Ronald B. Goldberg

Cardiovascular Events and Their Reduction With Pravastatin in Diabetic and Glucose-Intolerant Myocardial Infarction Survivors With Average Cholesterol Levels Subgroup Analyses in the Cholesterol And Recurrent Events (CARE) Trial

BACKGROUND Although diabetes is a major risk factor for coronary heart disease (CHD), little information is available on the effects of lipid lowering in diabetic patients. We determined whether lipid-lowering treatment with pravastatin prevents recurrent cardiovascular events in diabetic patients with CHD and average cholesterol levels. METHODS AND RESULTS The Cholesterol And Recurrent Events (CARE) trial, a 5-year trial that compared the effect of pravastatin and placebo, included 586 patients (14.1%) with clinical diagnoses of diabetes. The participants with diabetes were older, more obese, and more hypertensive. The mean baseline lipid concentrations in the group with diabetes--136 mg/dL LDL cholesterol, 38 mg/dL HDL cholesterol, and 164 mg/dL triglycerides--were similar to those in the nondiabetic group. LDL cholesterol reduction by pravastatin was similar (27% and 28%) in the diabetic and nondiabetic groups, respectively. In the placebo group, the diabetic patients suffered more recurrent coronary events (CHD death, nonfatal myocardial infarction [MI], CABG, and PTCA) than did the nondiabetic patients (37% versus 25%). Pravastatin treatment reduced the absolute risk of coronary events for the diabetic and nondiabetic patients by 8.1% and 5.2% and the relative risk by 25% (P=0.05) and 23% (P<0.001), respectively. Pravastatin reduced the relative risk for revascularization procedures by 32% (P=0.04) in the diabetic patients. In the 3553 patients who were not diagnosed as diabetic, 342 had impaired fasting glucose at entry defined by the American Diabetes Association as 110 to 125 mg/dL. These nondiabetic patients with impaired fasting glucose had a higher rate of recurrent coronary events than those with normal fasting glucose (eg, 13% versus 10% for nonfatal MI). Recurrence rates tended to be lower in the pravastatin compared with placebo group (eg, -50%, P=0.05 for nonfatal MI). CONCLUSIONS Diabetic patients and nondiabetic patients with impaired fasting glucose are at high risk of recurrent coronary events that can be substantially reduced by pravastatin treatment.

The Effect of Metformin and Intensive Lifestyle Intervention on the Metabolic Syndrome: The Diabetes Prevention Program Randomized Trial

Context Intensive diet and exercise or metformin can prevent the development of diabetes in individuals with impaired fasting glucose, but the effects of these interventions on development of the metabolic syndrome are unknown. Contribution This secondary analysis of Diabetes Prevention Program data showed that lifestyle intervention and metformin each reduced the development of the metabolic syndrome among the 45% of participants who did not have it at baseline. The impact of lifestyle intervention was much more marked than that of metformin. Implications Interventions that prevent diabetes will also reduce the development of the metabolic syndrome. The Editors Considerable attention has recently been paid to the metabolic syndrome, a constellation of risk factors associated with insulin resistance and increased cardiovascular and diabetes risk. The third report of the National Cholesterol Education Programs Adult Treatment Panel now calls for the identification and treatment of this high-risk state and provides a simple set of criteria for diagnosis (1). The World Health Organization (WHO) and the American College of Endocrinology have also provided definitions (2). Although recent studies have provided estimates of the prevalence of the metabolic syndrome in the United States (3, 4), its interrelationship with impaired glucose tolerance is unclear. In particular, it is largely unknown what proportion of participants with impaired glucose tolerance have the metabolic syndrome and whether this varies by ethnicity, age, and sex. Clearly, because an elevated blood glucose level is a common criterion for all definitions, a close association is to be expected. This association may be even stronger in the subgroup of persons with both impaired glucose tolerance and impaired fasting glucose (that is, a fasting plasma glucose level 6.1 to 6.9 mmol/L [110 to 125 mg/dL]). The extent to which we may be able to reduce cardiovascular risk in patients with impaired glucose tolerance by preventing the metabolic syndrome through lifestyle or medication interventions is also unknown. The Diabetes Prevention Program (5, 6) provides a unique opportunity to begin to address these issues. It involves a large sample of more than 3000 participants with impaired glucose tolerance who were carefully followed and randomly allocated to treatment with an intensive lifestyle intervention, metformin, or placebo. In this report, we address 2 questions: the prevalence of the metabolic syndrome at baseline in the trial population (and how this varies by age and sex) and whether the 2 interventions reduced the incidence of new cases of the metabolic syndrome or increased resolution of existing cases compared with placebo. Methods Participants and Procedures Full details of the protocol have been published elsewhere (5, 6). The current report includes 3234 participants seen at baseline. This number includes participants from the 3 treatment arms investigated (that is, standard lifestyle or placebo, intensive lifestyle, and metformin), but not participants from the troglitazone arm, which was discontinued. Individuals were recruited between June 1996 and May 1999 from a variety of sources, including community screenings and household mailings, on the basis of perceived risk for diabetes. Written informed consent was obtained from all participants before screening, consistent with the Declaration of Helsinki and the guidelines of each centers institutional review board. The initial screening step consisted of a fasting glucose measurement. If the participant was eligible, this was followed by a 75-g oral glucose tolerance test. Inclusion criteria were as follows: a fasting plasma glucose level of 5.3 to 7.0 mmol/L (95 to 125 mg/dL) (7.0 mmol/L [125 mg/dL] for Native Americans); a 2-hour plasma glucose level of 7.8 to 11.1 mmol/L (140 to 199 mg/dL) following the glucose load; age of at least 25 years; and body mass index of at least 24 kg/m2 (22 kg/m2 for Asian Americans because of differences in body size in this group). Main exclusion criteria were recent myocardial infarction, symptoms of coronary heart disease, major illness, previous diagnosis of diabetes, use of medications known to impair glucose tolerance, or triglyceride level of at least 6.8 mmol/L (600 mg/dL), as previously detailed (5). Standardized interviewer-administered questionnaires were used to obtain self-reported data on personal medical history, medications, and diet. Self-reported race or ethnicity was classified according to the question used in the 1990 U.S. Census questionnaire (7). Overall, adiposity was assessed by body mass index. Waist circumference was assessed in the standing position midway between the highest point of the iliac crest and the lowest point of the costal margin in the mid-axillary line. All anthropometric measures reflected the average of 2 measurements. Blood pressure was measured twice at 30-second intervals by using a standard mercury manometer. The participant was seated in a chair for 5 minutes before the first measurement was taken, and the mean of the 2 readings was used in the analyses. The metabolic syndrome was defined according to criteria from the National Cholesterol Education Programs Adult Treatment Panel III (1), namely 3 or more of the following conditions: waist circumference greater than 102 cm in men and greater than 88 cm in women; serum triglyceride level of at least 1.7 mmol/L (150 mg/dL); high-density lipoprotein (HDL) cholesterol level less than 1.03 mmol/L (<40 mg/dL) in men and less than 1.3 mmol/L (<50 mg/dL) in women; blood pressure of 130/85 mm Hg or greater; and fasting plasma glucose level of 6.2 mmol/L (110 mg/dL). Participants who were being treated with blood pressurelowering or triglyceride-lowering medications (niacin or fibric acid derivatives) were classified as positive for the respective criterion. We chose the Adult Treatment Panel III (1) criteria because they are commonly used in the United States and are simpler to apply in clinical practice than, for example, the WHO criteria (2). Participants were randomly assigned to receive 1 of 3 interventions: standard lifestyle recommendations plus metformin, 850 mg twice per day; standard lifestyle recommendations plus placebo; or an intensive program of lifestyle intervention. The randomization was done centrally by computer; assignments to the lifestyle group were blinded until randomization, while assignments to the medication groups were blinded until the end of the study. The goals of the lifestyle program were to achieve and maintain a weight reduction of at least 7% of clinical body weight through a healthy low-calorie, low-fat diet and to engage in physical activity of moderate intensity, such as brisk walking, for at least 150 minutes per week. Participants were seen quarterly, when blood pressure was assessed. Fasting glucose levels were determined at the 6-month visits, and fasting lipid levels and waist circumference were measured annually. Further details have been published elsewhere (5, 6). Figure 1 shows the number of participants observed at each annual examination by treatment group. Figure 1. Randomly assigned participants by treatment group and annual visit. Laboratory Methods All of the analytic measurements were performed at the central biochemistry laboratory (Northwest Lipid Research Laboratories, University of Washington, Seattle, Washington). Fasting plasma glucose level was measured on a chemistry autoanalyzer by the glucokinase method. Insulin measurements were performed by using a polyethylene glycolaccelerated double antibody radioimmunoassay method developed in the Diabetes Endocrinology Research Center Immunoassay Core Laboratory (University of Washington, Seattle, Washington). This method is based on the use of an antihuman insulin guinea pig antibody and measures total immunoreactive insulin. The homeostasis model assessment for insulin resistance was calculated as follows (8): Measurements of total plasma cholesterol and triglycerides were performed enzymatically on a chemistry autoanalyzer by using methods standardized to the Centers for Disease Control and Prevention reference methods (9). We obtained HDL fractions for cholesterol analysis by treating whole plasma with dextran sulfate magnesium chloride to precipitate all of the apolipoprotein Bcontaining lipoproteins (10). We calculated low-density lipoprotein cholesterol by using the Friedewald equation (11). In participants with triglyceride levels higher than 4.5 mmol/L (>400 mg/dL), the lipoprotein fractions were separated by using preparative ultracentrifugation of plasma by beta quantification (12). Statistical Analyses Participants were followed for an average of 3.2 years (range, 0.04 to 5.0 years) from the start of the study in June 1996 through 31 July 2001, a period 4 months longer than that reported previously (5). This period was chosen to maximize the available data that were collected during the masked phase of the Diabetes Prevention Program, since unmasking occurred in early August 2001. Random treatment assignments were stratified according to clinical center and were generated by the coordinating center through computer linkup to the field center at time of randomization. Therefore, assignment was unknown until randomization. Assignments to metformin and placebo were double-blinded. The study design and analysis followed the intention-to-treat principle. Nominal (unadjusted) P values and confidence intervals are reported. Logistic regression was used to compare the prevalence of the metabolic syndrome and its components at baseline among the demographic variables. The time to the outcome was assessed by using life-table methods (13). Modified product-limit curves for the cumulative incidence of the metabolic syndrome and for its resolution were compared by using the log-rank test. The estimated cumulative incidence, or resolution, at 3 years and the ris

Lipoprotein Management in Patients With Cardiometabolic Risk Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation

Risk factors for type 2 diabetes and cardiovascular disease (CVD) often cluster, including obesity (particularly central), insulin resistance, hyperglycemia, dyslipoproteinemia, and hypertension. These conditions can also occur in isolation, and they are exaggerated by physical inactivity and smoking. Since each of these factors increases risk of CVD, the concept of global cardiometabolic risk (CMR) (Fig. 1) is of value (1). Lipoprotein abnormalities, including elevated triglycerides, low HDL cholesterol, and increased numbers of small dense LDL particles, are common findings in patients with CMR. Clinical entities with increased CMR include type 2 diabetes, familial combined hyperlipidemia, familial hypoalphalipoproteinemia, and polycystic ovary syndrome (2). These disorders often share the CMR characteristics of central obesity, insulin resistance, dyslipoproteinemia, and hypertension. There are stringent lipid treatment goals for patients with type 2 diabetes or CVD; however, guidelines for treatment of dyslipoproteinemia in high-risk subjects without diabetes or CVD are less intense and are based primarily on LDL cholesterol concentrations, with non-HDL concentrations a secondary consideration in some subjects. Numerous trials have demonstrated that therapies (primarily statins) directed at LDL cholesterol lowering clearly reduce risk of CVD events in patients with diabetes and in those without diabetes but with other CVD risk factors; yet, a number of questions remain. Even with adequate LDL cholesterol lowering, many patients on statin therapy have significant residual CVD risk. It is unclear whether lipoprotein parameters other than LDL or non-HDL cholesterol provide clinically significant additional prognostic information regarding CVD risk, yield more information about the effectiveness of therapy, or indicate more appropriate treatment targets. Many patients with CMR or diabetes have relatively normal levels of LDL cholesterol but increased numbers of small dense LDL particles and other atherogenic lipoproteins. Some have advocated that assessment of other lipoprotein parameters might be more helpful than assessment limited to LDL or non-HDL …

Lipoprotein Management in Patients With Cardiometabolic Risk : Consensus Conference Report From the American Diabetes Association and the American College of Cardiology Foundation

Risk factors for type 2 diabetes and cardiovascular disease (CVD) often cluster, including obesity (particularly central), insulin resistance, hyperglycemia, dyslipoproteinemia, and hypertension. These conditions can also occur in isolation, and they are exaggerated by physical inactivity and

Cytokine and Cytokine-Like Inflammation Markers, Endothelial Dysfunction, and Imbalanced Coagulation in Development of Diabetes and Its Complications

CONTEXT Recent developments indicate that pathophysiological mechanisms leading to beta-cell damage, insulin resistance, and the vascular complications of diabetes include an activation of the inflammation cascade, endothelial dysfunction, and procoagulant imbalance. Their circulating biomarkers may therefore provide opportunities for early diagnosis and targets for novel treatments. EVIDENCE Circulating biomarkers of these pathways such as TNFalpha, IL-6, C-reactive protein (CRP) (inflammation), vascular cellular adhesion molecule-1, interstitial cellular adhesion molecule-1, E-selectin, von Willebrand factor (endothelial dysfunction), plasminogen activator inhibitor-1, fibrinogen, P-selectin (procoagulant state), and adiponectin (antiinflammation) may be associated with development of both type 1 and type 2 diabetes and some studies, particularly in type 2 diabetes, have demonstrated that certain biomarkers may have independent predictive value. Similarly studies have shown that these biomarkers may be associated with development of diabetic nephropathy and retinopathy, and again, particularly in type 2 diabetes, with cardiovascular events as well. Finally, the comorbidities of diabetes, namely obesity, insulin resistance, hyperglycemia, hypertension and dyslipidemia collectively aggravate these processes while antihyperglycemic interventions tend to ameliorate them. CONCLUSIONS Increased CRP, IL-6, and TNFalpha, and especially interstitial cellular adhesion molecule-1, vascular cellular adhesion molecule-1, and E-selectin are associated with nephropathy, retinopathy, and cardiovascular disease in both type 1 and type 2 diabetes. Whereas further work is needed, it seems clear that these biomarkers are predictors of increasing morbidity in prediabetic and diabetic subjects and should be the focus of work testing their clinical utility to identify high-risk individuals as well as perhaps to target interventions.

Clinical utility of inflammatory markers and advanced lipoprotein testing: Advice from an expert panel of lipid specialists

The National Cholesterol Education Program Adult Treatment Panel guidelines have established low-density lipoprotein cholesterol (LDL-C) treatment goals, and secondary non-high-density lipoprotein (HDL)-C treatment goals for persons with hypertriglyceridemia. The use of lipid-lowering therapies, particularly statins, to achieve these goals has reduced cardiovascular disease (CVD) morbidity and mortality; however, significant residual risk for events remains. This, combined with the rising prevalence of obesity, which has shifted the risk profile of the population toward patients in whom LDL-C is less predictive of CVD events (metabolic syndrome, low HDL-C, elevated triglycerides), has increased interest in the clinical use of inflammatory and lipid biomarker assessments. Furthermore, the cost effectiveness of pharmacological intervention for both the initiation of therapy and the intensification of therapy has been enhanced by the availability of a variety of generic statins. This report describes the consensus view of an expert panel convened by the National Lipid Association to evaluate the use of selected biomarkers [C-reactive protein, lipoprotein-associated phospholipase A(2), apolipoprotein B, LDL particle concentration, lipoprotein(a), and LDL and HDL subfractions] to improve risk assessment, or to adjust therapy. These panel recommendations are intended to provide practical advice to clinicians who wrestle with the challenges of identifying the patients who are most likely to benefit from therapy, or intensification of therapy, to provide the optimum protection from CV risk.

Colesevelam Hydrochloride Therapy in Patients With Type 2 Diabetes Mellitus Treated With Metformin: Glucose and Lipid Effects

BACKGROUND Bile acid sequestrants are a well-accepted class of cholesterol-lowering drugs. Over the last decade, small studies have indicated that these agents may also lower glucose levels in patients with type 2 diabetes mellitus (T2DM). METHODS This 26-week, randomized, double-blind, placebo-controlled, parallel-group study was conducted between August 2004 and July 2006 at 54 sites in the United States and 2 in Mexico to determine the effects of colesevelam hydrochloride, a bile acid sequestrant, in patients with inadequately controlled T2DM (hemoglobin A(1c) [HbA(1c)] level, 7.5%-9.5% [baseline HbA(1c) level, 8.1%]), who were receiving metformin monotherapy or metformin combined with additional oral anti-diabetes mellitus drugs. In total, 316 subjects were randomized (159 to colesevelam hydrochloride, 3.75 g/d, and 157 to matching placebo). The primary efficacy parameter was mean placebo-corrected change in HbA(1c) level from baseline to week 26 (analysis was on an intent-to-treat population using a last-observation-carried-forward approach). RESULTS Colesevelam lowered the mean HbA(1c) level compared with placebo at week 26 (-0.54%; P < .001). Similar results were observed in the metformin monotherapy (-0.47%; P = .002) and combination therapy cohorts (-0.62%; P < .001). In addition, colesevelam significantly (1) lowered fasting plasma glucose (-13.9 mg/dL P = .01), fructosamine (-23.2 micromol/L; P < .001), total cholesterol (TC) (-7.2%; P < .001), low-density lipoprotein cholesterol (LDL-C) (-15.9%; P < .001), apolipoprotein B (-7.9%; P < .001), non-high-density lipoprotein cholesterol (HDL-C) (-10.3%; P < .001), and high-sensitivity C-reactive protein (-14.4%; P = .02) levels and (2) improved other measures of glycemic response, as well as TC/HDL-C, LDL-C/HDL-C, non-HDL-C/HDL-C, and apolipoprotein B/apolipoprotein A-I ratios (P < .003 for all). Triglyceride, HDL-C, and apolipoprotein A-I levels were not statistically significantly increased. CONCLUSION Colesevelam improves glycemic and lipid parameters in patients with T2DM inadequately controlled with metformin-based therapy.

Lipid Disorders in Diabetes

Hyperlipidemia is common in diabetic patients. While our understanding of lipid and lipoprotein metabolism in diabetes is incomplete, a pathophysiologic approach to this problem is presented. It is based on the recognition that diabetes is metabolically heterogeneous. Thus the roles of insulin deficiency, insulin resistance, obesity, and genetic factors are discussed in relation to their effects on lipoprotein production and catabolism. The most important defect in insulin-deficient subjects appears to be a deficiency of lipoprotein lipase, which is responsible for the removal of the triglyceride-rich lipoproteins. In non-insulin-dependent subjects there is evidence for a removal defect as well as, in some patients, for overproduction of VLDL-triglyceride. Cholesterol levels may be elevated and it is important to distinguish between VLDL, LDL, and HDL as the causes for these increases. HDL-cholesterol levels may be increased in insulin-dependent subjects, whereas they may be decreased in obese non-insulin-dependent patients. Mild elevations of LDL-cholesterol may occur in inadequately controlled type I and II diabetic patients, while elevated VLDL may raise the serum cholesterol in addition to the triglyceride levels. The rationale for therapy is based on the complications of severe hypertriglyceridemia and the risk of occlusive atherosclerosis. Management is directed at improving glycemic control, altering dietary composition, and reducing calories in obese patients. Improved glycemic control is effective in reducing triglyceride and cholesterol levels in insulin-deficient subjects. The response of the non-insulin-dependent diabetic patient to improved control may be complicated by associated obesity or familial hyperlipidemia. The advantages and disadvantages of fat versus carbohydrate restriction in the diet are discussed. Finally, resistant hyperlipidemia may require drug therapy. Diabetic hyperlipidemia should be viewed as resulting from an interaction between the diabetic syndrome, the genetic background of the patient, and the environment.

Efficacy and Safety of Colesevelam in Patients With Type 2 Diabetes Mellitus and Inadequate Glycemic Control Receiving Insulin-Based Therapy

BACKGROUND Poor glycemic control is a risk factor for microvascular complications in patients with type 2 diabetes mellitus. Achieving glycemic control safely with insulin therapy can be challenging. METHODS A prospective, 16-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study conducted at 50 sites in the United States and 1 site in Mexico between August 12, 2004, and December 28, 2005. Subjects had type 2 diabetes mellitus that was not adequately controlled (glycated hemoglobin level, 7.5%-9.5%, inclusive) receiving insulin therapy alone or in combination with oral antidiabetes agents. In total 287 subjects (52% men; mean age, 57 years; with a mean baseline glycated hemoglobin level of 8.3%) were randomized: 147 to receive colesevelam hydrochloride, 3.75 g/d, and 140 to receive placebo. RESULTS Using the least squares method, the mean (SE) change in glycated hemoglobin level from baseline to week 16 was -0.41% (0.07%) for the colesevelam-treated group and 0.09% (0.07%) for the placebo group (treatment difference, -0.50% [0.09%]; 95% confidence interval, -0.68% to -0.32%; P < .001). Consistent reductions in fasting plasma glucose and fructosamine levels, glycemic-control response rate, and lipid control measures were observed with colesevelam. As expected, the colesevelam-treated group had a 12.8% reduction in low-density lipoprotein cholesterol concentration relative to placebo (P < .001). Of recipients of colesevelam and placebo, respectively, 30 and 26 discontinued the study prematurely; 7 and 9 withdrew because of protocol-specified hyperglycemia, and 10 and 4 withdrew because of adverse events. Both treatments were generally well tolerated. CONCLUSIONS Colesevelam treatment seems to be safe and effective for improving glycemic control and lipid management in patients with type 2 diabetes mellitus receiving insulin-based therapy, and it may provide a novel treatment for improving dual cardiovascular risk factors.

Circuit resistance training improves the atherogenic lipid profiles of persons with chronic paraplegia.

Abstract Background: People with chronic paraplegia frequently experience dyslipidemias characterized by depressed levels of high-densitylipoprotein cholesterol (HDL-C) and elevated levels of low-density lipoprotein cholesterol (LDL-C). These anormal lipid profiles andpoor fitness levels increase their risk for cardiovascular disease. Methods: To test the hypothesis that circuit resistance exercise training improves both upper-extremity fitness and the atherogenic lipid profile in persons with chronic paraplegia, a homogeneous cohort of 5 men with neurologically complete spinal cord injuriesat T6 to L 1 underwent 3 months of exercise training using uninterrupted resistance and endurance exercises of the upper extremities.Training was performed 3 times a week on alternating days. Results: Results of graded arm exercise testing showed a 30.3% improvement in peak oxygen consumption (P ° .01 ), a 33.5% increasein time to fatigue (P ° .01) and a 30.4% increase in peak power output (P <.05). Pretraining total cholesterol levels (TC) were in thelow-risk category and were nonsignificantly lowered following training. Similar nonsignificant reductions of plasma triglycerides averaging12 mgldL were attained. Conversely, a 25.9% lowering of LDL-C (P <.05) and 9.8% elevation of HDL-C (P <.05) were observed aftertraining. These changes reduced the average LDL-C- to- HDL-C ratio by 1 unit (P <.05) and the TC-to- HDL-C ratio from 5.0 ± 1.1(mean ± SO) to 3.9 ± 0.7 (P <.05). Conclusions: This change reflects a cardiovascular risk reduction of almost 25%; the TC/ HDL-C declined from the high-risk scoreof 5.0 to near the desired score of 3.5. These findings support the beneficial effects of circuit exercise resistance training on fitnessand atherogenic lipid profiles in persons with chronic paraplegia.