Vadim Bubes

Age-Related Cataract in a Randomized Trial of Vitamins E and C in Men

OBJECTIVE To test whether supplementation with alternate-day vitamin E or daily vitamin C affects the incidence of age-related cataract in a large cohort of men. METHODS In a randomized, double-masked, placebo-controlled trial, 11,545 apparently healthy US male physicians 50 years or older without a diagnosis of cataract at baseline were randomly assigned to receive 400 IU of vitamin E or placebo on alternate days and 500 mg of vitamin C or placebo daily. MAIN OUTCOME MEASURE Incident cataract responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-report confirmed by medical record review. APPLICATION TO CLINICAL PRACTICE Long-term use of vitamin E and C supplements has no appreciable effect on cataract. RESULTS After 8 years of treatment and follow-up, 1174 incident cataracts were confirmed. There were 579 cataracts in the vitamin E-treated group and 595 in the vitamin E placebo group (hazard ratio, 0.99; 95% confidence interval, 0.88-1.11). For vitamin C, there were 593 cataracts in the treated group and 581 in the placebo group (hazard ratio, 1.02; 95% confidence interval, 0.91-1.14). CONCLUSION Long-term alternate-day use of 400 IU of vitamin E and daily use of 500 mg of vitamin C had no notable beneficial or harmful effect on the risk of cataract. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00270647.

Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL)

Evidence for a role of supplemental vitamin D and marine omega-3 fatty acids in preventing cancer and cardiovascular disease (CVD) remains inconclusive and insufficient to inform nutritional recommendations for primary prevention. The VITamin D and Omega-A 3 TriaL (VITAL) is an ongoing nationwide, randomized, double-blind, placebo-controlled clinical trial designed to fill this knowledge gap. The study population consists of 25,874 U.S. adults without cancer or CVD at baseline, who were selected only on age (men aged ≥50 and women aged ≥55), with an oversampling of African Americans (n=5,107). In a 2 × 2 factorial design, participants were randomized to one of four supplement groups: [1] active vitamin D3 (cholecalciferol; 2000 IU/d) and active marine omega-3 fatty acids (Omacor® fish oil, eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA], 1g/d); [2] active vitamin D and omega-3 placebo; [3] vitamin D placebo and active marine omega-3 fatty acids; or [4] vitamin D placebo and omega-3 placebo. The mean length of the randomized treatment period will be 5 years. The randomization was successful, as evidenced by similar distributions of baseline demographic, health, and behavioral characteristics across treatment groups. The similar distribution of known potential confounders across treatment groups strongly suggests that unmeasured or unknown potential confounders are also equally distributed. VITAL is expected to provide important information on the benefit-risk balance of vitamin D and omega-3 fatty acid supplementation when taken for the primary prevention of cancer and CVD.

Effects of multivitamin supplement on cataract and age-related macular degeneration in a randomized trial of male physicians.

PURPOSE To test whether long-term multivitamin supplementation affects the incidence of cataract or age-related macular degeneration (AMD) in a large cohort of men. DESIGN Randomized, double-blind, placebo-controlled trial. PARTICIPANTS A total of 14,641 US male physicians aged ≥ 50 years. INTERVENTION Daily multivitamin or placebo. MAIN OUTCOME MEASURES Incident cataract and visually significant AMD responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-reports confirmed by medical record review. RESULTS During an average of 11.2 years of treatment and follow-up, a total of 1817 cases of cataract and 281 cases of visually significant AMD were confirmed. There were 872 cataracts in the multivitamin group and 945 cataracts in the placebo group (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.83-0.99; P = 0.04). For visually significant AMD, there were 152 cases in the multivitamin group and 129 cases in the placebo group (HR, 1.19; 95% CI, 0.94-1.50; P = 0.15). CONCLUSIONS These randomized trial data from a large cohort of middle-aged and older US male physicians indicate that long-term daily multivitamin use modestly and significantly decreased the risk of cataract but had no significant effect on visually significant AMD.

Vitamins E and C and Medical Record-Confirmed Age-related Macular Degeneration in a Randomized Trial of Male Physicians

PURPOSE To test whether supplementation with alternate-day vitamin E or daily vitamin C affects the incidence of the diagnosis of age-related macular degeneration (AMD) in a large-scale randomized trial of male physicians. DESIGN Randomized, double-masked, placebo-controlled trial. PARTICIPANTS We included 14 236 apparently healthy United States male physicians aged ≥50 years who did not report a diagnosis of AMD at baseline. METHODS Participants were randomly assigned to receive 400 international units (IU) of vitamin E or placebo on alternate days, and 500 mg of vitamin C or placebo daily. Participants reported new diagnoses of AMD on annual questionnaires and medical record data were collected to confirm the reports. MAIN OUTCOME MEASURES Incident diagnosis of AMD responsible for a reduction in best-corrected visual acuity to ≤20/30. RESULTS After 8 years of treatment and follow-up, a total of 193 incident cases of visually significant AMD were documented. There were 96 cases in the vitamin E group and 97 in the placebo group (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.78-1.37). For vitamin C, there were 97 cases in the active group and 96 in the placebo group (HR, 0.99; 95% CI, 0.75-1.31). CONCLUSIONS In a large-scale, randomized trial of United States male physicians, alternate-day use of 400 IU of vitamin E and/or daily use of 500 mg of vitamin C for 8 years had no appreciable beneficial or harmful effect on risk of incident diagnosis of AMD.

Effect of Baseline Nutritional Status on Long-term Multivitamin Use and Cardiovascular Disease Risk: A Secondary Analysis of the Physicians’ Health Study II Randomized Clinical Trial

Importance Long-term multivitamin use had no effect on risk of cardiovascular disease (CVD) in the Physicians’ Health Study II. Baseline nutritional status may have modified the lack of effect. Objective To investigate effect modification by various baseline dietary factors on CVD risk in the Physicians’ Health Study II. Design, Setting, and Participants The Physicians’ Health Study II was a randomized, double-blind, placebo-controlled trial testing multivitamin use (multivitamin [Centrum Silver] or placebo daily) among US male physicians. The Physicians’ Health Study II included 14 641 male physicians 50 years or older, 13 316 of whom (91.0%) completed a baseline 116-item semiquantitative food frequency questionnaire and were included in the analyses. This study examined effect modification by baseline intake of key foods, individual nutrients, dietary patterns (Alternate Healthy Eating Index and Alternate Mediterranean Diet Score), and dietary supplement use. The study began in 1997, with continued treatment and follow-up through June 1, 2011. Interventions Multivitamin or placebo daily. Main Outcomes and Measures Major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, and CVD mortality. Secondary outcomes included myocardial infarction, total stroke, CVD mortality, and total mortality individually. Results In total, 13 316 male physicians (mean [SD] age at randomization, 64.0 [9.0] years in those receiving the active multivitamin and 64.0 [9.1] years in those receiving the placebo) were observed for a mean (SD) follow-up of 11.4 (2.3) years. There was no consistent evidence of effect modification by various foods, nutrients, dietary patterns, or baseline supplement use on the effect of multivitamin use on CVD end points. Statistically significant interaction effects were observed between multivitamin use and vitamin B6 intake on myocardial infarction, between multivitamin use and vitamin D intake on CVD mortality, and between multivitamin use and vitamin B12 intake on CVD mortality and total mortality. However, there were inconsistent patterns in hazard ratios across tertiles of each dietary factor that are likely explained by multiple testing. Conclusions and Relevance The results suggest that baseline nutritional status does not influence the effect of randomized long-term multivitamin use on major CVD events. Future studies are needed to investigate the role of baseline nutritional biomarkers on the effect of multivitamin use on CVD and other outcomes. Trial Registration clinicaltrials.gov Identifier: NCT00270647

Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL): Effects on Bone Structure and Architecture

Vitamin D supplements are often used to benefit skeletal health, although data on effects of daily high-dose vitamin D alone on bone density and structure are lacking. The ongoing VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, randomized, placebo-controlled trial testing effects of high-dose supplemental vitamin D3 (cholecalciferol; 2000 IU/day) and/or omega-3 fatty acids (FAs; 1 g/day) for the primary prevention of cancer and cardiovascular disease. The study has a mean treatment period of 5 years among 25,874 U.S. men ≥50 years and women ≥55 years old from all 50 states. The ancillary study, VITAL: Effects on Bone Structure and Architecture, is testing effects of vitamin D3 and/or omega-3 FAs on musculoskeletal outcomes and body composition in a subcohort of 771 participants. At in-person visits at the Harvard Catalyst Clinical and Translational Science Center (CTSC), participants completed bone density/architecture, body composition, and physical performance assessments at baseline and two-year follow-up. Baseline characteristics were evenly distributed among treatment groups, suggesting that any uninvestigated confounders will be evenly distributed; sex differences were also analyzed. Future analyses of the two-year follow-up visits will elucidate whether daily high-dose, supplemental vitamin D3 and/or omega-3 FAs improve musculoskeletal outcomes, helping to advance clinical and public health recommendations. CLINICAL TRIAL REGISTRATION NUMBER NCT01747447.

Vitamin D and omega-3 trial to prevent and treat diabetic kidney disease: Rationale, design, and baseline characteristics

Diabetic kidney disease (DKD), defined as reduced glomerular filtration rate (GFR), elevated urine albumin excretion, or both that is clinically attributable to diabetes, is a common and morbid diabetes complication. Animal-experimental data, observational human studies, and short-term clinical trials suggest that vitamin D and omega-3 fatty acid supplements may be safe and inexpensive interventions to reduce the incidence and progression of DKD. The Vitamin D and Omega-3 Trial to Prevent and Treat DKD (VITAL-DKD) was designed as an ancillary study to the VITAL trial of 25,871 US adults. In a 2 × 2 factorial design, VITAL participants were randomly assigned to vitamin D3 (cholecalciferol, 2000 IU daily) or placebo and to marine omega-3 fatty acids (eicospentaenoic acid and docosahexaenoic acid, 1 g/d) or placebo. VITAL-DKD enrolled a subset of 1326 VITAL participants with type 2 diabetes at baseline to test the effects of vitamin D and omega-3 fatty acids on changes in estimated GFR and urine albumin excretion. Over five years of follow-up, VITAL-DKD collected blood and urine samples to quantify changes in estimated GFR (the primary study outcome) and urine albumin excretion. At baseline, mean age of VITAL-DKD participants was 67.6 years, 46% were women, 30% were of racial or ethnic minority, and the prevalence of DKD (estimated GFR <60 mL/min/1.73m2 or urine albumin-creatinine ratio ≥ 30 mg/g) was 17%. In this type 2 diabetes population, VITAL-DKD will test the hypotheses that vitamin D and omega-3 fatty acids help prevent the development and progression of DKD.

Abstract 3245: Multivitamins and cancer in the Physicians’ Health Study II: Expanded analyses and insights

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The Physicians’ Health Study (PHS) II, the only clinical trial testing a daily multivitamin, recently reported a significant 8% reduction in the primary endpoint of total cancer. We conducted expanded post hoc analyses to test the effects of a common multivitamin (daily Centrum Silver) on the risk of site-specific cancer in a randomized, double-blind, placebo-controlled trial of 14,641 U.S. male physicians initially aged ≥50 years, including 1,312 with cancer at randomization. Treatment and follow-up occurred from 1997 to 2011. Cancer endpoints were confirmed by an Endpoints Committee of physicians blinded to randomized treatment. PHS II maintained high rates of morbidity and mortality follow-up. Computing hazard ratios (HRs) and 95% confidence intervals (95% CIs), we examined the effect of a daily multivitamin on cancers grouped by anatomic site (defined by ICD9 codes) and by previously unreported cancer sites. During a median follow-up of 11.2 years among men with mean age of 64.3 y at baseline, men taking a daily multivitamin had consistent, non-significant reductions in cancers of the digestive organs and peritoneum (HR, 0.82; 95% CI, 0.67-1.00; P=.05) and respiratory and intrathoracic organs (HR, 0.81; 95% CI, 0.60-1.09; P=.17) (Table). Men with a history of cancer had a significant reduction in genitourinary cancers (HR, 0.56; 95% CI, 0.35-0.89; P=.01). For individual cancer sites, there were strong but nonsignificant reductions in brain, colon, esophageal, gallbladder, kidney, liver, myeloid myeloma, small intestine, stomach, and thyroid cancer, and nonsignificant increases in connective tissue, multiple myeloma, other lymphoid, and rectum cancer. These expanded trial data in middle-aged and older men indicate that daily multivitamin use may benefit digestive and respiratory cancers, and genitourinary cancer among men with a history of cancer. These results support the need to understand the mechanisms and long-term effects of daily multivitamin use. View this table: Citation Format: Howard D. Sesso, William G. Christen, Vadim Bubes, JoAnn E. Manson, Robert J. Glynn, Julie E. Buring, J. Michael Gaziano. Multivitamins and cancer in the Physicians’ Health Study II: Expanded analyses and insights. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3245. doi:10.1158/1538-7445.AM2014-3245