Uzi Milman

Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective double-blinded clinical trial.

Objective—Clinical trials of vitamin E have failed to demonstrate a decrease in cardiovascular events. However, these studies did not address possible benefit to subgroups with increased oxidative stress. Haptoglobin (Hp), a major antioxidant protein, is a determinant of cardiovascular events in patients with Type 2 diabetes mellitus (DM). The Hp gene is polymorphic with 2 common alleles, 1 and 2. The Hp 2 allelic protein product provides inferior antioxidant protection compared with the Hp 1 allelic product. We sought to test the hypothesis that vitamin E could reduce cardiovascular events in DM individuals with the Hp 2-2 genotype, a subgroup that comprises 2% to 3% of the general population. Methods and Results—1434 DM individuals ≥55 years of age with the Hp 2-2 genotype were randomized to vitamin E (400 U/d) or placebo. The primary composite outcome was myocardial infarction, stroke, and cardiovascular death. At the first evaluation of events, 18 months after initiating the study, the primary outcome was significantly reduced in individuals receiving vitamin E (2.2%) compared with placebo (4.7%; P=0.01) and led to early termination of the study. Conclusions—Vitamin E supplementation appears to reduce cardiovascular events in individuals with DM and the Hp 2-2 genotype (ClinicalTrials.gov NCT00220831).

Correction of HDL Dysfunction in Individuals With Diabetes and the Haptoglobin 2-2 Genotype

OBJECTIVE—Pharmacogenomics is a key component of personalized medicine. The Israel Cardiovascular Events Reduction with Vitamin E Study, a prospective placebo-controlled study, recently demonstrated that vitamin E could dramatically reduce CVD in individuals with diabetes and the haptoglobin (Hp) 2-2 genotype (40% of diabetic individuals). However, because of the large number of clinical trials that failed to demonstrate benefit from vitamin E coupled with the lack of a mechanistic explanation for why vitamin E should be beneficial only in diabetic individuals with the Hp 2-2 genotype, enthusiasm for this pharmacogenomic paradigm has been limited. In this study, we sought to provide such a mechanistic explanation based on the hypothesis that the Hp 2-2 genotype and diabetes interact to promote HDL oxidative modification and dysfunction. RESEARCH DESIGN AND METHODS—Hb and lipid peroxides were assessed in HDL isolated from diabetic individuals or mice with the Hp 1-1 or Hp 2-2 genotypes. HDL function was assessed based on its ability to promote cholesterol efflux from macrophages. A crossover placebo-controlled study in Hp 2-2 diabetic humans and in Hp 1-1 and Hp 2-2 diabetic mice assessed the ability of vitamin E to favorably modify these structural and functional parameters. RESULTS—Hb and lipid peroxides associated with HDL were increased and HDL function was impaired in Hp 2-2 diabetic individuals and mice. Vitamin E decreased oxidative modification of HDL and improved HDL function in Hp 2-2 diabetes but had no effect in Hp 1-1 diabetes. CONCLUSIONS—Vitamin E significantly improves the quality of HDL in Hp 2-2 diabetic individuals.

Vitamin E reduces cardiovascular disease in individuals with diabetes mellitus and the haptoglobin 2-2 genotype

AIMS Individuals with both diabetes mellitus (DM) and the Haptoglobin (Hp) 2-2 genotype are at increased risk of cardiovascular disease. As the antioxidant function of the Hp 2-2 protein is impaired, we sought to test the pharmacogenomic hypothesis that antioxidant vitamin E supplementation would provide cardiovascular protection to Hp 2-2 DM individuals. MATERIALS & METHODS We determined the Hp genotype on DM participants from two trials (HOPE and ICARE) and assessed the effect of vitamin E by Hp genotype on their common prespecified outcome, the composite of stroke, myocardial infarction and cardiovascular death. Data was analyzed with a fixed-effect model. These results were input into a simulation model, the Evidence Based Medicine Integrator, in order to estimate their long-term implications in a real-world population from Kaiser Permanente (CA, USA). RESULTS Meta-analysis of the two trials demonstrated a significant overall reduction in the composite end point in Hp 2-2 DM individuals with vitamin E (odds ratio: 0.58; 95% CI: 0.40-0.86; p = 0.006). There was a statistically significant interaction between the Hp genotype and vitamin E on the composite end point. In these trials, Hp typing of 69 DM individuals and treating those with the Hp 2-2 with vitamin E prevented one myocardial infarct, stroke or cardiovascular death. Lifelong administration of vitamin E to Hp 2-2 DM individuals in the Kaiser population would increase their life expectancy by 3 years. CONCLUSION A pharmacogenomic strategy of screening DM individuals for the Hp genotype and treating those with Hp 2-2 with vitamin E appears to be highly clinically effective.

Haptoglobin Genotype Is a Regulator of Reverse Cholesterol Transport in Diabetes In Vitro and In Vivo

Two common alleles exist at the haptoglobin (Hp) locus, and the Hp2 allele is associated with an increased incidence of cardiovascular disease, specifically in diabetes mellitus (DM). Oxidative stress is increased in Hp2 mice and humans with DM. Oxidative modification of the apolipoprotein A-I inhibits reverse cholesterol transport. We sought to test the hypothesis that reverse cholesterol transport is impaired in Hp2 DM mice and humans. In vitro, using serum from non-DM and DM individuals, we measured cholesterol efflux from 3H-cholesterol–labeled macrophages. In vivo, we injected 3H-cholesterol–loaded macrophages intraperitoneally into non-DM and DM mice with the Hp1-1 or Hp2-2 genotype and monitored 3H-tracer levels in plasma, liver, and feces. In vitro, in DM individuals only, we observed significantly decreased cholesterol efflux from macrophages incubated with serum from Hp2-1 or Hp2-2 as compared with Hp1-1 individuals (P<0.01). The interaction between Hp type and DM was recapitulated using purified Hp and glycated Hb. In vivo, DM mice loaded with 3H-cholesterol–labeled macrophages had a 40% reduction in 3H-cholesterol in plasma, liver, and feces as compared with non-DM mice (P<0.01). The reduction in reverse cholesterol transport associated with DM was significantly greater in Hp2-2 mice as compared with Hp1-1 mice (54% versus 25% in plasma; 52% versus 27% in liver; 57% versus 32% in feces; P<0.03). reverse cholesterol transport is decreased in Hp2-2 DM. This may explain in part the increased atherosclerotic burden found in Hp2-2 DM individuals.

Dual Therapy With Statins and Antioxidants Is Superior to Statins Alone in Decreasing the Risk of Cardiovascular Disease in a Subgroup of Middle-Aged Individuals With Both Diabetes Mellitus and the Haptoglobin 2-2 Genotype

Diabetes Mellitus (DM) is associated with a state of increased oxidative stress.1 Paradoxically, however, antioxidants have not been found to provide CVD benefit to DM individuals in several prospective clinical trials.2–11 However, the inability to demonstrate benefit may have been attributable to inadequate patient selection as antioxidants may only benefit those with particularly high levels of oxidative stress.12 A polymorphism in the Haptoglobin (Hp) gene, an antioxidant protein, appears to permit identification of individuals with high oxidative stress and who may benefit from antioxidant therapy.13 There exists 2 classes of alleles at the Hp genetic locus, 1 and 2, and the antioxidant capacity of the Hp 2 protein is inferior to the Hp 1 protein.14–18 Robust clinical data has shown that individuals homozygous for the Hp 2 allele (Hp 2-2 genotype), 40% of DM individuals, have an up to 500% increased risk of CVD.19–22 A vast amount of basic science, animal, and epidemiological data has provided the logic for targeting vitamin E administration specifically to DM individuals with the Hp 2-2 genotype.13 Most importantly we have recently reported in the ICARE study (Israel CArdiovascular events Reduction with vitamin E [ClinicalTrials.gov# NCT00220831]) a prospective randomized placebo controlled trial of vitamin E therapy in DM individuals with the Hp 2-2 genotype, that vitamin E therapy results in a 50% reduction in CVD events.22 …

Obesity and risk taking: A male phenomenon

There is a growing tendency to regard overeating as an addiction, with obesity as its primary symptom. We propose that similar to other addictions, obesity is associated with excessive risk-taking in men, though not in women. To examine this suggestion we conducted two studies, one involving a sample of overweight and normal-weight students, and the other involving obese adults drawn from a dataset of health care clients, and a control sample of normal-weight adults. In both of these studies, we found that overweight and obese men took more risk in a laboratory task than normal-weight men, while overweight and obese women did not differ from normal-weight women in this respect. At the same time, obese women (but not overweight women) displayed higher impulsivity levels than normal-weight women. These findings shed light on the cognitive characteristics of obesity in men, and accent the importance of taking gender into account when developing research paradigms and treatment methods for obesity.

Hospitalizations of Patients Treated with Anti-Tumor Necrosis Factor-α Agents — A Retrospective Cohort Analysis

Objective. To assess the association between treatment with anti-tumor necrosis factor-α (TNF-α) agents and the occurrence of hospitalizations, their causes and complications, compared to treatment with traditional disease-modifying antirheumatic drugs in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Methods. A retrospective cohort study was conducted of patients with RA, AS, and PsA treated with anti-TNF-α agents between April 2002 and December 2007. Patients were assessed during the period of anti-TNF-α treatment (Group B) and compared to an equivalent period before initiation of anti-TNF-α therapy (Group A). All hospitalization charts were reviewed and diagnoses, comorbidities, concomitant medications, and clinical course were analyzed. Statistical analysis was performed using multivariate mixed Poisson regression. Results. In the study period of 57 months, 735 hospitalization events of 327 patients were analyzed. Statistically significant decreases were seen in the total number of hospitalization events as well as hospitalizations due to exacerbation of rheumatic diseases in Group B compared to Group A (44.4 vs 74.2 and 21.9 vs 47.5 per 100 patient-years, respectively; p < 0.0001). More infectious events (7.4 in Group B compared to 4.6 per 100 patient-years in Group A; p = 0.043) were associated with anti-TNF-α treatment, older age, and underlying disease, because patients with RA had higher rates of infections compared to patients with PsA and patients with AS. Conclusion. The overall effect of anti-TNF-α therapy was a significant decline in total hospitalization events. The decrease was more prominent in patients with RA than in patients with AS and patients with PsA, and reflected the significant decrease in hospitalizations due to rheumatic disease exacerbation. The decrease was more pronounced than the observed increase in infectious events.

Pharmacogenomic application of the haptoglobin genotype in the prevention of diabetic cardiovascular disease

Shany Blum1, Uzi Milman2, Chen Shapira3 & Andrew P Levy1† †Author for correspondence 1Department of Anatomy and Cell Biology, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, POB 9649, Haifa, Israel Tel.: +972 4829 5202; Fax: +972 4851 4103; E-mail: alevy@ tx.technion.ac.il 2Clinical Research Unit, Clalit Health Services, Haifa and Western Galilee, and the Department of Family Medicine, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel 3Clalit Health Services, Haifa and Western Galilee, and the Lady Davis Carmel Medical Center, Haifa, Israel ‘A total of five independent longitudinal studies have demonstrated that DM individuals with the Hp 2-2 genotype have a twoto five-fold increased risk of CVD as compared with DM individuals without the Hp 2-2 genotype.’

Effects of anti-TNF-α treatment on lipid profile in rheumatic diseases: an analytical cohort study

BackgroundThe aim was to assess the influence of long-term treatment with tumor necrosis factor alpha (TNF-α) inhibitors on total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and atherogenic index (AI) in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) patients.MethodsA retrospective cohort study was conducted on RA, PsA, and AS patients treated with TNF-α inhibitors for at least 270 days between 2001 and 2011. Levels of TC, TG, LDL, and HDL and the AI were compared with baseline values at 0–6, 6–12, 12–18, and 18–24 months. Patients were further subdivided into three groups according to their HMG CoA reductase inhibitor (statin) treatment status in order to assess their effect on the results.ResultsThe records of 311 patients (152 RA, 90 PsA, and 69 AS) were reviewed. TC and TG increased following treatment with TNF-α inhibitors, from 180.85 ± 2.12 mg/dl and 116.00 ± 3.55 mg/dl at baseline to 188.12 ± 2.35 mg/dl (p = 0.02) and 132.02 ± 4.63 mg/dl at 0–6 months (p < 0.01), respectively, and to 184.88 ± 2.09 mg/dl (p = 0.02) and 129.36 ± 4.32 mg/dl at 18–24 months (p < 0.01), respectively. AI increased following treatment with TNF-α inhibitors, from –0.032 ± 0.017 at baseline to 0.004 ± 0.019 at 18–24 months (p < 0.01). LDL decreased significantly in patients who were treated with statins before and during the entire study period, from 119.97 ± 2.86 mg/dl at baseline to 104.02 ± 3.57 mg/dl at 18–24 months (p < 0.01), in contrast to an increase in LDL values in patients who did not receive statins during the study.ConclusionsTNF-α inhibitor treatment was associated with a significant increase in TC and TG levels and the AI. Adding statins to the treatment was associated with a significant decrease in LDL levels.

Effect of Magnesium Oxide Supplementation on Nocturnal Leg Cramps: A Randomized Clinical Trial

Importance Magnesium supplements are widely marketed for prophylaxis of nocturnal leg cramps (NLC) despite no evidence of significant benefit. Objective To determine whether magnesium oxide is better than placebo for NLC prophylaxis. Design, Setting, and Participants A randomized, double-blind, placebo-controlled clinical trial of 2 weeks eligibility screening followed by 4 weeks of treatment was conducted in northern Israel, from February to October 2013. An intention-to-treat data analysis was performed from March 22, 2014, to April 17, 2016. We used a volunteer sample of community-dwelling individuals experiencing NLC, 21 years or older, with 4 or more documented episodes of NLC during 2 weeks of screening. Interventions Capsules containing either magnesium oxide or a similar-looking placebo to be taken orally, once daily at bedtime for a period of 4 weeks. Main Outcomes and Measures The primary outcome was the difference in the mean number of NLC per week between the screening and treatment phases. Secondary outcomes included severity and duration of NLC, quality of life, and quality of sleep. Results Of the 166 volunteers, 72 (43%) were excluded, of whom 15 declined to participate and 57 did not meet the inclusion criteria. Of the 94 individuals (39% male; mean [SD] age, 64.9 [11.1] years) randomly assigned to magnesium oxide (48) or placebo (46), 6 did not complete the study protocol (3 in each group). Mean (SD) change of NLC was −3.41 (4.05) (from 7.84 [5.68] to 4.44 [5.66]) and −3.03 (4.53) (from 8.51 [5.20] to 5.48 [4.93]) per week in the magnesium oxide and placebo groups, respectively, a difference between groups of 0.38 (0.48) NLC per week (P = .67 in an intention-to-treat analysis). There were no between-group differences in the severity and duration of NLC, quality of life, or quality of sleep. Conclusions and Relevance Oral magnesium oxide was not superior to placebo for older adults experiencing NLC. The decrease in the mean number of NLC per week, from the screening to the treatment phase in both groups, is probably a placebo effect that may explain the wide use of magnesium for NLC. Trial Registration clinicaltrials.gov Identifier: NCT01709968