Post on 24-Feb-2016
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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