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 MSAssociate Professor of Medicine

Division of Endocrinology, Diabetes and MetabolismTufts Medical Center

apittas@tuftsmedicalcenter.orgwww.D2dstudy.org

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

multivitamin)

Panacea (Greek goddess of healing)

Vitamin D, the 21st century version of Panacea

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

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

18%

82%

Due to low vitamin DOther

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 2011

1988-1994 2001-2006 ~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 (D3) 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

VDRRXR

1,25(OH)2D25(OH)D

1-hydroxylase

Ca2+

[Ca2+]i

Gene Expression

1,25(OH)2D25(OH)D

1-hydroxylase

gene

Vitamin D and Cellular Function Implications for Health beyond Bone

Pancreas (beta cell)Vasculature Immune cells SkinColonProstateBreastPlacentaBrain

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 2006 29:3:650

Prospective Observational; Nurses Health Study cohort

Risk of Incident Type 2 Diabetes by Joint Categories of

Vitamin D and Calcium Intake

Risk by 33%Risk by 33%

Pittas et al Diabetes Care 2006 29:3:650

Prospective Observational; Nurses Health Study cohort

Association of 25OHD with Incident Type 2 Diabetes

5 10 15 20 25 30 35 40 45 500

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

Plasma 25(OH)D levels (ng/mL)

Odd

s ra

tio (9

5% C

I) of

type

2 d

iabe

tes

Pittas et al, Diabetes Care 2010

>33 ng/ml

Risk by 48%

Nested Case-Control; Nurses Health Study cohortSupported by NIDDK R21DK78867

p for trend 0.008

Relative Risk.1 .25 .50 .75 1.0 2.0 5.0

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 (0.52-0.82)

0.90 (0.40-1.90) 0.53 (0.43-0.65)0.56 (0.36-0.86) 0.68 (0.29-1.61)0.73 (0.48-1.12)1.05 (0.62-1.76)0.52 (0.33-0.83)1.45 (0.58-3.62)0.17 (0.05-0.52)0.91 (0.37-2.23) 0.49 (0.15-1.64)

Relative Risk

Risk by 35% for 25OHD (ng/mL) >25-30 vs. <8-20

Association of 25OHD with Incident DiabetesMeta-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 > 43o, altitude; duration of sunlight; cloud cover; ozone cover; air pollution; time of day;Protective clothing; sunscreenPhysical inactivity; homebound

Diabetes

UVB Exposure

Skin Pigmentation

Vitamin D

25(OH)D

1,25(OH)2D 1,25(OH)2D

Bioavailability ( in obesity)Vit D

Milk

Dairy

“Medit diet”

Nutrient

Food

Food group

Dietary pattern

Aging, GeneticsBaseline 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 > 43o, altitude; duration of sunlight; cloud cover; ozone cover; air pollution; time of day;Protective clothing; sunscreenPhysical inactivity; homebound

Diabetes

UVB Exposure

Skin Pigmentation

Vitamin D

25(OH)D

1,25(OH)2D 1,25(OH)2D

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, GeneticsBaseline 25OHD

>90%

Beta cell 1-a hydroxylase

Kidney 1-a hydroxylase

ConfoundingIs 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 D3 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

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 (D3) yearly

Fractures (biomarker of effect?)after infrequent very high-dose vitamin D

supplementation

Sanders et al 2010 JAMA

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

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 IntakeInstitute of Medicine (U.S.) 2011 Report *

≤ 70 years 600 IU

RDA 1

800 IU> 70 years

UL 2

4,000 IU

4,000 IU

* RDA for skeletal outcomes (fractures and falls) ONLYUnder conditions of minimal sun exposure

Applicable to normal healthy population groups1Recommended Dietary Allowance, intake that meets needs of 97.5% of

healthy population2Tolerable Upper Intake Level, above which potential risk of adverse effects

may increase with chronic use. UL is not highest dose recommended

Optimal 25OHD ConcentrationInstitute of Medicine (U.S.) 2011

Sufficiency

Deficiency

30 - 50

20 - 29

< 12

ng/mL

Rickets, Osteomalacia

Risk of Chronic Disease ????

12 - 19Inadequacy

Risk of Skeletal Outcomes ONLY

Optimal 25OHD ConcentrationEndocrine Society, 2011

Inadequacy

Deficiency

30 - 50

20 - 29

< 12

ng/mL

Rickets, Osteomalacia

Risk of Skeletal Outcomes

12 - 19Inadequacy

Which 25OHD threshold to follow, IOM or Endocrine Society?

IOM Endo Society0%

20%

40%

60%

80%

100% 25 77

Insuf -fi-ciencySufficiency

~100 million adultsAnn Intern Med. 2012;156(9):627-634

22 ng/mL 30 ng/mL

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 ?

Vitamin D is flying off shelves

Local Pharmacy October 2012