Cardiovascular Disease Benefits Research Articles

Should we stop prescribing pioglitazone?

We read with interest the paper ‘Thiazolidinediones and associated risk of bladder cancer: a systematic review and meta-analysis’ by Turner et al. [1]. The authors present the results of a meta-analysis including a large number of patients. They concluded that pioglitazone use is associated with a modest but significant increase in the risk of bladder cancer, which further increases with both higher cumulative dose (>28 g) and duration of exposure (>12–24 months). Interestingly, the effect of rosiglitazone on bladder cancer risk was not significant [1]. A few comments might be of interest, based on the results of a recent study (published in August 2013), not included in the meta-analysis [2]. This was an observational follow-up study of patients included in the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) trial, who had received pioglitazone for 2.6 years. PROactive had shown a modest but significant reduction in the composite of all cause mortality, non-fatal myocardial infarction (MI) and stroke in high cardiovascular disease (CVD) risk type 2 diabetes mellitus (T2DM) patients [3]. After a mean follow-up time of 8.7 years (including the PROactive period), the CVD benefit was lost, since only 13.5% continued on pioglitazone [2]. There was no evidence of increased risk of bladder cancer in these patients (89% of them were at the maximum dose of 45 mg day−1) [2]. Interestingly, no significant between group differences were observed in the percentage of patients reporting any other malignancies, except for prostate malignancy, a finding that needs further confirmation [3]. The leading cause of death in patients with T2DM is CVD [3]. As PROactive has shown, 40 patients would need to be treated for 3 years in order to prevent one first CVD event. In other words, the number needed to treat is approximately 120 per year [3], while the number needed to treat for harm (that is to develop one case of bladder cancer) shown by the meta-analysis was 3408 for ever pioglitazone use, 1119 for >28 g cumulative dose and 1404 for >24 months cumulative duration [1]. On the contrary, rosiglitazone use has been associated with increased risk for MI (although not for CVD or all cause mortality) in an older meta-analysis, showing one additional MI per 52 patients treated for 5 years [4]. These results were confirmed by a comparative meta-analysis, showing a significant increase in the odds of MI, congestive heart failure and death (170 excess MIs, 649 excess cases of heart failure and 431 excess deaths for every 100 000 patients receiving rosiglitazone rather than pioglitazone) [5]. It seems therefore prudent to prescribe an agent that has been shown to protect the cardiovascular system, for at least 3 years, rather than avoid it for the fear of causing bladder cancer, the possibility of which for such a period seems very low (taking into account that the cumulative dose of 28 g stands for a 31 month period of 30 mg day−1, which is the usual pioglitazone dose). This becomes more important in an era when clinicians, the Food and Drug Administration and the European Medicines Agency are very cautious about the effect of any anti-diabetic and anti-obesity drug on the cardiovascular system [6]. New studies are already being conducted to test the effect of other drug categories, such as glucagon-like peptide (GLP)-1 based therapies, on the cardiovascular system [6]. In conclusion, we believe that pioglitazone should continue to be considered a reliable therapeutic option in patients with T2DM for a period of up to 2 years (with a potential extension to 3 years), since its benefit and safety on the cardiovascular system overweigh the potential risk for bladder cancer. Patients at high risk for bladder cancer, such as those with a family history, microscopic haematuria and exposure to carcinogenic substances, should be excluded.

Abstract 18968: Bromocriptine-QR: A Potential Novel Strategy for Cardiovascular Risk Reduction in Type 2 Diabetes

Type 2 diabetes (T2D) is associated with a substantially increased risk of cardiovascular disease (CVD). Of the available therapies for T2D, none have been conclusively shown to reduce CVD risk. Metformin has long been considered the only agent with some evidence, albeit limited, of a potential CVD benefit. Bromocriptine-QR (BQR), a quick release sympatholytic dopamine agonist, is a newer FDA-approved therapy for T2D. Based on preclinical and clinical study findings, it is postulated that BQR restores the normal circadian peak in central dopaminergic tone diminished in insulin resistant states, which in turn reduces hyperactive sympathetic tone and improves central fuel sensing thereby reducing postprandial hepatic glucose and lipid output as well as reduces vascular resistance, oxidative stress, and inflammation. In a one-year randomized trial of BQR vs. placebo added to standard therapy (diet and/or ≤ 2 diabetes medications including sulfonylureas, TZD, metformin, or insulin) in 3070 T2D subjects (average duration of T2D: 7.9 years), including individuals with pre-existing CVD, BQR therapy resulted in a 40% hazard rate reduction (HRR) in major CVD events, pre-specified as a composite of time to first myocardial infarction, stroke, coronary revascularization, hospitalization for angina or congestive heart failure. In the present study, this CVD effect of BQR was evaluated in a subset of this original study population on metformin +/- another anti-diabetes therapy at baseline (N = 1791). The composite CVD end point occurred in 16/1208 BQR-treated (1.3%) and 18/583 placebo-treated (3.1%) subjects resulting in a 53% CVD HRR (ITT group, Cox regression analysis; HR 0.47, 95% CI 0.24, 0.92, P = 0.028) adjusted by age (HR 1.08, 95% C.I. 1.04, 1.12, P = 0.0003) and pre-existing CVD (HR 2.27, 95% C.I. 1.02, 5.07, P = 0.041). Kaplan-Meier Curves of the cumulative incidence rate yielded a CVD HRR of 58% (HR 0.42, 95% C.I. 0.21, 0.85, Log-Rank = 0.017). These findings reaffirm prior observations of CVD risk reduction with BQR therapy and further demonstrate the potential for a marked additive effect of BQR above any derived from metformin, suggesting a potential novel strategy for CVD risk reduction in T2D.

Projected impact of a sodium consumption reduction initiative in Argentina: an analysis from the CVD policy model--Argentina.

BackgroundCardiovascular disease (CVD) is the leading cause of death in adults in Argentina. Sodium reduction policies targeting processed foods were implemented in 2011 in Argentina, but the impact has not been evaluated. The aims of this study are to use Argentina-specific data on sodium excretion and project the impact of Argentina’s sodium reduction policies under two scenarios - the 2-year intervention currently being undertaken or a more persistent 10 year sodium reduction strategy.MethodsWe used Argentina-specific data on sodium excretion by sex and projected the impact of the current strategy on sodium consumption and blood pressure decrease. We assessed the projected impact of sodium reduction policies on CVD using the Cardiovascular Disease (CVD) Policy Model, adapted to Argentina, modeling two alternative policy scenarios over the next decade.ResultsOur study finds that the initiative to reduce sodium consumption currently in place in Argentina will have substantial impact on CVD over the next 10 years. Under the current proposed policy of 2-year sodium reduction, the mean sodium consumption is projected to decrease by 319–387 mg/day. This decrease is expected to translate into an absolute reduction of systolic blood pressure from 0.93 mmHg to 1.81 mmHg. This would avert about 19,000 all-cause mortality, 13,000 total myocardial infarctions, and 10,000 total strokes over the next decade. A more persistent sodium reduction strategy would yield even greater CVD benefits.ConclusionThe impact of the Argentinean initiative would be effective in substantially reducing mortality and morbidity from CVD. This paper provides evidence-based support to continue implementing strategies to reduce sodium consumption at a population level.

Is Plasma Pentadecanoic Acid a Reasonable Biomarker of Dairy Consumption?

Despite advances in biomedical research and clinical medicine, the burden of cardiovascular disease (CVD) remains extremely high.[1][1] This underscores the importance of primary prevention and the search for novel therapeutic strategies. Modifiable lifestyle factors, including dietary habits, play

Dietary fatty acids and lipoprotein metabolism

Dyslipidemia is a powerful risk factor for cardiovascular disease (CVD). Dietary fatty acid composition regulates lipids and lipoprotein metabolism and may confer CVD benefit. This review updates understanding of the effect of dietary fatty acids on lipoprotein metabolism in humans. High dietary fish-derived n-3 polyunsaturated fatty acid (PUFA) consumption diminished hepatic triglyceride-rich lipoprotein (TRL) secretion and enhanced TRL to LDL conversion. n-3 PUFA also decreased TRL-apoB-48 concentration by decreasing TRL-apoB-48 secretion. High n-6 PUFA intake decreased liver fat, and plasma proprotein convertase subtilisin/kexin type 9, triglycerides, total-cholesterol and LDL-cholesterol concentrations. Intake of saturated fatty acids with increased palmitic acid at the sn-2 position was associated with decreased postprandial lipemia, which might be due to decreased triglyceride absorption. Replacing carbohydrate with monounsaturated fatty acids increased TRL catabolism. Ruminant trans-fatty acid decreased HDL cholesterol, but the mechanisms are unknown. A new role for APOE genotype in regulating lipid responses was also described. The major advances in understanding the effect of dietary fatty acids on lipoprotein metabolism have focused on n-3 PUFA. This knowledge provides insights into the importance of regulating lipoprotein metabolism as a mode to improve plasma lipids and potential CVD risk. Further studies are required to better understand the cardiometabolic effects of other dietary fatty acids.

Abstract MP42: Reduction in Dietary Transfat Intake is Associated with Improved Lipid Particle Number in a Primary Prevention Population

Background: Recent public policy has focused on elimination of dietary transfats. The extent to which changes in transfat intake correlate with changes in cardiovascular disease (CVD) risk in real world settings is not established. Lipid Particle Number (LPN) is a novel marker of CVD risk and data from the Framingham Offspring Study indicate a doubling of CVD risk among those with LPN values in the highest versus lowest quartile. The purpose of this study was to determine if a decrease in transfat intake is associated with a decrease in LPN in a free living population at risk of CVD. Methods: This was a 1 year follow-up study of family members (n = 400, 33% male, 36% racial/ethnic minority, mean age 48 +/- 13) of patients hospitalized with CVD who participated in a 1 year NHLBI sponsored randomized controlled primary prevention lifestyle intervention trial and had complete dietary data and LPN measures at baseline and 1 year. Transfat (% of total kilocalories per day) was assessed by the validated Block Food Frequency Questionnaire and LPN (nmol/L) was measured at a central lab using NMR spectroscopy at baseline and 1 year. Traditional CVD risk factors and potential confounders were assessed by trained research personnel using standardized measures and questionnaires. Change in transfat as a percentage of total diet and mean absolute change in LPN at 1 year was assessed using multivariate adjusted linear regression models. Results: Over 1 year 57% (n = 226) of the study population decreased their transfat intake which did not vary significantly by group assignment. There was a significant positive correlation between baseline dietary transfat intake and LPN (p = 0.04). At baseline higher mean LPN was also associated with male sex (p < 0.001), overweight/obesity (≥ 25 kg/m 2 , p < 0.001), waist size (men ≥ 40 inches, women ≥ 35 inches, p < 0.001), HgA1c (≥ 6.5%, p = 0.003), and current smoking (p = 0.01). Over 1 year, for every 1 percent change in transfat intake there was a 27 nmol/L change in LPN (p = 0.04). The association between the change in transfat intake and change in LPN was independent of baseline predictors, confounders, and group assignment (p = 0.03). Conclusion: In a free living population at risk of CVD, a reduction in transfat intake over 1 year was significantly associated with a reduction in LPN. These data suggest how improved LPN may be one potential mechanism by which elimination of transfat may confer CVD benefit, and provide insight into the potential for a decrease in transfat intake to decrease the burden of CVD.

Association of smoking cessation and weight change with cardiovascular disease among adults with and without diabetes.

Smoking cessation reduces the risks of cardiovascular disease (CVD), but weight gain that follows quitting smoking may weaken the CVD benefit of quitting. To test the hypothesis that weight gain following smoking cessation does not attenuate the benefits of smoking cessation among adults with and without diabetes. Prospective community-based cohort study using data from the Framingham Offspring Study collected from 1984 through 2011. At each 4-year examination, self-reported smoking status was assessed and categorized as smoker, recent quitter (≤ 4 years), long-term quitter (>4 years), and nonsmoker. Pooled Cox proportional hazards models were used to estimate the association between quitting smoking and 6-year CVD events and to test whether 4-year change in weight following smoking cessation modified the association between smoking cessation and CVD events. Incidence over 6 years of total CVD events, comprising coronary heart disease, cerebrovascular events, peripheral artery disease, and congestive heart failure. After a mean follow-up of 25 (SD, 9.6) years, 631 CVD events occurred among 3251 participants. Median 4-year weight gain was greater for recent quitters without diabetes (2.7 kg [interquartile range {IQR}, -0.5 to 6.4]) and with diabetes (3.6 kg [IQR, -1.4 to 8.2]) than for long-term quitters (0.9 kg [IQR, -1.4 to 3.2] and 0.0 kg [IQR, -3.2 to 3.2], respectively, P < .001). Among participants without diabetes, age- and sex-adjusted incidence rate of CVD was 5.9 per 100 person-examinations (95% CI, 4.9-7.1) in smokers, 3.2 per 100 person-examinations (95% CI, 2.1-4.5) in recent quitters, 3.1 per 100 person-examinations (95% CI, 2.6-3.7) in long-term quitters, and 2.4 per 100 person-examinations (95% CI, 2.0-3.0) in nonsmokers. After adjustment for CVD risk factors, compared with smokers, recent quitters had a hazard ratio (HR) for CVD of 0.47 (95% CI, 0.23-0.94) and long-term quitters had an HR of 0.46 (95% CI, 0.34-0.63); these associations had only a minimal change after further adjustment for weight change. Among participants with diabetes, there were similar point estimates that did not reach statistical significance. In this community-based cohort, smoking cessation was associated with a lower risk of CVD events among participants without diabetes, and weight gain that occurred following smoking cessation did not modify this association. This supports a net cardiovascular benefit of smoking cessation, despite subsequent weight gain.

Association between bilirubin and cardiovascular disease risk factors: using Mendelian randomization to assess causal inference

BackgroundElevated serum bilirubin has been associated with reduced risk of cardiovascular disease (CVD). However, serum bilirubin is also related with several potential confounders related to CVD, such as obesity. Mendelian randomization has been proposed as a method to address challenges to validity from confounding and reverse causality. It utilizes genotype to estimate causal relationships between a gene product and physiological outcomes. In this report, we demonstrate its use in assessing direct causal relations between serum bilirubin levels and CVD risk factors, including obesity, cholesterol, measures of vascular function and blood pressure.MethodsStudy subjects included 868 asymptomatic individuals. Study subjects were genotyped at the UGT1A1*28 locus, which is strongly associated with bilirubin levels.ResultsSerum bilirubin levels were inversely associated with levels of several cardiovascular disease risk factors, including body mass index (p = 0.003), LDL (p = 0.0005) and total cholesterol (p = 0.0002). In contrast, UGT1A1*28 genotype, a known cause of elevated bilirubin levels, was not significantly associated with any of these traditional CVD risk factors. We did observe an association between genotype and brachial artery diameter (p = 0.003) and cold pressor reactivity (p = 0.01).ConclusionsOur findings imply that the observed association of serum bilirubin levels with body mass index and cholesterol are likely due to confounding and suggest that previously established CVD benefits of increased bilirubin may in part be mediated by the early regulation of vascular structure and reactivity.

Progression of Carotid Intima-Media Thickness in a Contemporary Human Immunodeficiency Virus Cohort

Persons with human immunodeficiency virus (HIV) infection are at risk for premature cardiovascular disease (CVD). Predictors of atherosclerotic disease progression in contemporary patients have not been well described. Using data from a prospective observational cohort of adults infected with HIV (Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy), we assessed common carotid artery intima-media thickness (CIMT) at baseline and year 2 by ultrasound. We examined HIV-associated predictors of CIMT progression after adjusting for age, sex, race/ethnicity, body mass index, smoking, hypertension, diabetes, low-density lipoprotein cholesterol level, and baseline CIMT using linear regression. Among 389 participants (median age at baseline, 42 years; male sex, 77%; median CD4+ cell count at baseline, 485 cells/mm³; 78% receiving antiretroviral therapy), the median 2-year CIMT change was 0.016 mm (interquartile range, -0.003 to 0.033 mm; P < .001). Lesser CIMT progression was associated with a suppressed viral load at baseline (-0.009 mm change; P = .015) and remaining virologically suppressed throughout follow-up (-0.011 mm change; P < .001). After adjusting for additional risk factors and a suppressed viral load during follow-up, nonnucleoside reverse transcriptase inhibitor versus protease inhibitor exposure was associated with lesser CIMT progression (-0.011 mm change; P = .02). Suppressing HIV replication below clinical thresholds was associated with less progression of atherosclerosis. The proatherogenic mechanisms of HIV replication and the net CVD benefit of different antiretroviral drugs should be a focus of future research.

Primary Prevention of Coronary Heart Disease With Statins

In the current issue of Circulation , Lazar et al report the results of their modeling of the cost-effectiveness of alternative statin treatment strategies for primary prevention using low-cost, lower-potency generic statins.1 Lazar's study informs clinical decisions and practice guidelines about the potential use of statin therapy in people at low to moderate risk for coronary heart disease. It also provides an opportunity to consider the appropriate use and potential misuse of decision models to inform and guide clinical practice, and it highlights research opportunities, challenges, and potential limitations of comparative effectiveness, as well. Patients and providers commonly express the desire to make medical decisions solely on the basis of anticipated clinical benefits, harms, and patient preferences and values, without considering the distorting effects of cost. With the widespread availability of generic forms of most US-licensed statins (as of November 2011, rosuvastatin will be the only Food and Drug Administration-approved patent-protected statin in the United States), the cost of statin therapy has dropped precipitously. All currently available generic statins, with the exception of simvastatin 80 mg, can be purchased for as little $0.11 to $0.13 a pill at 1 or more major national pharmacy chains. Article see p 146 At these acquisition costs, Lazar et al find that low/moderate potency statin therapy is cost saving for those without a prior cardiovascular event at a moderately high risk of experiencing a coronary heart disease (CHD) event (10% to 20% over 10 years; 2 Framingham Heart Study [FHS] risk factors and a low-density lipoprotein-cholesterol [LDL-C] >100 mg/dL), and those with 2 risk factors but a 130 mg/dL, as well. They further identify a cost-effective maximum impact strategy that comprises all people with 2 Framingham risk factors, regardless of 10-year FHS risk or LDL-C level, those …

Lycopene and Cardiovascular Diseases: An Update

Cardiovascular disease (CVD) is the leading cause of death in Western societies and accounts for up to a third of all deaths worldwide. In comparison to the Northern European or other Western countries, the Mediterranean area has lower rates of mortality from cardiovascular diseases and cancer, and this is attributed, at least in part, to the so-called Mediterranean diet, which is rich in plantderived bioactive phytochemicals. Identification of the active constituents of the Mediterranean diet is therefore crucial to the formulation of appropriate dietary guidelines. Lycopene is a natural carotenoid found in tomato, an essential component of the Mediterranean diet, which, although belonging to the carotenoid family, does not have pro-vitamin A activity but many other biochemical functions as an antioxidant scavenger, hypolipaemic agent, inhibitor of pro-inflammatory and pro-thrombotic factors, thus potentially of benefit in CVD. In particular, the review intends to conduct a systematic analysis of the literature (epidemiological studies and interventional trials) in order to critically evaluate the association between lycopene (or tomato products) supplementation and cardiovascular diseases and/or cardiovascular disease risk factors progression, and to prepare provision of evidence-based guidelines for patients and clinicians. Several reports have appeared in support of the role of lycopene in the prevention of CVD, mostly based on epidemiological studies showing a dose-response relationship between lycopene and CVD. A less clear and more complex picture emerges from the interventional trials, where several works have reported conflicting results. Although many aspects of lycopene in vivo metabolism, functions and clinical indications remain to be clarified, supplementation of low doses of lycopene has been already suggested as a preventive measure for contrasting and ameliorating many aspects of CVD.

The new Sheffield risk and benefit tables for the elderly

Several charts or tables are used to guide treatment in primary prevention of cardiovascular disease (CVD). These usually relate to patients up to 75 years of age, leaving older patients without guidance. Most also present this information as risk, leaving patients to estimate the benefit of treatment and decide whether it is worthwhile. We present tables to display both CVD risk and benefit from treatment in the elderly. A systematic review identified CVD risk functions for the elderly. The Dubbo study of older patients' 5-year CVD risk equation was deemed most appropriate, due to the population studied, endpoints observed and risk factors recorded. By dichotomizing most risk factors, we produced a new risk table in the form of the original 'Sheffield table'. Risk is calculated by selecting the appropriate table for gender and the appropriate cell from the rows and columns, representing age and risk factor contributors, respectively. Total cholesterol above a cell value corresponds to a 20 or 40% 10-year CVD risk. A simple risk scoring system was then derived from the Dubbo equation. Calculation of risk score requires knowledge of a patient's simple demographics, systolic blood pressure and total and high-density lipoprotein cholesterol. Positive integers corresponding to level of risk for each contributing factor are then added together to give a final risk score. A Markov chain model was produced based on the Dubbo derived risk and relative risk reductions from published meta-analyses of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) and anti-hypertensive treatment. Using this model, individual scores were mapped to likely benefit from treatment in terms of disease free years. Our risk table provides a simple means for calculating risk in the elderly, to two major thresholds, while the benefit table explores the concept of presenting benefit of taking CVD-preventing medication.

The effect of mixed fruit and vegetable concentrates on biomarkers of cardiovascular disease: a review of the clinical evidence

Increased intake of fruit and vegetable (FV) has been associated with a reduced risk of chronic diseases, including cardiovascular disease (CVD). However, public health campaigns to increase FV intake have had limited success. A variety of mixed FV concentrates are available in the marketplace which may help certain individuals to achieve FV intake recommendations. However, the possible CVD benefits of FV concentrates have not been systematically reviewed. Our purpose, therefore, was to review the clinical trials that have studied the effects of these concentrates on CVD risk factors. A systematic search of EMBASE and MEDLINE databases identified 12 randomized, controlled clinical trials of 2 weeks duration or longer, which reported on at least one CVD risk factor. These studies assessed markers of oxidative stress (e.g. protein carbonyls, interleukin‐6), endothelial function and homocysteine. Daily consumption of FV concentrates significantly increased serum concentrations of antioxidant vitamins in 5 of 6 studies and significantly improved at least one marker (oxidative stress, endothelial function, homocysteine) of CVD risk in 10 of 12 studies. While longer term studies are required, these data indicate that FV concentrates may be of benefit in terms of improving antioxidant vitamin status, decreasing oxidative stress and reducing certain risk factors for CVD. (The study is not funded)

Combination therapy of statin and ezetimibe for the treatment of familial hypercholesterolemia.

High-dose potent statin therapy in combination with ezetimibe is now standard practice for the treatment of adult patients with heterozygous familial hypercholesterolemia (heFH), as the result of numerous studies in patients with primary hypercholesterolemia or heFH. These studies have shown the combination to be both effective and safe in the short to medium term. Recently, short-term ezetimibe therapy has also been shown to be effective and safe in combination with statin therapy for children and adolescents with heFH. Effective statin–ezetimibe combination therapy is capable of achieving near-normal lipid profiles in heFH patients, with expected improvement in risk for cardiovascular disease (CVD) and improved life expectancy resulting predominantly from reduction in levels of low-density lipoprotein cholesterol. There are few data to support a pleiotropic action of ezetimibe with regard to CVD benefit, unlike therapy with statins. No serious and unexpected clinical adverse effects of combination statin–ezetimibe therapy have emerged till date, although data are limited in children and adolescents, for whom longer-term studies are required. Recent data suggesting possible proatherogenic effects of ezetimibe require confirmation. One large long-term randomized controlled clinical outcomes trial is in progress in non-FH patients to determine the efficacy and safety of ezetimibe therapy; it is unlikely that such a trial will ever be performed in patients with FH.

Pleiotropic effects: Should statins be considered an essential component in the treatment of dyslipidemia?

Cardiovascular disease (CVD) is the leading cause of death in the developed world. Lower risks of morbidity and mortality in trials of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) have changed the conventional wisdom regarding lipid lowering. Since 2001, there have been surprising results concerning the early benefits of statin therapy, which suggest that some benefits may be derived from effects other than those of simply improving dyslipidemias. The earlier than expected CVD benefits from statin trials have led to the theory that statins have effects other than, or concomitant to, the benefits on serum lipid levels, and that these effects may be at least partly responsible for their early and often significant reduction in CVD risk. These have been defined as pleiotropic effects. Possible means by which statins reduce CVD risk independent of their lipid regulation may include antithrombotic and anti-inflammatory effects, antioxidation, plaque stabilization, and endothelial wall relaxation resulting in lower intra-arterial pressure and increased blood flow.

Vitamin E dietary supplementation significantly affects multiple risk factors for cardiovascular disease in baboons

Background: Oxidative stress is a widely accepted risk factor for cardiovascular disease (CVD), but the CVD benefit of dietary antioxidants, such as vitamin E, is controversial.Objective: Therefore, we have investigated, in the baboon model, the effects of dietary vitamin E supplementation on risk factors for CVD.Design: Pedigreed baboons (n = 251) were fed 2 atherogenic diets, high in fat and cholesterol, that differed in vitamin E concentrations. After 7 wk on each diet, blood samples were taken, and a panel of CVD risk factor traits (ie, indicators of lipoprotein metabolism and oxidative stress) were measured.Results: Vitamin E supplementation caused significantly higher total antioxidant status (TAS) and lower oxidized LDL as expected. In addition, vitamin E caused 2 paradoxical effects on HDL metabolism: higher apolipoprotein A-I (apo A-I) concentrations and lower HDL sizes. We calculated a difference (Δ) variable for each trait as the value on the high-vitamin E diet minus that on the low-vitamin E diet and determined that several HDL concentration Δ variables were significantly correlated with Δ TAS, but only one, Δ apo A-I, was independently correlated. Genetic analyses showed that 2 Δ variables, Δ paraoxonase and Δ HDL2, were significantly heritable, but that neither Δ TAS nor Δ apo A-I were heritable.Conclusions: Thus, our data show that dietary vitamin E improves TAS and LDL quality. They also show 2 apparently paradoxical effects on HDL metabolism: lower HDL2, which is mediated by genes, and higher apo A-I, which is not. These effects have contrasting associations with CVD risk and may help account for the mixed results from clinical trials of dietary vitamin E.

Prevention of Cardiovascular Disease in Persons with Type 2 Diabetes Mellitus: Current Knowledge and Rationale for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial

Patients with type 2 diabetes mellitus die of cardiovascular disease (CVD) at rates 2-4 times higher than patients without diabetes but with similar demographic characteristics. The prevalence of diabetes is increasing in the United States and, thus, the prevention of CVD in patients with diabetes poses an urgent public health challenge. The objective of this report is to review the current knowledge base for the prevention of CVD in patients with diabetes, with particular emphasis on the control of glycemia, lipids, and blood pressure. Epidemiologic analyses suggest that each 1% increase in glycosylated hemoglobin increases the risk for CVD by approximately 18%; however, evidence from the randomized trials that have examined whether glucose lowering reduces this risk is conflicting. Randomized trials have shown that lowering low-density lipoprotein cholesterol reduces CVD event rates by 17%-43% in patients with diabetes. Limited data support a role for lowering triglycerides and increasing high-density lipoprotein cholesterol in the prevention of CVD. Evidence from clinical trials shows that reducing systolic blood pressure to <140 mm Hg results in 30%-60% reductions in CVD events; however, epidemiologic evidence suggests that lowering to optimal systolic blood pressure levels (<120 mm Hg) may be additionally beneficial. Important questions regarding prevention of CVD in patients with diabetes remain unresolved, including the benefits of near-normal glycemic control, comprehensive therapy for diabetes-related dyslipidemia, and optimal blood pressure control. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial will test hypotheses to address these unanswered questions.

Management of Dyslipidemias in Patients with Diabetes and Chronic Kidney Disease

Cardiovascular disease (CVD) is the leading cause of death in patients with stage 5 chronic kidney disease (CKD), and the mortality rate in stage 5 CKD is even higher in patients with diabetes. CVD risk reduction includes control of hyperglycemia, dyslipidemia, and BP. An LDL cholesterol goal of 70 mg/dl has been suggested for such high-risk patients. Most studies that have showed CVD risk reduction with statins have been in patients without CKD. However, some studies have had sufficient numbers of patients with CKD stages 2 to 3 to permit analysis, and these generally have shown CVD benefits similar to those found in patients without CKD. Studies that have shown benefit in patients who were on dialysis or after transplantation have been mixed, in part because CVD in such patients is far advanced and may not respond as well to intervention. As GFR falls, the dosages of many of the drugs that are used for the treatment of dyslipidemias need to be modified. In general, however, atorvastatin and fluvastatin dosages do not have to be modified. Drug interactions with cyclosporine also occur. In general, combinations of statins and fibrates should be avoided, and fenofibrate should be avoided in all patients with decreased GFR levels. Overall, on the basis of the very high risk for CVD in patients with diabetes and CKD, aggressive management of dyslipidemias is warranted, with an LDL goal of 70 mg/dl.

Thiazide-Associated Glucose Abnormalities: Prognosis, Etiology, and Prevention

Thiazide diuretics have been recommended as the preferred class of antihypertensive (AHT) drugs for initial therapy and for inclusion in a regimen of multiple drugs.1 This recommendation is based on 4 decades of randomized clinical events trials with placebo (or usual care) comparators, meta-analyses of such trials, and active-controlled trials, including the very large Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial (ALLHAT).2,3 In the latter, treatment beginning with the thiazide-like diuretic chlorthalidone reduced the risk for major coronary events (the primary outcome) similar to treatment based on representatives of newer drug classes (amlodipine, doxazosin, and lisinopril); diuretic-based treatment was more effective at preventing heart failure, and in some comparisons, other cardiovascular disease (CVD) events. However, in ALLHAT mean fasting blood glucose (FBG) and incident diabetes mellitus (IDM) were slightly but significantly increased in the chlorthalidone compared with the other arms.3 Although the design precluded distinguishing between a benefit of the alternate drugs (especially lisinopril) and an adverse effect of the diuretic, previous evidence suggested that thiazides can cause dysglycemia (impaired glucose tolerance, impaired fasting glucose, or diabetes).4 One point about the ALLHAT results that has not received enough emphasis is that if the calcium channel blocker is taken as metabolically neutral, the 4-year IDM rates in the diuretic and calcium channel blocker arms (11.6% and 9.8%, respectively) imply that 83% of IDM occurring in association with thiazide use is not because of the diuretic. Nevertheless, based on the assumption that there is a direct relationship between thiazide exposure and dysglycemia, several key questions need to be addressed: (1) What are the long-term morbidity/mortality consequences, if any? (2) What are the mechanisms? and (3) Are the changes preventable and/or reversible? The role of potassium may be important to addressing each of these issues. Evidence …

Cardiovascular risk factors and confounders among nondrinking and moderate-drinking U.S. adults

Studies suggest that moderate drinkers have lower cardiovascular disease (CVD) mortality than nondrinkers and heavy drinkers, but there have been no randomized trials on this topic. Although most observational studies control for major cardiac risk factors, CVD is independently associated with other factors that could explain the CVD benefits ascribed to moderate drinking. Data from the 2003 Behavioral Risk Factor Surveillance System, a population-based telephone survey of U.S. adults, was used to assess the prevalence of CVD risk factors and potential confounders among moderate drinkers and nondrinkers. Moderate drinkers were defined as men who drank an average of two drinks per day or fewer, or women who drank one drink or fewer per day. After adjusting for age and gender, nondrinkers were more likely to have characteristics associated with increased CVD mortality in terms of demographic factors, social factors, behavioral factors, access to health care, and health-related conditions. Of the 30 CVD-associated factors or groups of factors that we assessed, 27 (90%) were significantly more prevalent among nondrinkers. Among factors with multiple categories (e.g., body weight), those in higher-risk groups were progressively more likely to be nondrinkers. Removing those with poor health status or a history of CVD did not affect the results. These findings suggest that some or all of the apparent protective effect of moderate alcohol consumption on CVD may be due to residual or unmeasured confounding. Given their limitations, nonrandomized studies about the health effects of moderate drinking should be interpreted with caution, particularly since excessive alcohol consumption is a leading health hazard in the United States.