1. Vitamins B, E, and Health Partha Paul Endocrinology Rounds

2. Outline Function/deficiency of B vitamins and Vit E Review trial of B-vitamins on progression of diabetic retinopathy Review vitamin E component of HOPE TOO trial Review use of Vit E supplementation in Pt's with Haptoglobin 2-2 subtype and DM

3. Function/deficiency of B vitamins and vitamin E B1 (thiamine) deficiency – dry beri beri (periph neuropathy), wet beri-beri (CHF, confusion), wernicke-korsokoff B6 function – amino acid metabolism, gluconeogenesis, lipid metabolism (component of enzymes involved in synthesis of sphingolipids) B12 deficiency – periph neuropathy, subacute combined degeneration, anemia Vitamin E – fat soluble antioxidant – deficiency causes myopathy, spinocerebellar ataxia

4. Effect of B-Vitamin Therapy on Progression of Diabetic Nephropathy Andrew House, et al. JAMA, April 2010, 303(16), p 1603 Context: Observational studies have shown an association between high plasma homocysteine and risk of developing: -diabetic nephropathy -diabetic retinopathy -vascular disease (including MI and stroke) B vitamin therapy (folate, B6, B12) has been shown to lower plasma homocysteine

5. B-vitamin therapy Hypothesis: B vitamin therapy will slow the progression of diabetic nephropathy and prevent vascular events Design: Multicenter, randomized, double-blind, placebo controlled trial. 5 centers, between May 2001 and July 2007.

6. B-vitamin therapy Participants: Recruited from nephrology and diabetes clinics DM type I or II and a clinical diagnosis of diabetic nephropathy with at least 300 mg/d urinary albumin or 500 mg/d proteinuria 18 years or older Exclusion criteria: Expected to survive <3 yrs, stage 4/5 CKD, awaiting dialysis, pregnant

7. B-vitamin therapy Participants randomized to recieve single tablet that contained 2.5mg/d folate, 25 mg/d vitamin B6, and 1 mg/d vitamin B12 or matching placebo. Participants, research coordinators, treating physicians blinded to assignment

10. Results (renal)

11. Other outcomes

12. Conclusion High doses of combined B vitamins significantly lowered plasma homocysteine in patients with diabetic nephropathy However, they had more rapid decrease in radionuclide GFR, and higher rate of MI and stroke. ?homocysteine lowering offset by toxicity associated with high dose B vitamins

13. Effects of Long-Term Vitamin E supplementation on CV events and Cancer Eva Lonn, HOPE and HOPE-TOO trial investigators. JAMA, March 2005, 293 (11), p 1338 Context: LDL is more atherogenic with oxidative modification and carcinogens create free radicals that damage DNA. Therefore antioxidant vitamins may prevent cancer and CV events. Epidemiological data suggests inverse relationship between CV risk and vitamin E intake. HOPE study was extended to evaluate whether longterm vitamin E prevents CV events and cancer.

14. Long Term vitamin E Design: Randomized, double-blind, placebo- controlled international trial as an extension of the HOPE trial (Apr 1999 – May 2003). Patients at least 55 yo, with CAD, PVD, CVD or DM plus 1 other CV risk factor. Excluded if had EF <40%, uncontrolled HTN, overt nephropathy, MI or CVA in last 4 weeks. Intervention: 400 IU vitamin E daily or matching placebo

17. Results (Cancer) No statistical difference

19. Results (cardiovascular)

23. Conclusions 400 IU vitamin E for median 7 years: -no clear impact on fatal and nonfatal cancer -no impact on major CV events or death -increased risk of heart failure -authors suggest that vitamin E not be used in patients with vascular disease or DM

24. Vitamin E Supplementaion in subgroup of middle aged individuals with type 2 DM and Haptoglobin 2-2 Genotype Uzi Milman et al, Arterioscler Thromb Vasc Biol 2008; 28: 341-347 Context: Clinical trials of vitamin E have failed to demonstrate a decrease in CV events. However, these studies did not address possible benefits to subgroups with increased oxidative stress. Haptoglobin in an antioxidant protein and has 2 common alleles. Hp 2 provides inferior antioxidant protection compared with Hp 1.

25. Vit E in supgroup Hypothesis: Vitamin E can reduce CV events in DM individuals with Hp 2-2 genotype (2-3% of general population have both) Design: Prospective, double-blind, randomized, placebo controlled trial.

26. Vit E in supgroup Inclusion: Type 2 DM, 55 year or older. Exclusion: Uncontrolled HTN, MI or CVA within 1 month, known allergy to vitamin E. Individulals with Hp 2-2 genotype were randomly allocated to placebo or 400 IU daily vitamin E. Primary outcome: composite of CV death, nonfatal MI, stroke

29. Results Stopped early for benefit.

30. Results

32. Authors Conclusions Vitamin E provides CV benefit to individuals with DM and the Hp 2-2 genotype over 55 years of age. Limitations: -No attempt made to optimize other medications -Stopped early for benefit

33. Summary Patients given high doses of combined B vitamins had more rapid decrease in radionuclide GFR, and higher rate of MI and stroke. 400 IU vitamin E for median 7 years had no clear impact on fatal and nonfatal cancer, no impact on major CV events or death, and increased risk of heart failure Vitamin E provides CV benefit to individuals with DM and the Hp 2-2 genotype over 55 years of age - maybe.