Anastassios G Pittas, MD MS Associate Professor of Medicine
description
Transcript of Anastassios G Pittas, MD MS Associate Professor of Medicine
![Page 1: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/1.jpg)
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
![Page 2: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/2.jpg)
Please raise your hand if you take a specific vitamin D supplement (outside of a
multivitamin)
![Page 3: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/3.jpg)
Panacea (Greek goddess of healing)
![Page 4: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/4.jpg)
Vitamin D, the 21st century version of Panacea
![Page 5: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/5.jpg)
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)
![Page 6: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/6.jpg)
Vitamin D is Big Business
![Page 7: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/7.jpg)
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
![Page 8: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/8.jpg)
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.
![Page 9: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/9.jpg)
Vitamin D Dietary Sources are Limited
Holick NEJM
![Page 10: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/10.jpg)
Solar UVB Exposure in Decline
![Page 11: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/11.jpg)
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
![Page 12: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/12.jpg)
Summary and Conclusions
• Population 25OHD is lower than it used to be… but, so what?
![Page 13: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/13.jpg)
Definition of Biomarker
• Biomarker of exposure– Validated measure to reflect intake or exposure– Example: 25-hydroxyvitamin D
![Page 14: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/14.jpg)
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
![Page 15: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/15.jpg)
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
![Page 16: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/16.jpg)
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
![Page 17: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/17.jpg)
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
![Page 18: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/18.jpg)
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
![Page 19: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/19.jpg)
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
![Page 20: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/20.jpg)
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
![Page 21: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/21.jpg)
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
![Page 22: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/22.jpg)
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)
![Page 23: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/23.jpg)
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
![Page 24: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/24.jpg)
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
![Page 25: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/25.jpg)
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
![Page 26: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/26.jpg)
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
![Page 27: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/27.jpg)
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
![Page 28: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/28.jpg)
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
![Page 29: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/29.jpg)
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]
![Page 30: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/30.jpg)
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
![Page 31: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/31.jpg)
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.
![Page 32: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/32.jpg)
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
![Page 33: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/33.jpg)
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
![Page 34: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/34.jpg)
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
![Page 35: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/35.jpg)
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.
![Page 36: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/36.jpg)
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
![Page 37: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/37.jpg)
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
![Page 38: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/38.jpg)
Optimal 25OHD ConcentrationEndocrine Society, 2011
Inadequacy
Deficiency
30 - 50
20 - 29
< 12
ng/mL
Rickets, Osteomalacia
Risk of Skeletal Outcomes
12 - 19Inadequacy
![Page 39: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/39.jpg)
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
![Page 40: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/40.jpg)
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 ?
![Page 41: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/41.jpg)
Vitamin D is flying off shelves
Local Pharmacy October 2012
![Page 42: Anastassios G Pittas, MD MS Associate Professor of Medicine](https://reader036.fdocuments.in/reader036/viewer/2022062302/56816761550346895ddc3744/html5/thumbnails/42.jpg)