Showing papers by "Scott M. Grundy published in 2008"

Metabolic Syndrome Pandemic

Abstract: The metabolic syndrome is a multiplex risk factor that consists of several risk correlates of metabolic origin. In addition, to dyslipidemia, hypertension, and hyperglycermia, the syndrome carries a prothrombotic state and a proinflammatory state. Persons with the metabolic syndrome are at essentially twice the risk for cardiovascular disease compared with those without the syndrome. It further raises the risk for type 2 diabetes by about 5-fold. Although some investigators favor keeping risk factors separate for purposes of clinical management, others believe that identifying individuals with an aggregation of risk factors provides additional useful information to guide clinical management. In particular it focuses attention on obesity and sedentary life habits that are the root of the syndrome. This review addresses the prevalence of this clustering phenomenon throughout the world. Such seems appropriate because of the increasing prevalence of obesity in almost all countries. The available evidence indicates that in most countries between 20% and 30% of the adult population can be characterized as having the metabolic syndrome. In some populations or segments of the population, the prevalence is even higher. On the other hand, in parts of developing world in which young adults predominate, the prevalence is lower; but with increasing affluence and aging of the population, the prevalence undoubtedly with rise.

Lipids, Apolipoproteins, and Their Ratios in Relation to Cardiovascular Events With Statin Treatment

Abstract: Background— Low-density lipoprotein (LDL) cholesterol is the principal target of lipid-lowering therapy, but recent evidence has suggested more appropriate targets. We compared the relationships of on-treatment levels of LDL cholesterol, non–high-density lipoprotein (HDL) cholesterol, and apolipoprotein B, as well as ratios of total/HDL cholesterol, LDL/HDL cholesterol, and apolipoprotein B/A-I, with the occurrence of cardiovascular events in patients receiving statin therapy. Methods and Results— A post hoc analysis was performed that combined data from 2 prospective, randomized clinical trials in which 10 001 (“Treating to New Targets”) and 8888 (“Incremental Decrease in End Points through Aggressive Lipid Lowering”) patients with established coronary heart disease were assigned to usual-dose or high-dose statin treatment. In models with LDL cholesterol, non-HDL cholesterol and apolipoprotein B were positively associated with cardiovascular outcome, whereas a positive relationship with LDL cholesterol w...

Primary Prevention of Cardiovascular Disease and Type 2 Diabetes in Patients at Metabolic Risk: An Endocrine Society Clinical Practice Guideline

Abstract: Objective: The objective was to develop clinical practice guidelines for the primary prevention of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) in patients at metabolic risk. Conclusions: Healthcare providers should incorporate into their practice concrete measures to reduce the risk of developing CVD and T2DM. These include the regular screening and identification of patients at metabolic risk (at higher risk for both CVD and T2DM) with measurement of blood pressure, waist circumference, fasting lipid profile, and fasting glucose. All patients identified as having metabolic risk should undergo 10-yr global risk assessment for either CVD or coronary heart disease. This scoring will determine the targets of therapy for reduction of apolipoprotein B-containing lipoproteins. Careful attention should be given to the treatment of elevated blood pressure to the targets outlined in this guideline. The prothrombotic state associated with metabolic risk should be treated with lifestyle modification measures and in appropriate individuals with low-dose aspirin prophylaxis. Patients with prediabetes (impaired glucose tolerance or impaired fasting glucose) should be screened at 1- to 2-yr intervals for the development of diabetes with either measurement of fasting plasma glucose or a 2-h oral glucose tolerance test. For the prevention of CVD and T2DM, we recommend that priority be given to lifestyle management.Thisincludesantiatherogenicdietarymodification,aprogramofincreasedphysicalactivity, andweightreduction.Effortstopromotelifestylemodificationshouldbeconsideredanimportant component of the medical management of patients to reduce the risk of both CVD and T2DM. (J Clin Endocrinol Metab 93: 3671–3689, 2008)

AJC Editor's Consensus: Psoriasis and Coronary Artery Disease

Abstract: Dr. Friedewald has received honoraria for speaking from Novartis, East Hanover, New Jersey. Dr. Cather has received honoraria for speaking, consulting, and board membership from Amgen; Abbott Laboratories, Abbott Park, Illinois; Astellas, Tokyo, Japan; and Genentech, South San Francisco, California. Dr. Gelfand has received consulting fees from Amgen; Genentech; Pfizer, New York, New York; Celgene, Summit, New Jersey; and Centocor, Horsham, Pennsylvania. Dr. Gelfand is a grants investigator for Amgen, Centocor, and Pfizer. Dr. Gordon has received honoraria for consulting and research grants from Abbott and Centocor and honoraria for consulting from Amgen. Dr. Gibbons has received honoraria for speaking from Merck, Whitehouse Station, New Jersey; and Novartis. Dr. Grundy is a consultant for Merck; Merck/Schering-Plough, Kenilworth, New Jersey; Kos, Abbott Park, Illinois; Pfizer; Eli Lilly, Indianapolis, Indiana; GlaxoSmithKline, Research Triangle Park, North Carolina; Abbott Laboratories; Fournier, Chenove, France; Bristol-Myers Squibb, Plainsboro, New Jersey; Sankyo, Santa Clara, California; AstraZeneca, Wilmington, Delaware; and Sanofi-Aventis, Bridgewater, New Jersey. Dr. Grundy is a research grants investigator for Merck, Abbott, and Kos. Dr. Jarratt is a research grants investigator for Abbott, Amgen, and Genentech. Dr. Krueger has no relevant financial relationships to disclose. Dr. Ridker has received investigator-initiated research grants from the National Heart, Lung, and Blood Institute, Bethesda, Maryland; the National Cancer Institute, Bethesda, Maryland; AstraZeneca; Novartis; Merck; Sanofi-Aventis; the Donald W. Reynolds Foundation, Las Vegas, Nevada; and the Leducq Foundation, Paris, France. Dr. Ridker is a consultant for AstraZeneca; Merck/Schering-Plough; Dade Behring, Deerfield, Illinois; and Isis Pharmaceuticals, Carlsbad, California. Dr Ridker is listed as a co-inventor on patents held by the Brigham and Women’s Hospital, Boston, Massachusetts, that relate to the use of inflammatory biomarkers in the detection and treatment of cardiovascular disease. Dr. Stone is a consultant for Abbott; Merck; Schering-Plough; and Unilever, Rotterdam, The Netherlands (donated to American Heart Association). Dr. Stone has received honoraria for educational activities from Abbott, Merck, Pfizer, and Unilever. Dr. Roberts has received honoraria for speaking from Merck/ScheringPlough, AstraZeneca, and Novartis.

The influence of age and body mass index on the metabolic syndrome and its components

Abstract: Objective: The aim of this study was to evaluate the influence of ageing and body mass index (BMI) on the revised National Cholesterol Education Program (NCEP)-defined metabolic syndrome, its components, diabetes and coronary heart disease prevalence using the Third National Health and Nutrition Examination Survey. Methods: Data from adults aged 20 and older who received morning physical examinations after a fast of at least 9 h (n = 7959), representing 196.8 million Americans were used in this analysis. The population was stratified by age deciles and BMI categories using standard definitions of overweight and obesity. Due to small sample size, those few individuals with BMI <18.5 were excluded. Results: Fasting glucose, diabetes and systolic blood pressure (SBP) seem to have a linear relationship with age and BMI, that is, increasing BMI seems to linearly reduce the age decile when the mean exceeds the NCEP cutpoint. Regardless of BMI, the prevalence of diabetes and hypertension increases with age. Triglyceride levels and prevalence of metabolic syndrome follow a pattern that is less linear. Fasting insulin and C-reactive protein (CRP) levels correlate better with BMI than age. Diastolic BP and HDL cholesterol for men and women (analysed separately) did not correlate with either age or BMI. Conclusion: For each component of the metabolic syndrome and associated factors, there is a complex interaction between ageing and obesity. Some components are associated with obesity but not ageing (e.g. CRP), while others are associated with both obesity and ageing (e.g. glucose). Even when the association exists, the specific relationship can appear to be more (e.g. SBP) or less (e.g. triglycerides) linear.

Promise of low-density lipoprotein-lowering therapy for primary and secondary prevention.

Abstract: One of the foremost medical advances of the past 2 decades has been proof that elevated low-density lipoprotein (LDL) is a cause of atherosclerotic cardiovascular disease (ASCVD) and that lowering of LDL levels will reduce risk for ASCVD.1,2 The application of this knowledge in clinical and public health arenas offers the opportunity to greatly reduce morbidity and mortality from ASCVD. This article outlines the rationale underlying this opportunity. Response by Superko and King p 573 Although several major risk factors for ASCVD exist, the realization that elevated plasma LDL is the driving force of atherogenesis highlights the possibilities for prevention. Many studies in laboratory animals have shown that high serum cholesterol levels induce atherosclerotic lesions resembling those found in humans.1 Similarly, humans with severe forms of hypercholesterolemia commonly exhibit premature atherosclerotic disease. Epidemiological studies reveal a strong association between serum cholesterol levels and ASCVD prevalence3; moreover, in populations in which cholesterol levels are low, ASCVD is correspondingly low even when other risk factors are common.4 The latter observation has recently been confirmed through genetic epidemiology; in those persons who carry a mutation causing low cholesterol levels over a lifetime, ASCVD is virtually absent even in the presence of other risk factors.5 Finally, many recent clinical trials have documented that LDL-lowering therapy reduces risk for ASCVD.6 All told, these several lines of evidence indicate that a lifetime of low LDL levels lowers risk for ASCVD by up to 80% to 90% compared with the general population of the United States,5 whereas intensive LDL-lowering therapy even in the presence of advanced atherosclerotic disease reduces risk for major ASCVD events by 40% to 50%.6–8 However, the latter response leaves 50% to 60% of risk untouched; this has called been residual risk. Because of the …

Independent associations between metabolic syndrome, diabetes mellitus and atherosclerosis: observations from the Dallas Heart Study:

Abstract: Diabetes mellitus (DM) has been termed a "coronary disease equivalent", yet data suggest that only those DM subjects with metabolic syndrome (MetS) are at increased coronary risk. Using data from the Dallas Heart Study, a large, probability-based population study, we assessed the individual and joint associations between MetS, DM and atherosclerosis, defined as coronary artery calcium (CAC) detected by electron-beam computerised tomography (EBCT) and abdominal aortic plaque (AAP) detected by magnetic resonance imaging. Among 2,735 participants, the median age was 44 years; 1,863 (68%) were non-white; 1,509 (55%) were women; 697 (25.5%) had MetS without DM; 53 (1.9%) had DM without MetS; and 246 (9.0%) had both DM and MetS. The prevalence of CAC increased from those with neither MetS nor DM (16.6%) to MetS only (24.0%) to DM only (30.2%) to both MetS and DM (44.7%) (ptrend <0.0001). The prevalence of CAC was higher in those with both DM and MetS versus either alone (p<0.0001). After adjustment, MetS and DM were each independently associated with CAC (odds ratio [OR] 1.4, 95% confidence intervals [CI] 1.1‐1.8; OR 1.8, 95% CI 1.3‐2.5, respectively). Compared with the group without DM or MetS, those with both MetS and DM had the most CAC (adjusted OR 2.3; 95% CI 1.6‐3.2). All analyses of AAP yielded qualitatively similar results. In conclusion, both MetS and DM are independently associated with an increased prevalence of atherosclerosis, with the highest observed prevalence in subjects with both DM and MetS.

Effects of N-3 Fatty Acids on Hepatic Triglyceride Content in Humans

Abstract: Background Because dietary N-3 fatty acids reduce plasma triglycerides, they may also decrease hepatic triglyceride content. If so, N-3 fatty acids might constitute a therapy for fatty liver. Methods Twenty-two subjects were recruited into a study designed to test the effects of N-3 fatty acids on liver fat content. Seventeen completed the trial that had a sequential design of 4-week placebo followed by an 8-week treatment with 9 g/d of fish oil. Liver fat was measured during placebo and treatment by magnetic resonance spectroscopy. Compliance was assessed by capsule count at the end of each study phase and measurement of fatty acid composition in plasma triglyceride and phospholipid. Plasma lipoproteins and adiponectin were also measured. Results Treatment with fish oils reduced significantly levels of plasma triglyceride by 46% ( P P P Conclusions N-3 fatty acids at high doses lower plasma triglyceride levels, but there are no significant decreases in hepatic content of triglyceride for the group as a whole. Whereas the triglyceride lowering is uniform, the liver response is more variable.

Variable Contributions of Fat Content and Distribution to Metabolic Syndrome Risk Factors

Abstract: Background: Previous reports indicate that both distribution and amount of body fat confers susceptibility to metabolic syndrome. However, the relative contributions of these two different parameters of body fat to the various components of the metabolic syndrome have not been well defined. Methods: Dual-energy X-ray absorptiometry (DXA) was used to measure and compare the relative amounts of total body fat, truncal fat, and lower body fat in a representative sample of 2587 black, white, and Hispanic men and women from the Dallas Heart Study (DHS). The relationships among these variables and fasting plasma levels of lipids, glucose, insulin, C-reactive protein (CRP), and leptin as well as blood pressure were analyzed. Results: Beyond total body fat, fat distribution had the greatest impact on plasma triglycerides in all subjects and on high-density lipoprotein cholesterol (HDL-C) levels in women only. An intermediate effect of fat distribution was observed for homeostasis model assessment of insulin resistance (HOMA-IR) and for blood pressure. Plasma CRP levels were much more sensitive to body fat content than to body fat distribution and leptin levels were determined almost exclusively by body fat content. Although there were minor differences among the different ethnic groups, the major relationship patterns between these variables were similar. Conclusion: For most metabolic risk factors, both body fat content and distribution independently contributed to levels, although significant differences were seen between the relative contributions of each variable to individual risk factors.

Comparison of effectiveness of atorvastatin 10 mg versus 80 mg in reducing major cardiovascular events and repeat revascularization in patients with previous percutaneous coronary intervention (post hoc analysis of the Treating to New Targets [TNT] Study).

Abstract: The Treating to New Targets (TNT) study demonstrated that intensive atorvastatin therapy to achieve low-density lipoprotein cholesterol concentrations well below recommended target levels provides an incremental clinical benefit in patients with stable coronary artery disease. This post hoc analysis of the TNT study was conducted to investigate whether this benefit extends to patients with previous percutaneous coronary intervention (PCI). A total of 10,001 patients with clinically evident coronary artery disease, including 5,407 patients with previous PCI, were randomized to atorvastatin 10 or 80 mg/day and followed for a median of 4.9 years. The primary end point was the occurrence of a first major cardiovascular event. Revascularization, a component of a secondary end point, was also examined. In patients with previous PCI, mean low-density lipoprotein cholesterol levels at study end were 79.5 mg/dl in the 80-mg arm and 100.8 mg/dl in the 10-mg arm. First major cardiovascular events occurred in 230 patients (8.6%) receiving high-dose atorvastatin and 289 patients (10.6%) receiving low-dose atorvastatin (hazard ratio 0.79, 95% confidence interval 0.67 to 0.94, p = 0.008). Repeat revascularization during follow-up (PCI or coronary artery bypass grafting) was performed in 466 patients (17.3%) in the 80-mg arm and 624 patients (22.9%) in the 10-mg arm (hazard ratio 0.73, 95% confidence interval 0.65 to 0.82, p <0.0001). In conclusion, intensive lipid lowering to a mean low-density lipoprotein cholesterol level of 79.5 mg/dl (2.1 mmol/L) with atorvastatin 80 mg/day in patients with previous PCI reduces major cardiovascular events by 21% and repeat revascularizations by 27% compared with a less intensive lipid-lowering regimen.

A changing paradigm for prevention of cardiovascular disease: emergence of the metabolic syndrome as a multiplex risk factor

Abstract: The traditional major risk factors for cardiovascular disease (CVD) are cigarette smoking, hypertension, elevated serum cholesterol, and hyperglycaemia (diabetes). The majority of patients with CVD have multiple risk factors. In recent years a common pattern of multiple risk factors has emerged. This is the metabolic syndrome, which is driven largely by obesity. The metabolic syndrome is particularly important because it is a multiplex risk factor for both CVD and Type 2 diabetes. Although obesity is the primary cause of the metabolic syndrome, there are other endogenous and exogenous factors.

Application of the screening for Heart Attack Prevention and Education Task Force recommendations to an urban population: observations from the Dallas Heart Study.

Abstract: Background The Screening for Heart Attack Prevention and Education (SHAPE) Task Force recommends noninvasive atherosclerosis imaging of all asymptomatic men (aged 45-75 years) and women (aged 55-75 years), except those at very low risk, to augment conventional cardiovascular risk assessment algorithms. Methods Among 2611 participants in the Dallas Heart Study aged 30 to 65 years who underwent computed tomography to measure coronary artery calcification, low-density lipoprotein cholesterol (LDL-C) therapeutic targets were calculated using both National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) and SHAPE algorithms. The proportion of subjects reclassified as being “at goal” for LDL-C vs “not at goal” after implementation of the SHAPE recommendations was determined. Results More subjects were identified with LDL-C levels greater than or equal to goal based on SHAPE than on NCEP-ATP III (27.4% vs 21.6%), with 7.0% of individuals reclassified as having unmet LDL-C goals and 1.1% of individuals reclassified as at goal. When more aggressive optional LDL-C goals were implemented, 31.7% had LDL-C levels greater than or equal to goal using SHAPE recommendations vs 28.1% using NCEP-ATP III recommendations, with 6.3% of subjects reclassified as being not at goal and 2.7% as being at goal. Conclusions The SHAPE recommendations resulted in bidirectional reclassification of eligibility for lipid-lowering therapy in subjects aged 30 to 65 years. While broad implementation of these recommendations would modestly increase cholesterol-lowering drug use in this age range, the magnitude of the increase depends on whether standard or optional LDL-C goals are targeted.

Oxandrolone enhances hepatic ketogenesis in adult men.

Abstract: Background Immediate administration of oxandrolone markedly increases hepatic lipase activity and reduces levels of plasma high-density lipoprotein. Rationale for the study We postulated that oxandrolone should increase hepatic lipase and that the nonesterified fatty acids generated would enhance hepatic ketogenesis during an extended fat tolerance test. Main Results Eighteen men participated in the study using short-term administration of oxandrolone (10 mg/d) over a week. Subjects had evaluation of hepatic ketogenesis at baseline and after 7 days of administration of oxandrolone. Ketogenesis was assessed by measuring plasma levels of 3-hydroxybutyrate during a fat tolerancetest. Oxandrolone increased fasting levels of 3-hydroxybutyrate by 70%, and increased the area under the curve during an FFT by 53% above pretreatment levels without affecting the areas under the curve for nonesterified fatty acids, glycerol, or triglycerides. Fasting 3-hydroxybutyrate levels correlated with nonesterified fatty acids and with triglycerides; however, there were no significant correlations with any other parameter. Conclusions This study shows that short-term administration of oxandrolone results in marked increases in hepatic ketogenesis. This finding is consistent with an increased influx of fatty acids into the liver secondary to lipoprotein lipolysis by increased hepatic lipase. However, the possibility cannot be ruled out that oxandrolone acts directly in the liver to stimulate fatty acid oxidation. Therefore, the observation of increased ketogenesis will require further studies to determine the molecular basis of the response.

Thyroid mimetic as an option for lowering low-density lipoprotein

Abstract: In this issue of PNAS, Berkenstam et al. (1) demonstrate that the synthetic thyroid hormone mimetic KB2115 produces a marked reduction in low-density lipoprotein (LDL) cholesterol. This mimetic is designed to have a selective effect on the β-isoform of the thyroid hormone receptor. Activation of this receptor has been reported to modify cholesterol metabolism in the liver but not to affect the heart (2, 3). The β-isoform of the receptor is to be distinguished from the α-isoform, which mediates the cardiogenic actions of thyroid hormone.