05 (0.62-1.76) Robinson_WHI Grimnes_Nonsmokers 0.73 (0.48-1.12) Grimnes_Smokers 0.68 (0.29-1.61) Gagnon_AusDiab 0.56 (0.36-0.86) Anderson_Healthcare Population 0.53 (0.43-0.65) 0.90 (0.40-1.90) Bolland_Women 0.65 (0.52-0.82) Combined .1 .25 .50 .75 1.0 2.0 5.0 Relative Risk Song et al(under review)

  23. Prerequisites for Causal Association of vitamin D with Diabetes • Biological plausibility • Specificity [not required] • Temporal relationship: longitudinal studies • Strength of the association: high relative risk • Dose response (except in thresholds) • Experimental evidence • Cessation/removal of exposure, intervention [RCT] • Consideration of alternative explanations • Coherence [consistency among studies]  X     Bradford Hill’s criteria

  24. Factors that Contribute to Vitamin D Deficiency/Insufficiency Skin Pigmentation UVB Exposure Season, Latitude > 43o, altitude; duration of sunlight; cloud cover; ozone cover; air pollution; time of day; Protective clothing; sunscreen Physical inactivity; homebound Dietary pattern “Medit diet” Food group Dairy Aging, Genetics Baseline 25OHD Cutaneous synthesis Food Milk Nutrient Vit D >90% Bioavailability ( in obesity) Intake Vitamin D Beta cell 1-a hydroxylase Malabsorption Aging Lactose intolerance Gluten enteropathy Gastric surgery Biliary disease 25(OH)D Kidney 1-a hydroxylase 1,25(OH)2D 1,25(OH)2D Diabetes

  25. Factors that Contribute to Vitamin D Deficiency/Insufficiency & Diabetes Skin Pigmentation UVB Exposure Season, Latitude > 43o, altitude; duration of sunlight; cloud cover; ozone cover; air pollution; time of day; Protective clothing; sunscreen Physical inactivity; homebound Dietary pattern “Medit diet” Food group Dairy Aging, Genetics Baseline 25OHD Cutaneous synthesis Food Milk Nutrient Vit D >90% Bioavailability ( in obesity) Intake Vitamin D Beta cell 1-a hydroxylase Malabsorption Aging Lactose intolerance Gluten enteropathy Gastric surgery Biliary disease 25(OH)D Kidney 1-a hydroxylase 1,25(OH)2D 1,25(OH)2D Diabetes

  26. Pitfalls of Observational Studies with Vitamin D and Disease Confounding Is vitamin D simply a marker of increased risk for disease Association ≠ “supplementation would be beneficial” Need Randomized Clinical Trials

  27. Prerequisites for Causal Association of vitamin D with Diabetes • Biological plausibility • Specificity [not required] • Temporal relationship: longitudinal studies • Strength of the association: high relative risk • Dose response (except in thresholds) • Experimental evidence • Cessation/removal of exposure, intervention [RCT] • Consideration of alternative explanations • Coherence [consistency among studies]  X    X X  Bradford Hill’s criteria

  28. Trials with vitamin D supplementationand type 2 Diabetes related outcomes 9 studies in participants without diabetes => no statistically significant effect on measures of glycemia 5 studies in patients with established type 2 Diabetes => 4 no statistically significant effect on measures of glycemia => 1 improvement on measures of glycemia Nilas et al 1984; Pittas et al 2007; Do Boer et al 2008;Avenell et al 2009; Nagpal et al 2009; Zittermannet al 2009; Von Hurst et al, 2010; Jorde et al 2010; Grimnes et al 2011 Sugden et al 2008; Jorde and Figenschau 2009; Witham et al 2010; Nikooyehet al 2012; Soric et al 2012

  29. Limitations of Published Trials on Vitamin D Supplementation and Type 2 Diabetes • Small, underpowered studies • Inadequate duration • Large dropout rates [20-40%] • Post-hoc analyses • Choice of vitamin D regimen • Large infrequent doses • Populations studied • Normal glucose tolerance [unlikely to benefit] • Established type 2 diabetes [difficult to show]

  30. Effect of Vitamin D3 Supplementation (2,000 IU/day) on Disposition Index (beta-cell function) and HbA1c Supported by NIDDK/ODS R01DK76092 Participants at riskfordiabetes (IFG, IGT) p=0.08 Mitri et al AJCN 2011

  31. Summary and Conclusions • Population 25OHD is lower than it used to be… but, so what? • Promising findings from observational research need confirmation in trials. • Supplementation with vitamin D is unnatural and potentially dangerous.

  32. Proposed solutions to decreased UVB exposure and altered lifestyle Take a large vitamin D pill daily (weekly, monthly or [why not] yearly The sunshine pill Alternatively, supplement all food with vitamin D * Disclaimer : There is no fruit in “Fruity” Pebbles

  33. 25OHD concentration (biomarker of exposure)after infrequent very high-dose vitamin D supplementation 500,000 IU of cholecalciferol (D3) yearly Sanders et al 2010 JAMA

  34. Fractures (biomarker of effect?)after infrequent very high-dose vitamin D supplementation 500,000 IU of cholecalciferol (D3) yearly High infrequent (non-daily) doses of vitamin D may be metabolized differently and have an unfavorable benefit/risk profile Sanders et al 2010 JAMA

  35. Summary and Conclusions • Population 25OHD is lower than it used to be… but, so what? • Promising findings from observational research need confirmation in trials. • Supplementation with vitamin D is unnatural and potentially dangerous.

  36. Vitamin D Recommended IntakeInstitute of Medicine (U.S.) 2011 Report * RDA 1 UL 2 ≤ 70 years 600 IU 4,000 IU > 70 years 800 IU 4,000 IU * RDA for skeletal outcomes (fractures and falls) ONLY Under conditions of minimal sun exposure Applicable to normal healthy population groups 1Recommended Dietary Allowance, intake that meets needs of 97.5% of healthy population 2Tolerable Upper Intake Level, above which potential risk of adverse effects mayincrease with chronic use. UL is not highest dose recommended

  37. Optimal 25OHD ConcentrationInstitute of Medicine (U.S.) 2011 ng/mL Deficiency < 12 Rickets, Osteomalacia Inadequacy 12 - 19 Sufficiency 20 - 29 • Risk of Skeletal Outcomes ONLY 30 - 50 Risk of Chronic Disease ????

  38. Optimal 25OHD ConcentrationEndocrine Society, 2011 ng/mL Deficiency < 12 Rickets, Osteomalacia Inadequacy 12 - 19 Inadequacy 20 - 29 30 - 50 Risk of Skeletal Outcomes

  39. Which 25OHD threshold to follow, IOM or Endocrine Society? 22 ng/mL 30 ng/mL ~100 million adults Ann Intern Med. 2012;156(9):627-634

  40. All I needed to know I learned in kindergartenHard lessons learned along the alphabet A, B, C, D, E, Is Vitamin D the new vitamin A, the new vitamin B, the new vitamin C, the new vitamin E ?

  41. Vitamin D is flying off shelves Local Pharmacy October 2012

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