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

Please raise your hand if you take a specific vitamin D supplement (outside of a multivitamin)

Panacea (Greek goddess of healing)

Vitamin D, the 21 st 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 Vitamin D supplementation might increase testosterone levels, Pilz et al Vtamin D predicts breast cancer tumor size, Brouwers (abstract)

Vitamin D is Big Business

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

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.

Vitamin D Dietary Sources are Limited Holick NEJM

Solar UVB Exposure in Decline

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

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

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

25OHD concentration (biomarker of exposure) after infrequent very high-dose vitamin D supplementation Sanders et al 2010 JAMA 500,000 IU of cholecalciferol (D 3 ) yearly

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

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

VDRE VDR RXR 1,25(OH) 2 D25(OH)D 1  -hydroxylase Ca 2+ [Ca 2+ ] i Gene Expression 1,25(OH) 2 D25(OH)D 1  -hydroxylase gene Vitamin D and Cellular Function Implications for Health beyond Bone Pancreas (beta cell) Vasculature Immune cells Skin Colon Prostate Breast Placenta Brain 1  -hydroxylase expression All cells VDR expression

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

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

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

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

Relative Risk Combined Bolland_Women Anderson_Healthcare Population Gagnon_AusDiab Grimnes_Smokers Grimnes_Nonsmokers Robinson_WHI Pittas_NHS_Women Knekt_MFH_Women Knekt_MFH_Men Knekt_FMC_Women Knekt_FMC_Men 0.65 ( ) 0.90 ( ) 0.53 ( ) 0.56 ( ) 0.68 ( ) 0.73 ( ) 1.05 ( ) 0.52 ( ) 1.45 ( ) 0.17 ( ) 0.91 ( ) 0.49 ( ) Relative Risk Risk by 35% for 25OHD (ng/mL) >25-30 vs. <8-20 Association of 25OHD with Incident Diabetes Meta-analysis of Longitudinal Observational Studies Song et al (under review)

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 

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

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

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

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  X X

Trials with vitamin D supplementation and 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; Zittermann et 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; Nikooyeh et al 2012; Soric et al 2012

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]

Effect of Vitamin D 3 Supplementation (2,000 IU/day) on Disposition Index (beta-cell function) and HbA1c Mitri et al AJCN 2011 Supported by NIDDK/ODS R01DK76092 Participants at risk for diabetes (IFG, IGT) p=0.08

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.

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

25OHD concentration (biomarker of exposure) after infrequent very high-dose vitamin D supplementation Sanders et al 2010 JAMA 500,000 IU of cholecalciferol (D 3 ) yearly

Fractures (biomarker of effect?) after infrequent very high-dose vitamin D supplementation Sanders et al 2010 JAMA 500,000 IU of cholecalciferol (D 3 ) yearly High infrequent (non-daily) doses of vitamin D may be metabolized differently and have an unfavorable benefit/risk profile

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.

Vitamin D Recommended Intake Institute of Medicine (U.S.) 2011 Report * ≤ 70 years 600 IU RDA IU > 70 years UL 2 4,000 IU * RDA for skeletal outcomes (fractures and falls) ONLY 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 2 Tolerable Upper Intake Level, above which potential risk of adverse effects may increase with chronic use. UL is not highest dose recommended

Optimal 25OHD Concentration Institute of Medicine (U.S.) 2011 Sufficiency Deficiency < 12 ng/mL Rickets, Osteomalacia  Risk of Chronic Disease ???? Inadequacy  Risk of Skeletal Outcomes ONLY

Optimal 25OHD Concentration Endocrine Society, 2011 Inadequacy Deficiency < 12 ng/mL Rickets, Osteomalacia  Risk of Skeletal Outcomes Inadequacy

Institute of Medicine vs. Endocrine Society “Existing evidence is not yet sufficient” Shapses and Manson, JAMA 2011 “To the Editor: “We take issue with Drs. Shapses and Manson in their defense of the Institute of Medicine recommendations” O’Keefe et al, JAMA 2011 In Reply: “Several of the (Endo Society) guideline’s conclusions are unsubstantiated and require reconsideration” Shapses and Manson, JAMA 2011 Consensus that guidelines will need to be changed based on results of long-term randomized controlled trials “The Endocrine Society guidelines are unsubstantiated and in need of reconsideration.” Rosen et al, JCEM 2012 “At this time, the existing Endo Society guidelines provide reasonable recommendations for clinical care” Holick et al, JCEM 2012

Which 25OHD threshold to follow, IOM or Endocrine Society? ~100 million adults Ann Intern Med. 2012;156(9): ng/mL30 ng/mL

Vitamin D in Health and Disease Promising yet unproven Population 25OHD is lower than it used to be…but 25OHD is not yet a validated biomarker of effect Promising findings from observational research need confirmation in trials. Supplementation with vitamin D is unnatural and potentially dangerous. Caution with high doses and special populations Widespread screening in not necessary –Aim for 25OHD >20 ng/mL –Vitamin D IU per day (1000 IU/day OK)

All I needed to know I learned in kindergarten Hard 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 ?

Vitamin D is flying off shelves Local Pharmacy October 2012