Chen Shapira

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.

Complementary medicine in the primary care setting: Results of a survey of gender and cultural patterns in Israel.

OBJECTIVE The purpose of this study was to examine the use of complementary and alternative medicine (CAM) in a primary care practice in Israel to determine prevalence and patterns of use. METHODS Trained research assistants invited all patients attending the administrative, medical, pharmaceutical, or nursing services of 7 clinics in urban and rural areas of northern Israel over a 16-month period, from April 1, 2005, through August 1, 2006, to complete a 13-item written questionnaire about CAM use and beliefs about CAM safety and efficacy. CAM was defined as therapies often referred to as alternative, complementary, natural, or folk/traditional medicine, and which are not usually offered as part of the medical treatment in the clinic, including herbal medicine, Chinese medicine (including acupuncture), homeopathy, folk and traditional remedies, dietary/nutritional therapy (including nutritional supplements), chiropractic, movement/manual healing therapies (including massage, reflexology, yoga, and Alexander and Feldenkrais techniques), mind-body techniques (including meditation, guided imagery, and relaxation), energy and healing therapies, and other naturopathic therapies. The Pearson chi(2) test and multivariate logistic regression were used to assess univariate associations with the odds ratios of CAM use among Arab and Jewish women. A t test was performed to determine whether there were any differences in the continuous variables between the 2 groups. RESULTS Of 3972 consecutive patients who received the questionnaire, 3447 responded; 2139 respondents (62%) were women. Of the female respondents, 2121 reported their religion (1238 respondents [58%] self-identified as being Arab, and 883 [41.6%] as being Jewish). Compared with men, more women used CAM during the previous year (46.4% vs 39.4%; P < 0.001). Women were more likely to use CAM and to be interested in receiving CAM at primary care clinics. Arab women reported less CAM use than Jewish women but were more interested in experiencing CAM, had a higher degree of confidence in CAM efficacy and safety, and more frequently supported the integration of CAM practitioners in primary care clinics. CONCLUSIONS In this study, women visiting primary care clinics in northern Israel used CAM more often than men did. Arab women reported less use of CAM than did Jewish women but also reported greater confidence in CAM efficacy and safety.

Fosinopril reduces ADP-induced platelet aggregation in hypertensive patients

Platelets are intimately involved in atherosclerosis, and hypertension is a known risk factor for coronary artery disease. The angiotensin-converting enzyme (ACE) inhibitors were demonstrated to reduce hypertension and attenuate atherosclerosis. Because increased platelet aggregation was shown in hypertensive patients, the effect of a new ACE inhibitor, fosinopril, on platelet aggregation was studied. Fosinopril therapy (10 mg/day for 4 weeks) in 18 male hypertensive patients showed > or = 31% reduction in ADP-induced platelet aggregation. In vitro studies showed that fosinopril had similar inhibitory effect on ADP-induced platelet aggregation. No inhibitory effect could be detected with collagen as the aggregating agent. Finally, inhibition of platelet aggregation by fosinopril was less effective in platelets derived from hypertensive patients as compared with platelets derived from normal subjects. We conclude that fosinopril possesses a significant inhibitory activity on ADP-induced platelet aggregation both in vitro and in vivo.

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 …

Attitudes of Arab-Muslims toward integration of complementary medicine in primary-care clinics in Israel: the Bedouin mystery.

Introduction. In this study, we have compared attitudes of two social groups within the Israeli-Muslim population in order to examine the influence of modernization on the use of traditional and Complementary/Alternative Medicine (CAM). Research design and methods. We developed a 13-item questionnaire that addresses issues of CAM use, expectations from the primary-care physicians concerning CAM and attitudes toward CAM integration within the patients primary-care clinic. Data for statistical analysis were obtained from 472 respondents who defined themselves as Bedouins and 869 non-Bedouins attending five primary-care clinics. Results. Respondents in the two groups were equally distributed by demographic characteristics. Bedouin respondents reported less CAM use during the previous year (26.3% vs. 50.2%, P<0.0001), and less use of traditional medicine and herbs. Compared to non-Bedouins, Bedouin respondents who were considering CAM use expressed more drug reluctance. Respondents in both groups greatly supported a theoretical scenario of CAM integration in primary-medical care, and expected their family practitioner to initiate the referral to CAM. Bedouin respondents held higher expectations for their physician to refer them to CAM and to offer CAM treatment in the clinic. Moreover, Bedouins expected to receive CAM in a primary-care setting, and supported the option that their family physician would provide CAM in such a setting more than the non-Bedouin Muslims did. Conclusions. We hypothesize that the two communities differ due to later modernization in the Bedouin society that may highly regard and pursue medical science while forsaking traditional and herbal medicine.

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.’

Clinical determinants and treatment gaps in familial hypercholesterolemia: Data from a multi-ethnic regional health service

Background Familial hypercholesterolemia is characterized by markedly increased low-density lipoprotein cholesterol and risk for premature atherosclerotic cardiovascular disease. Models of care vary and reflect differing health policies and resources. The availability of electronic databases may enable better identification and assessment of familial hypercholesterolemia in the community. Methods A regional healthcare database was utilized to identify patients with a high probability of familial hypercholesterolemia, clinically defined by age-dependent-peak low-density lipoprotein cholesterol cutoffs and exclusion of secondary causes of severe hypercholesterolemia. Clinical characteristics, low-density lipoprotein cholesterol goal attainment, and treatment gaps were investigated. Results Probable familial hypercholesterolemia was diagnosed in 1932 of 685,314 individuals (1:355; median age 47 years). Atherosclerotic cardiovascular disease was present in 16.3% of adults (38% in males aged 50–74 years). Median peak low-density lipoprotein cholesterol was 264 mg/dl (interquartile range 252–288). Statins and/or ezetimibe were prescribed to 83% of patients and high-intensity statins to 53%, whereas prescriptions were filled in 57% and 40% cases respectively over the last six months, p < 0.001. Treatment gaps were wider among ethnic minorities, younger individuals, and those without atherosclerotic cardiovascular disease. Low-density lipoprotein cholesterol < 100 mg/dl was attained in 10.1% overall and 28.7% of those with atherosclerotic cardiovascular disease. Predictors of low-density lipoprotein cholesterol goal attainment included recent issue of high-intensity statins, presence of atherosclerotic cardiovascular disease, diabetes, older age and lack of smoking. Conclusions The population with high probability for familial hypercholesterolemia was characterized by low attainment of low-density lipoprotein cholesterol treatment goals despite high prescription rates of lipid-lowering medications. Low utilization of intensified therapies, non-adherence, and ethnic disparities were contributing factors. These findings emphasize the need to improve awareness and quality of care of familial hypercholesterolemia in the community.