Vitamins B, E, and Health

Partha PaulEndocrinology Rounds

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

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

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

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.

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

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

Results (renal)

Other outcomes

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

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.

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

Results (Cancer)No statistical difference

Results (cardiovascular)

Results (cardiovascular)

Results (cardiovascular)

Results (cardiovascular)

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

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.

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.

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

ResultsStopped early for benefit.

Results

Results

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

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.