Emerging Areas Relating Vitamin D to Health

Transcription

1 ILSI SEA Region Vit D Conference, Australia, June 2012 ( Region) Emerging Areas Relating Vitamin D to Health Peter R Ebeling MD FRACP NorthWest Academic Centre and Dept Endocrinology The University of Melbourne Western Health, Melbourne, Australia ILSI SEAR Australasia / AAS Meeting on Vitamin D Melbourne - June Disclosure: Research funding or speaking fees to Institution from Novartis, Amgen, Merck, sanofi-aventis, Eli-Lilly

2 Serum 25(OH)D nmol/l Prevalence of Vitamin D Deficiency and Insufficiency in Australia A National, Population-based Study Baseline 1999/ Serum 25(OH)D by Age and Sex % Prevalence of Deficiency / Insufficiency % 21% Vitamin D Insufficiency 45% 39% Males: 68%; <75 nmol/l Men Women % 34% Females 79%; <75 nmol/l 3% 6% Men Women R. Daly et al. (unpublished) <25 nmol/l >50 75 nmol/l nmol/l >75 nmol/l

3 Vitamin D Treatment and Primary Fracture Prevention

4 Bone Mineralization Defects & Vitamin D Deficiency Bone Histomorphometry in 675 Patients No patient with serum 25(OH)D levels 75nmol/L had increased osteoid volume (osteomalacia) Priemel M et al, J Bone Miner Res 2010, 25:

5 Vitamin D + Ca in Institutionalised Elderly 3270 women, mean age 84, living in nursing homes, randomised to 1.2g Ca IU Vit D or placebo for 18 mths % p< p<0.04 Vit D + Ca Vit D + Ca Placebo 0 All Nonvertebral Hip Chapuy et al, NEJM, 1992

6 Primary Fracture Prevention by Cholecalciferol 100,000 IU cholecalciferol or placebo every 4 mths (n = 2686) 22% reduction in any fracture 33% reduction in osteoporotic fractures >80% compliance achieved in 76% of participants Trivedi D et al, bmj 2003

7 Vitamin D Treatment and Secondary Fracture Prevention

8 Secondary Prevention: RECORD Trial Recent low trauma fracture n 5292 Setting Comm Dose 800 IU 25OHD Adherence 54% Grant AM et al. Lancet 2005

9 Meta-Analyses

10 Effects of Vitamin D on Fractures Importance of Vitamin D Dose Effects on Hip and Non-vertebral Fracture 400 IU/d dose IU/d IU/d 400 IU/d dose RR 26% RR 23% Bischoff-Ferrari al. Am J Clin Nutr 2006

11 Effect of Calcium and Calcium+Vitamin D on Fracture Risk Reduction Meta-analysis Tang BM et al 2007 Lancet 370:657

12 Effect of Calcium and Calcium+Vitamin D on Fracture Risk Reduction Effect of compliance Tang BM et al 2007 Lancet 370:657

13 Effect of Calcium and Calcium + Vitamin D on Fracture Risk Reduction Calcium or calcium + vitamin D was associated with: Reduced bone loss (hip 0.54%; spine 1.19%) Higher compliance was associated with a greater risk reduction 24% risk reduction in trials with >80% compliance Those with low serum 25(OH)D (<25 nmol/l) had a greater risk reduction compared to those with normal 25(OH)D Treatment effect was best with calcium doses of 1200 mg/d or more, or vitamin D doses of 800 IU/d or more Tang BM et al. Lancet 2007

14 Vitamin D Treatment and Falls Prevention

15 Effect of Vitamin D on Body Sway & Falls 8 weeks of Ca alone or Ca IU D in 148 women with 25OHD < 50nmol/l Ca alone Ca + D Pfeifer et al, JBMR, 2000

16 Effects of Vitamin D + Calcium on the Risk of Falls in Elderly Australian Women Vitamin D 2 (1000 IU/d) + Calcium Citrate (1000 mg/d) vs Calcium for 1 year Inclusion criteria: Women aged years; a history of falling in the past 12 months and a serum 25(OH)D <60 nmol/l. Prince R et al. Arch Int Med 2008

17 Effects of IU/d vitamin D on Falls

18 Time to First Fracture and First Fall 500,000 IU Cholecalciferol vs Placebo Sanders K et al, JAMA, 2010

19 Vitamin D Reduces Falls Meta-analysis showed that vitamin D supplementation reduces falls by 22% in ambulatory or institutionalised elderly individuals 15 patients would need to be treated with vitamin D to prevent one fall Should be part of multi-faceted falls prevention programme Bischoff-Ferrari HA et al., JAMA 2004

20 Low Vitamin D and Other Diseases Autoimmune diseases multiple sclerosis, type 1 diabetes mellitus, rheumatoid arthritis, Crohn s disease Osteoarthritis Hypertension, vascular disease Type 2 diabetes Overall mortality Infectious diseases - common cold, influenza, tuberculosis Cancer

21 MS Prevalence in Australia MS Prevalence in Australia Predicted from UVB Supply (left) versus Recoded Values (right)

22 Vitamin D and Cancer Apperly first demonstrated an association between latitude and cancer mortality in 1941 Cancers associated with low vitamin D include: Colon Cancer (strongest association) Breast and Ovarian Cancer Prostate Cancer

23 Vitamin D and Calcium Supplementation Reduces Cancer Risk A 4-yr prospective, placebo-controlled study of 1100 IU vitamin D 3 and/or 1400 mg calcium and cancer risk in 1179 post-menopausal women Serum 25(OH)D rose from 71.8 to 96.0 nmol/l The all-cancer incidence for women over the age of 55 years at time of enrollment was reduced by 60% (p=0.01) Lappe JM et al. Am J Clin Nutr :

24 Vitamin D and Mortality Rates Individual Patient Data from RCTs (n=70,528) In patients taking Vitamin D with calcium, the risk of death was reduced by 9% NNT to prevent death was 151 over 3 years Rejnmark L et J Clin Endocrinol Metab 2012 epub May 17

25 Vitamin D and Mortality Rates Retrospective, Observational Cohort Study of Danish GP Referrals to Single Pathology Provider (n=247,574) Durup D et J Clin Endocrinol Metab 2012 epub May 9

26 Cardiovascular Disease A graded increase in CV risk across categories of serum 25(OH)D, with hazard ratios of 1.53 for levels 25 to 38 nmol/l & 1.8 for levels < 25 nmol/l Highest risk was in those with hypertension and vitamin D deficiency Wang TJ et al, Circulation 2008;117:

27 Effects of Vitamin D Deficiency on Islet Cell Function 1- hydroxylase enzyme, vitamin D binding protein and VDR are present in islet -cells It is unclear whether VDRKO mice or -cell specific VDRKO have reduced insulin secretion Vitamin D deficiency is related with a higher prevalence of T1DM 1,25(OH) 2 D prevents insulitis in NOD mice

28 Effects of Vitamin D and Calcium on Insulin Sensitivity ,25(OH) 2 vitamin D sites of action Calcium sites of action Harrison s On-line

29 Gagnon C et al. Diabetes Care, 2011; 34 (5):

30 AusDiab Cohort Home Interview Biomedical Review Biomedical Review Study Population

31 AusDiab Cohort Home Interview Biomedical Review Biomedical Review Study Population OGTT 2h post 75g serum 25OHD FFQ (calcium) OGTT 2h post 75g HOMA-S

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33 Quartiles of 25OHD and Risk of T2DM

34 25OHD and HOMA-S

35 Linear Relationship between 25OHD and T2DM Risk

36 25OHD is Associated with a Reduced Risk of Developing T2DM Each increase of 25 nmol / L in 25OHD is associated with: A decrease in risk of 24% of developing T2DM over 5 years: OR 0.76 ( ) An increase in insulin sensitivity (HOMA-S) at 5 years Gagnon C et al. Diabetes Care, 2011; 34 (5):

37 Inverse Association Between 25OHD Levels and log[hba1c] in Women with Gestational Diabetes Mellitus 41% of women with GDM had 25OHD < 50 nmol/l 25OHD levels were also inversely associated with fasting and 2-hour blood glucose levels during OGTT (r = 0.16; P = 0.05 for both) Lau SL et al., MJA 2011; 194 (7):

38 Replacement of vitamin D and T2DM: Difficulties with Data Interpretation Total of 15 studies including 12 with primary outcomes being surrogate markers for the development of T2DM - 7 studies with 1,25 (OH) 2 D or i.m. vitamin D 3 Small sample size (10 to 100) Often no control groups Doses of vitamin D 3 insufficient to achieve serum 25OHD 75 nmol / L Variable treatment duration Diverse populations

39 Replacement of vitamin D and T2DM Does not appear to benefit in patients with normal glucose tolerance Nilas L et al. Int J Obes, 1984; 8: Fliser D et al. Eur J Clin Invest, 1997; 27: Patients with glucose intolerance or high risk of developing type 2 diabetes, especially if vitamin D deficient, improve their secretion and insulin sensitivity Boucher B et al. Diabetologia, 1995; 38 (10: Pittas AG et al. Diabetes Care, 2007; 30 (4): Nagpal J et al. Diabetic Med, 2009; 26 (1): Von Hurst PR et al. Br J Nutr, 2010; 103 (04):

40 Replacement of vitamin D and T2DM Improved secretion of insulin sensitivity and glycaemic control in patients with type 2DM (on diet or oral hypoglycaemic agents) with vitamin D deficiency Inomata S et al. Bone and Mineral, 1986; Borissova AM et al. Int J Clin Pract, 2003; 57 (4): Nikooyeh B et al. Am J Clin Nutr, 2011; 93 (4):

41 Vitamin D UI + calcium 500 mg /d for 3 years in Postmenopausal Women Pittas AG et al. Diabetes Care, 2007; 30 (4):

42 Increased 25OHD, Decreased PTH, but Cytokines were Unchanged Pittas AG et al. Diabetes Care, 2007; 30 (4):

43 Treatment Prevents the Increase in Fasting Glucose and HOMA-IR only in those with IFG Pittas AG et al. Diabetes Care, 2007; 30 (4):

44 Vitamin D 3 120,000 IU every 2 weeks (x 3) in Indian Men with Central Obesity Nagpal J et al. Diabetic Med, 2009; 26:

45 Increased 25OHD, Decreased PTH, but Unchanged hs-crp Nagpal J et al. Diabetic Med, 2009; 26:

46 Enhanced Sensitivity to Insulin in the Treatment Group (Per-protocol) Nagpal J et al. Diabetic Med, 2009; 26:

47 Vitamin D IU/d for 6 months in Asian women with IR and Vitamin D deficiency von Hurst PR et al. Br J Nutr, 2010; 103 (4):

48 Significant Increase in Insulin Sensitivity in women who reached 25OHD > 80 nmol / L von Hurst PR et al. Br J Nutr, 2010; 103 (4):

49 Western Health Study: Effects of Vitamin D and Calcium on Insulin Sensitivity Aims To evaluate, in overweight / obese vitamin D-deficient individuals at high risk of type 2 diabetes, the effects of adequate vitamin D and calcium supplementation on: Glucose homeostasis (insulin secretion, insulin resistance and - cell function) Cardiovascular risk factors Markers of inflammation (hs-crp, fibrinogen, IL-6, TNF- ) Blood pressure Lipids

50 Effects of Vitamin D and Calcium on Insulin Sensitivity Treating to Target Entire Group (n=120) Randomisation* Vitamin D IU/d + Calcium Carbonate 1200 mg/d (n=60) Placebo (n=60) 8 and 16 weeks Extra vitamin D IU/d or placebo Extra placebo * Randomisation in block and Stratification according to sex, age (< or >50 yo) and BMI (< or >30 kg/m 2 ) If 25OHD < 75 nmol/l

51 Conclusion I It is probably important to check serum 250HD levels and treat vitamin D deficiency in patients with T2DM from at-risk groups It is important to check serum 250HD levels and treat vitamin D deficiency in pregnant women from at-risk groups for many reasons, including risk of GDM

52 Conclusion II Metabolic and other health benefits are likely to accrue from treating vitamin D deficiency However, more data are required from large well designed, randomised controlled trials: VITAL D funded by US NIH JoAnne Manson PI D-Health national pilot study funded by NHMRC of effects of vitamin D 60,000 IU / mth on mortality and other health outcomes in Australians Bischoff-Ferrari - Study of vitamin D or placebo on muscle strength and falls in the elderly funded by European Union

53 Western Centre for Health Research and Education The University of Melbourne, Victoria University & Western Health