1. Vitamin D status and the risk of type 2 diabetes - What is the nature of the association? Anna Rickard 14 th February 2011

2. Worldwide prevalence of diabetes: Estimated 285 million people in 2010 1 Predicted 439 million in 2030 1 Lifestyle modifications can make a difference 2 Interventions are hard to implement and sustain The impact of a feasible approach could be vast The context: Type 2 diabetes 1.Shaw JE et al. 2010 2.Gillies CL et al. 2007

3. Diabetes and Vitamin D: EPIC Norfolk Quartile 1 (Reference) Quartile 2Quartile 3Quartile 4P for trend 25(OH)D (nmol/l)<48·849·0-63·563·6-80·0>80·0 N396375345 331 Model 1 10·93 (0·69-1·25)0·71 (0·52-0·97)0·64 (0·47-0·88) 0·001 Model 210·88 (0·65-1·19)0·62 (0·45-0·86)0·47 (0·33-0·67) 3·96x10 -6 Model 31 0·88 (0·63-1·22) 0·61 (0·43-0·88)0·46 (0·31-0·67) 1·76x10 -5 Model 4 10·89 (0·65-1·24)0·64 (0·44-0·91) 0·48 (0·33-0·71) 7·84x10 -5 Model 5 10·66 (0·45-0·97)0·53 (0·34-0·82) 0·50 (0·32-0·76) 0·001 Data show hazard ratio (HR) and 95 % confidence intervals (95 % CI) Model 1: Age as underlying timescale, sex; Model 2: Model 1 plus season; Model 3: Model 2 plus family history of diabetes, cigarette smoking, physical activity and education level; Model 4: Model 3 plus alcohol intake and supplement and/or cod liver oil use; Model 5: Model 4 plus BMI Association between serum 25-hydroxy vitamin D concentration (nmol/l) and incident diabetes using Prentice weighted Cox regression

4. Population attributable fraction (PAF) Lowest vs. highest quartile 21.5 % Insufficiency ( =50nmol/l) 19.1 % Potential for a significant impact if causal Diabetes and Vitamin D: EPIC Norfolk

5. Focused only on studies using 25-hydroxy vitamin D (25(OH)D) 5 published studies 1-5 Strong inverse association Consistent findings Limitations: Confounding Diabetes and Vitamin D: Prospective Evidence 1.Mattila C et al. 2007 2.Knekt P et al. 2008 3.Grimnes et al. 2010 4.Pittas AG et al. 2010 5.Anderson JLl. 2010

6. Vitamin D Supplementation Trial Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women's Health Initiative 1 400 IU vitamin D + 1,000 mg calcium / day 33,951 participants 2,291 incident diabetes cases No effect (HR 1.01 (95 % CI 0.94-1.10)) 1.de Boer IH et al. 2008

7. Aim: To determine if vitamin D supplementation can help to prevent or delay the onset of diabetes. Vitamin D Supplementation Trial Recruit ‘at risk’

8. Aim: To determine if vitamin D supplementation can help to prevent or delay the onset of diabetes. Vitamin D Supplementation Trial Baseline Recruit ‘at risk’ Medical Screening / safety checks Randomise

9. Vitamin D Supplementation Trial Baseline Recruit ‘at risk’ Medical Screening / safety checks Vitamin D3 100,000 IU Vitamin D2 100,000 IU Placebo OR Randomise Aim: To determine if vitamin D supplementation can help to prevent or delay the onset of diabetes.

10. Vitamin D Supplementation Trial Baseline Recruit ‘at risk’ Medical Screening / safety checks Vitamin D3 100,000 IU Vitamin D2 100,000 IU Placebo OR Randomise Anthro / questionnaires HbA1c 25(OH)D

11. Aim: To determine if vitamin D supplementation can help to prevent or delay the onset of diabetes. Vitamin D Supplementation Trial Baseline Phone call 3 months 2 nd visit 1 month Recruit ‘at risk’ Medical Screening / safety checks 3 rd visit 2 months Vitamin D3 100,000 IU Vitamin D2 100,000 IU Placebo OR Safety checks Randomise Anthro / questionnaires HbA1c 25(OH)D Safety checks

12. Aim: To determine if vitamin D supplementation can help to prevent or delay the onset of diabetes. Vitamin D Supplementation Trial Baseline Phone call 3 months 2 nd visit 1 month Recruit ‘at risk’ Medical Screening / safety checks 3 rd visit 2 months 4 th visit 4 months Vitamin D3 100,000 IU Vitamin D2 100,000 IU Placebo OR Safety checks Randomise Anthro / questionnaires HbA1c 25(OH)D Safety checks HbA1c 25(OH)D Anthro / questionnaires Safety checks

13. Strong inverse association between vitamin D and incident type 2 diabetes in observational studies Possibility of confounding If found to be causal, potentially large impact Supplementation trial is ongoing to determine causality Conclusions

14. Nita Forouhi, Simon Griffin, Nick Wareham, Graham Hitman, Ravi Menon, Cheryl Chapman, Zheng Ye, Claudia Langenberg, Kay-Tee Khaw, Robert Luben, Field Epidemiology and Study Coordination teams at the Epidemiology Unit, EPIC-Norfolk team The study and trial volunteers Acknowledgements