1. Journal Club The effect of high-dose vitamin D supplementation on insulin resistance and arterial stiffness in patients with type 2 diabetes Prepared by: Amanda Bullock

2. Overview Vitamin D review Literature review Journal article ◦ Purpose ◦ Methods ◦ Results ◦ Conclusion Discussion

3. Vitamin D Health claims: ◦ Promotes healthy bones by assisting with calcium absorption ◦ Reduces risk of diabetes, heart disease, rheumatoid arthritis and multiple sclerosis ◦ Regulates immune system ◦ Prohibits cancer cell growth

4. Vitamin D Recommended blood level: 30-74ng/mL Food sources: ◦ Fatty fish: tuna, mackerel, salmon ◦ Cheese ◦ Egg yolks ◦ Fortified foods: milk, soy milk, orange juice

5. Vitamin D Best source: The SUN! ◦ Dubbed the “sunshine vitamin” ◦ Levels decrease during the winter months, especially if you are far from the equator

7. Literature Review Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient - a randomised, placebo-controlled trial. A randomized, controlled, double-blind study was performed on 100 non-diabetic insulin-resistant Asian females. Participants were given 4,000 IU of Vitamin D daily for 6 months.. (von Hurst, 2010)

8. Literature Review Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient - a randomised, placebo-controlled trial. When serum Vitamin D levels reached >32ng/mL, subjects showed significantly improved insulin resistance and sensitivity. (von Hurst, 2010)

9. Literature Review Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial A parallel-group, double-blind, placebo- controlled randomized trial was conducted with 159 subjects >70 years old who had low levels of Vitamin D and isolated systolic hypertension. 1,000 IU of Vitamin D or a placebo was administered each day. (Witham, 2013)

10. Literature Review Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial 12 months later when the study concluded, no improvement was seen in blood pressure or other markers of vascular health. (Witham, 2013)

11. Authors’ Review of Current Data “Vitamin D deficiency is more prevalent and severe in patients with type 2 diabetes compared with the normal population. Epidemiological studies revealed that vitamin D deficiency accompanied by type 2 diabetes is associated with an increased risk of all- cause and cardiovascular mortality.” (Ohk-Hyun, 2014)

12. Purpose Many claims have been made in support of Vitamin D supplementation, especially in regards to diabetes and heart disease This study aims to determine any impact on insulin resistance AND arterial stiffness secondary to Vitamin D supplementation in subjects with type 2 DM

13. Hypothesis Authors hypothesize that insulin resistance may link arterial stiffness and Vitamin D deficiency in type 2 DM… (Ohk-Hyun, 2014)

14. Subject Inclusion Criteria DM2 Vitamin D levels < 20ng/mL Ambulatory, aged 30-69 years HbA1c levels 6.5-8.4% Unchanged medications 3 months prior to study Normal calcium levels BMI > 23 (Ohk-Hyun, 2014)

15. Subject Exclusion Criteria Use of osteoporosis-related medications within 3 months before study Use of insulin 1 month before study Systolic BP >160mmHg or diastolic BP >100mmHg Acute MI/stroke within 6 months Abnormal liver function test Alcoholism (Ohk-Hyun, 2014)

16. Methods: Design Prospective Randomized Double-blind Placebo-controlled (Ohk-Hyun, 2014)

17. Methods: Design For 24 weeks, participants received either: ◦ 1,000 IU Vitamin D with 100mg calcium twice daily (n = 40) --or-- ◦ Placebo containing 100mg of calcium twice daily (n = 41) (Ohk-Hyun, 2014)

18. Methods: Design Participants were evaluated at: ◦ Baseline ◦ 12 weeks +/- 2 weeks ◦ 24 weeks +/- 4 weeks (Ohk-Hyun, 2014)

19. Methods: Design All participants received education regarding Vitamin D rich foods Participants were instructed to maintain the same lifestyle as before the study (Ohk-Hyun, 2014)

20. Methods: Design Physicians not allowed to change antihypertensive, antiplatelet or antilipid drugs during the study. Only antidiabetic drugs allowed to be altered (Ohk-Hyun, 2014)

21. Methods: Outcome Measures Vitamin D levels Fasting glucose Lipid profiles HbA1c Insulin The homeostasis model of assessment-IR [HOMA-IR] High-sensitivity C- reactive protein (Ohk-Hyun, 2014)

22. Methods: Outcome Measures Brachial-ankle pulse wave velocity Radial augmentation index Central systolic blood pressure Safety of high-dose vitamin D supplementation ◦ Serum calcium ◦ Liver and kidney function (Ohk-Hyun, 2014)

23. Methods: Data Collection Blood pressure was tested after a 10- minute resting period Blood tests were drawn after an overnight fast from 7pm-9am Arterial stiffness was measured while the subject was in a supine position for 10 minutes (Ohk-Hyun, 2014)

25. Statistical Analysis At the conclusion of the study, subjects were evaluated if they: ◦ Took the supplements/placebo >80% of the time ◦ Didn’t change medications A value of p < 0.05 was considered to be significant Two-tailed t-tests were used to compare the Vitamin D and placebo group A chi-square test was also used for categorical variables (Ohk-Hyun, 2014)

26. Results Vitamin D levels (adequate = > 30 ng/mL): ◦ Placebo group: 10% (n = 3) ◦ Vitamin D group: 68.8% (n = 22) ◦ p < 0.001 No significant change in arterial stiffness or insulin resistance between the two groups ◦ (No significant change in any outcome measure) (Ohk-Hyun, 2014)

27. Results Vitamin D supplementation at 2000 IU daily is safe in regards to liver/kidney function and serum calcium (Ohk-Hyun, 2014)

28. Conclusions No bias from the researchers was evident The conclusions are appropriate

29. EAL The evidence in this article receives an overall Fair (II) grade ElementsGrade QualityGood (I) ConsistencyFair (II) QuantityFair (II) Clinical ImpactLimited (III) GeneralizabilityFair (II)

30. Discussion Potential weaknesses of article: ◦ All subjects on different medications ◦ Low number or participants ◦ Not a high amount of Vitamin D tested

31. Discussion Discrepancies in conclusions of different articles ◦ More research needs to be done ◦ Consensus of a correlation between Vit D and metabolic syndrome

32. Discussion Questions If there is a link between Vitamin D deficiency and metabolic syndrome, should we fortify foods?

33. Discussion Questions Have any of you been asked about Vitamin D by patients? If so, what have they asked?

34. Discussion Questions If a link was proven between DM2 or cardiovascular disease and Vitamin D deficiency, do you think hospitals might incorporate supplements into clinical practice?

35. References 1. Ohk-Hyun R, Wankyo C, Sungwha L, Kyung-Soon H, Moon-Gi C, Hyung J Y. The effect of high-dose vitamin D supplementation on insulin resistance and arterial stiffness in patients with type 2 diabetes. Korean J Intern Med. 2014; 29(5): 620–629. 2. von Hurst PR, Stonehouse W, Coad J. Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient: a randomised, placebo- controlled trial. Br J Nutr. 2010; 103: 549–555. 3. Witham MD, Price RJ, Struthers AD, et al. Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial. JAMA Intern Med. 2013; 173: 1672–1679.