ILSI SEA Region Vit D Conference, Australia, June 2012 (www.ilsi.org/sea 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 12 2012 Disclosure: Research funding or speaking fees to Institution from Novartis, Amgen, Merck, sanofi-aventis, Eli-Lilly
Serum 25(OH)D nmol/l Prevalence of Vitamin D Deficiency and Insufficiency in Australia A National, Population-based Study Baseline 1999/2000 90 80 70 60 Serum 25(OH)D by Age and Sex % Prevalence of Deficiency / Insufficiency 100 80 60 32% 21% Vitamin D Insufficiency 45% 39% Males: 68%; <75 nmol/l 50 40 30 Men Women 40 20 0 20% 34% Females 79%; <75 nmol/l 3% 6% Men Women R. Daly et al. (unpublished) <25 nmol/l >50 75 nmol/l 25 50 nmol/l >75 nmol/l
Vitamin D Treatment and Primary Fracture Prevention
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, 25:305-312
Vitamin D + Ca in Institutionalised Elderly 3270 women, mean age 84, living in nursing homes, randomised to 1.2g Ca + 800 IU Vit D or placebo for 18 mths % 12 10 p<0.015 8 6 4 2 p<0.04 Vit D + Ca Vit D + Ca Placebo 0 All Nonvertebral Hip Chapuy et al, NEJM, 1992
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
Vitamin D Treatment and Secondary Fracture Prevention
Secondary Prevention: RECORD Trial Recent low trauma fracture n 5292 Setting Comm Dose 800 IU 25OHD 38 62 Adherence 54% Grant AM et al. Lancet 2005
Meta-Analyses
Effects of Vitamin D on Fractures Importance of Vitamin D Dose Effects on Hip and Non-vertebral Fracture 400 IU/d dose 700-800 IU/d 700-800 IU/d 400 IU/d dose RR 26% RR 23% Bischoff-Ferrari al. Am J Clin Nutr 2006
Effect of Calcium and Calcium+Vitamin D on Fracture Risk Reduction Meta-analysis Tang BM et al 2007 Lancet 370:657
Effect of Calcium and Calcium+Vitamin D on Fracture Risk Reduction Effect of compliance Tang BM et al 2007 Lancet 370:657
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
Vitamin D Treatment and Falls Prevention
Effect of Vitamin D on Body Sway & Falls 8 weeks of Ca alone or Ca + 800 IU D in 148 women with 25OHD < 50nmol/l Ca alone Ca + D Pfeifer et al, JBMR, 2000
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 70-90 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
Effects of 700-1000 IU/d vitamin D on Falls
Time to First Fracture and First Fall 500,000 IU Cholecalciferol vs Placebo Sanders K et al, JAMA, 2010
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
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
MS Prevalence in Australia MS Prevalence in Australia Predicted from UVB Supply (left) versus Recoded Values (right)
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
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 2007 85: 1586-91
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
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
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: 503-11
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
Effects of Vitamin D and Calcium on Insulin Sensitivity 1 1 2 2 1,25(OH) 2 vitamin D sites of action Calcium sites of action Harrison s On-line
Gagnon C et al. Diabetes Care, 2011; 34 (5): 1133-8.
AusDiab Cohort 1999-2000 20 347 Home Interview 11 247 Biomedical Review 2004-2005 6 537 Biomedical Review 5 200 Study Population
AusDiab Cohort 1999-2000 2004-2005 20 347 Home Interview 11 247 Biomedical Review 6 537 Biomedical Review 5 200 Study Population OGTT 2h post 75g serum 25OHD FFQ (calcium) OGTT 2h post 75g HOMA-S
Quartiles of 25OHD and Risk of T2DM
25OHD and HOMA-S
Linear Relationship between 25OHD and T2DM Risk
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 (0.63-0.92) An increase in insulin sensitivity (HOMA-S) at 5 years Gagnon C et al. Diabetes Care, 2011; 34 (5): 1133-8.
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): 334-337
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
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: 407-11. Fliser D et al. Eur J Clin Invest, 1997; 27: 629-33. 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: 1239-45. Pittas AG et al. Diabetes Care, 2007; 30 (4): 980-6. Nagpal J et al. Diabetic Med, 2009; 26 (1): 19-27. Von Hurst PR et al. Br J Nutr, 2010; 103 (04): 549-55.
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; 187-192. Borissova AM et al. Int J Clin Pract, 2003; 57 (4): 258-61. Nikooyeh B et al. Am J Clin Nutr, 2011; 93 (4): 764-71.
Vitamin D 3 700 UI + calcium 500 mg /d for 3 years in Postmenopausal Women Pittas AG et al. Diabetes Care, 2007; 30 (4): 980-6.
Increased 25OHD, Decreased PTH, but Cytokines were Unchanged Pittas AG et al. Diabetes Care, 2007; 30 (4): 980-6.
Treatment Prevents the Increase in Fasting Glucose and HOMA-IR only in those with IFG Pittas AG et al. Diabetes Care, 2007; 30 (4): 980-6.
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: 19-27.
Increased 25OHD, Decreased PTH, but Unchanged hs-crp Nagpal J et al. Diabetic Med, 2009; 26: 19-27.
Enhanced Sensitivity to Insulin in the Treatment Group (Per-protocol) Nagpal J et al. Diabetic Med, 2009; 26: 19-27.
Vitamin D 3 4000 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): 549-55.
Significant Increase in Insulin Sensitivity in women who reached 25OHD > 80 nmol / L von Hurst PR et al. Br J Nutr, 2010; 103 (4): 549-55.
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
Effects of Vitamin D and Calcium on Insulin Sensitivity Treating to Target Entire Group (n=120) Randomisation* Vitamin D 3 2000 IU/d + Calcium Carbonate 1200 mg/d (n=60) Placebo (n=60) 8 and 16 weeks Extra vitamin D 3 2000 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
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
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
Western Centre for Health Research and Education The University of Melbourne, Victoria University & Western Health