Clinical and angiographic risk stratification and differential impact on treatment outcomes in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.

BACKGROUND: The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial assigned patients with type 2 diabetes mellitus to prompt coronary revascularization plus intensive medical therapy versus intensive medical therapy alone and reported no significant difference in mortality. Among patients selected for coronary artery bypass graft surgery, prompt coronary revascularization was associated with a significant reduction in death/myocardial infarction/stroke compared with intensive medical therapy. We hypothesized that clinical and angiographic risk stratification would affect the effectiveness of the treatments overall and within revascularization strata. METHODS AND RESULTS: An angiographic risk score was developed from variables assessed at randomization; independent prognostic factors were myocardial jeopardy index, total number of coronary lesions, prior coronary revascularization, and left ventricular ejection fraction. The Framingham Risk Score for patients with coronary disease was used to summarize clinical risk. Cardiovascular event rates were compared by assigned treatment within high-risk and low-risk subgroups. Overall, no outcome differences between the intensive medical therapy and prompt coronary revascularization groups were seen in any risk stratum. The 5-year risk of death/myocardial infarction/stroke was 36.8% for intensive medical therapy compared with 24.8% for prompt coronary revascularization among the 381 coronary artery bypass graft surgery-selected patients in the highest angiographic risk tertile (P=0.005); this treatment effect was amplified in patients with both high angiographic and high Framingham risk (47.3% intensive medical therapy versus 27.1% prompt coronary revascularization; P=0.010; hazard ratio=2.10; P=0.009). Treatment group differences were not significant in other clinical-angiographic risk groups within the coronary artery bypass graft surgery stratum, or in any subgroups within the percutaneous coronary intervention stratum. CONCLUSION: Among patients with diabetes mellitus and stable ischemic heart disease, a strategy of prompt coronary artery bypass graft surgery significantly reduces the rate of death/myocardial infarction MI/stroke in those with extensive coronary artery disease or impaired left ventricular function. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

A randomized trial of therapies for type 2 diabetes and coronary artery disease.

BACKGROUND: Optimal treatment for patients with both type 2 diabetes mellitus and stable ischemic heart disease has not been established. METHODS: We randomly assigned 2368 patients with both type 2 diabetes and heart disease to undergo either prompt revascularization with intensive medical therapy or intensive medical therapy alone and to undergo either insulin-sensitization or insulin-provision therapy. Primary end points were the rate of death and a composite of death, myocardial infarction, or stroke (major cardiovascular events). Randomization was stratified according to the choice of percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) as the more appropriate intervention. RESULTS: At 5 years, rates of survival did not differ significantly between the revascularization group (88.3%) and the medical-therapy group (87.8%, P=0.97) or between the insulin-sensitization group (88.2%) and the insulin-provision group (87.9%, P=0.89). The rates of freedom from major cardiovascular events also did not differ significantly among the groups: 77.2% in the revascularization group and 75.9% in the medical-treatment group (P=0.70) and 77.7% in the insulin-sensitization group and 75.4% in the insulin-provision group (P=0.13). In the PCI stratum, there was no significant difference in primary end points between the revascularization group and the medical-therapy group. In the CABG stratum, the rate of major cardiovascular events was significantly lower in the revascularization group (22.4%) than in the medical-therapy group (30.5%, P=0.01; P=0.002 for interaction between stratum and study group). Adverse events and serious adverse events were generally similar among the groups, although severe hypoglycemia was more frequent in the insulin-provision group (9.2%) than in the insulin-sensitization group (5.9%, P=0.003). CONCLUSIONS: Overall, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing prompt revascularization and those undergoing medical therapy or between strategies of insulin sensitization and insulin provision. (ClinicalTrials.gov number, NCT00006305.)

Blood pressure, lipids and glucose in type 2 diabetes: how low should we go? Re-discovering personalized care.

Epidemiological studies have clearly shown a direct relationship between the levels of blood pressure, glycaemia and LDL-cholesterol, and the complications of diabetes. Although 'lower should be better', the results of recent clinical trials examining the benefits of normalizing risk factor levels have been counter-intuitive and, at times, disturbing, and have called into question this notion. This review focuses on patients with type 2 diabetes who make up 90% of patients with diabetes. It aims to provide a clear summary and interpretation of recent trials to help clinicians to set targets for cardiovascular risk factors in individual patients. It highlights areas of agreement and disagreement between current guidelines. Recent data indicate that some patient subgroups might respond differently to aggressive risk factor management. Our challenge is how to identify these patients and deliver truly personalized diabetes care that maximizes benefit, and minimizes harm. Guidelines and position statements stress the value of setting personalized targets. We explore what this means, and how this might be achieved in practice by outlining some solutions to issues that currently limit the delivery of personalized care. We call for further research assessing the overall clinical impact of cardiovascular risk factor intervention by finding appropriate ways of combining data on mortality, complications, side-effects, quality of life, and cost-effectiveness.

Effect of rosiglitazone on progression of coronary atherosclerosis in patients with type 2 diabetes mellitus and coronary artery disease: the assessment on the prevention of progression by rosiglitazone on atherosclerosis in diabetes patients with cardiovascular history trial.

BACKGROUND: Rosiglitazone has several properties that may affect progression of atherosclerosis. The Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Diabetes Patients With Cardiovascular History (APPROACH) study was undertaken to determine the effect of the thiazolidinedione rosiglitazone on coronary atherosclerosis as assessed by intravascular ultrasound compared with the sulfonylurea glipizide. METHODS AND RESULTS: This was a randomized, double-blind, controlled 18-month study in 672 patients aged 30 to 80 years with established type 2 diabetes mellitus treated by lifestyle, 1 oral agent, or submaximal doses of 2 oral agents who had at least 1 atherosclerotic plaque with 10% to 50% luminal narrowing in a coronary artery that had not undergone intervention during a clinically indicated coronary angiography or percutaneous coronary intervention. The primary outcome was change in percent atheroma volume in the longest and least angulated epicardial coronary artery that had not undergone intervention. Secondary outcomes included change in normalized total atheroma volume and change in total atheroma volume in the most diseased baseline 10-mm segment. Rosiglitazone did not significantly reduce the primary outcome of percent atheroma volume compared with glipizide (-0.64%; 95% confidence interval, -1.46 to 0.17; P=0.12). The secondary outcome of normalized total atheroma volume was significantly reduced by rosiglitazone compared with glipizide (-5.1 mm(3); 95% confidence interval, -10.0 to -0.3; P=0.04); however, no significant difference between groups was observed for the change in total atheroma volume within the most diseased baseline 10-mm segment (-1.7 mm(3); 95% confidence interval, -3.9 to 0.5; P=0.13). CONCLUSIONS: Rosiglitazone did not significantly decrease the primary end point of progression of coronary atherosclerosis more than glipizide in patients with type 2 diabetes mellitus and coronary atherosclerosis. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique Identifier: NCT00116831.

Type 2 diabetes and coronary heart disease: focus on myocardial infarction.

Individuals with type 2 diabetes are more likely to experience a myocardial infarction and have worse outcomes compared with nondiabetic individuals. The underlying pathophysiology of the atherosclerotic process is accentuated but not significantly different in patients with type 2 diabetes. In addition, the prothrombotic state associated with diabetes may also contribute to the higher incidence of and worse prognosis after myocardial infarction. Difficulties of re-establishing vessel patency by thrombolytic or mechanical means due to diffuse coronary disease, altered vessel structure, and prothrombotic state can contribute to the high morbidity and mortality in these patients. The concurrent metabolic dysfunction contributes to impair compensatory mechanisms, which can increase infarct size and cause more impairment of left ventricular function. Aggressive medical therapy and careful modulation of glucose metabolism in the acute and follow-up phase of a myocardial infarction may favorably influence outcome.

Influence of diabetes and/or myocardial infarction on prevalence of abnormal T-wave alternans.

BACKGROUND: Subjects with microvolt-level T-wave alternans (TWA) in association with structural heart disease have an increased risk for sudden cardiac death. The presence of diabetes (DM) is associated with an increased risk of sudden death but there is limited data on the impact of DM and previous myocardial infarction (MI) on TWA prevalence. METHODS: We performed a case-control cross-sectional study in 140 patients referred for routine exercise testing within a large multispecialty clinic. All patients with a history of DM and MI status within the past year were eligible: group 1 (no DM or MI), group 2 (DM only), group 3 (MI only), group 4 (DM and MI). Patients performed a symptom-limited Bruce protocol exercise test with assessment of TWA by the spectral method using commercially available equipment. We used published criteria for the blinded interpretation of TWA; all tests not unequivocally negative were considered abnormal. RESULTS: Age and gender were similar in all groups. The prevalence of abnormal TWA in groups 1-4 was 24%, 20%, 48%, and 62%, respectively (between group P = 0.002). Logistic regression analysis in all patients showed that abnormal TWA was related to prior MI [OR (95% CI): 4.0 (1.8-8.9), P < 0.001] but not to prevalent DM [0.9 (0.4-1.8), P = 0.72]. In patients with DM, the prevalence of abnormal TWA was related to reduced ejection fraction (P = 0.034) but not to BMI, DM duration, glycemic control, insulin use, or the presence of microvascular complications. CONCLUSION: The presence of DM alone does not increase risk of abnormal TWA. Prospective studies are required to establish the prognostic value of TWA in patients with DM.

Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association.

The American Heart Association (AHA) and the American Diabetes Association (ADA) have each published guidelines for cardiovascular disease prevention: The ADA has issued separate recommendations for each of the cardiovascular risk factors in patients with diabetes, and the AHA has shaped primary and secondary guidelines that extend to patients with diabetes. This statement will attempt to harmonize the recommendations of both organizations where possible but will recognize areas in which AHA and ADA recommendations differ.

Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials.

BACKGROUND: The overall clinical benefit of thiazolidinediones (TZDs) as a treatment for hyperglycaemia can be difficult to assess because of the risk of congestive heart failure due to TZD-related fluid retention. Since prediabetic and diabetic patients are at high cardiovascular risk, the outcome and natural history of such risks need to be better understood. We aimed to examine the risk of congestive heart failure and of cardiac death in patients given TZDs. METHODS: We used a search strategy to identify 3048 studies. 3041 were excluded, and we did a systematic review and meta-analysis of the seven remaining randomised double-blind clinical trials of drug-related congestive heart failure in patients given TZDs (either rosiglitazone or pioglitazone). We calculated pooled random-effects estimates of the risk ratios for development of congestive heart failure in patients given TZDs compared with controls. The main outcome measures were development of congestive heart failure and the risk of cardiovascular death. FINDINGS: 360 of 20 191 patients who had either prediabetes or type 2 diabetes had congestive heart failure events (214 with TZDs and 146 with comparators). Results showed no heterogeneity of effects across studies (I2=22.8%; p for interaction=0.26), which indicated a class effect for TZDs. Compared with controls, patients given TZDs had increased risk for development of congestive heart failure across a wide background of cardiac risk (relative risk [RR] 1.72, 95% CI 1.21-2.42, p=0.002). By contrast, the risk of cardiovascular death was not increased with either of the two TZDs (0.93, 0.67-1.29, p=0.68). INTERPRETATION: Congestive heart failure in patients given TZDs might not carry the risk that is usually associated with congestive heart failure which is caused by progressive systolic or diastolic dysfunction of the left ventricle. Longer follow-up and better characterisation of such patients is needed to determine the effect of TZDs on overall cardiovascular outcome.

Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in diabetes patients with Cardiovascular History (APPROACH): study design and baseline characteristics.

BACKGROUND: Rosiglitazone, a thiazolidinedione, has effects on insulin sensitivity and cardiovascular risk factors that may favorably impact the progression of coronary atherosclerosis. METHODS: APPROACH is a double-blind randomized clinical trial comparing the effects of the insulin sensitizer rosiglitazone with the insulin secretagogue glipizide on the progression of coronary atherosclerosis. Patients with type 2 diabetes and coronary artery disease undergoing clinically indicated coronary angiography or percutaneous coronary intervention are randomized to receive rosiglitazone or glipizide for 18 months using a titration algorithm designed to provide comparable glycemic control between treatment groups. The primary end point is change in percent atheroma volume from baseline to study completion in a nonintervened coronary artery, as measured by intravascular ultrasound. Cardiovascular events are adjudicated by an end point committee. RESULTS: A total of 672 patients were randomized. The mean age was 61 years, hemoglobin A(1c) (HbA(1c)) 7.2%, body mass index 29.5 kg/m(2), and median duration of diabetes 4.8 years. At baseline, approximately half of the participants were receiving oral antidiabetic monotherapy (53.9%) with 27.5% receiving dual combination therapy and 17.9% treated with diet and exercise alone. Approximately two thirds of the participants (68%) had dyslipidemia, 79.9% hypertension, and 24% prior myocardial infarction. CONCLUSIONS: APPROACH has fully enrolled a high-risk patient population and will compare the glucose-independent effects of rosiglitazone and glipizide on the progression of coronary atherosclerosis, as well as provide additional data on the cardiovascular safety of rosiglitazone in patients with type 2 diabetes and coronary artery disease.

Grand rounds: asbestos-related pericarditis in a boiler operator.

CONTEXT: Occupational and environmental exposures to asbestos remain a public health problem even in developed countries. Because of the long latency in asbestos-related pathology, past asbestos exposure continues to contribute to incident disease. Asbestos most commonly produces pulmonary pathology, with asbestos-related pleural disease as the most common manifestation. Although the pleurae and pericardium share certain histologic characteristics, asbestos-related pericarditis is rarely reported. CASE PRESENTATION: We present a 59-year-old man who worked around boilers for almost 30 years and was eventually determined to have calcific, constrictive pericarditis. He initially presented with an infectious exacerbation of chronic bronchitis. Chest radiographs demonstrated pleural and pericardial calcifications. Further evaluation with cardiac catheterization showed a hemodynamic picture consistent with constrictive pericarditis. A high-resolution computerized tomography scan of the chest demonstrated dense calcification in the pericardium, right pleural thickening and nodularity, right pleural plaque without calcification, and density in the right middle lobe. Pulmonary function testing showed mild obstruction and borderline low diffusing capacity. DISCUSSION: Based on the patient's occupational history, the presence of pleural pathology consistent with asbestos, previous evidence that asbestos can affect the pericardium, and absence of other likely explanations, we concluded that his pericarditis was asbestos-related. RELEVANCE TO CLINICAL PRACTICE: Similar to pleural thickening and plaque formation, asbestos may cause progressive fibrosis of the pericardium.

Myocardial glucose transport and utilization: a target for therapeutic intervention.

Patients with type 2 diabetes mellitus (T2DM) have a 2-fold to 4-fold greater risk of cardiovascular mortality than nondiabetic individuals. The overall mortality rate of patients with T2DM is approximately twice that of people without diabetes. The excess in-hospital mortality of these patients is primarily due to an increased risk of congestive heart failure. Reduced compensatory ability of the noninfarcted myocardium and an underlying abnormality in the myocardial substrate metabolism (referable to the diabetic state) may also contribute to poor outcomes. Insulin resistance (IR) is a significant predictor of cardiovascular mortality and morbidity across a spectrum of glucose tolerance. Cardiac mass increases across the range of IR in subjects without diabetes, as well as across the range of glucose intolerance in subjects with diabetes. In one study, elevated fasting plasma glucose was an independent predictor of hospitalization for heart failure. Optimization of cardiac metabolism could become a new target for therapeutic intervention in patients with ischemic heart disease and diabetes.

Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association.

The American Heart Association (AHA) and the American Diabetes Association (ADA) have each published guidelines for cardiovascular disease prevention: the ADA has issued separate recommendations for each of the cardiovascular risk factors in patients with diabetes, and the AHA has shaped primary and secondary guidelines that extend to patients with diabetes. This statement will attempt to harmonize the recommendations of both organizations where possible but will recognize areas in which AHA and ADA recommendations differ.

High yellow color intensity by angioscopy with quantitative colorimetry to identify high-risk features in culprit lesions of patients with acute coronary syndromes.

High yellow color intensity (HYCI) regions of atherosclerotic plaque, determined by angioscopy with quantitative colorimetry, are associated with lipid cores underneath thin fibrous caps in ex vivo tissue samples. To determine whether HYCI regions of coronary plaque are associated with disruption or thrombus in living patients, quantitative colorimetry was applied to angioscopy, and the color of culprit lesions was measured in patients with acute coronary syndromes. In 46 patients with acute coronary syndromes (acute myocardial infarction, n = 14; unstable angina pectoris [UAP] with culprit thrombus, n = 16; and UAP without culprit thrombus, n = 16), the recorded angioscopic images of culprit lesions were analyzed using a quantitative colorimetric method based on the L*a*b* color space applied to angioscopy (positive b* = yellow color intensity). HYCI was defined as b* value >23. Plaque disruption was significantly more prevalent in 19 of 24 HYCI regions (79%) than in 9 of 22 non-HYCI regions (41%) (p = 0.007). Culprit HYCI regions were prevalent in patients with myocardial infarction (11 of 14 [79%]), followed by those with UAP with thrombus (9 of 16 [56%]) and UAP without thrombus (4 of 16 [25%]) (p = 0.01 for trend), and were significantly more prevalent in 66% of patients with myocardial infarction and UAP with thrombus compared with 25% of those with UAP without thrombus (p = 0.007). In conclusion, HYCI regions of coronary plaque may be indicative of high-risk lesions vulnerable to thrombosis. Coronary angioscopy with quantitative colorimetry could be used to study the association between high-risk coronary lesions and future cardiovascular events.

Prevalence of metabolic syndrome in patients < or =45 years of age with acute myocardial infarction having percutaneous coronary intervention.

The prevalence of metabolic syndrome (MS) was determined in patients aged < or =45 years who presented with acute myocardial infarction and underwent primary percutaneous coronary intervention. Two hundred twenty-three consecutive patients aged 18 to 45 years who underwent cardiac catheterization for acute myocardial infarction from June 2001 to December 2004 were reviewed. MS was diagnosed by National Cholesterol Education Program Adult Treatment Panel III guidelines (modified by substituting body mass index > or =28.8 kg/m2 for waist circumference). One hundred sixty-one patients met all 5 criteria for MS available for evaluation. Seventy-six of these patients (47%) met > or =3 of the 5 criteria for MS. Sixteen patients with MS (21%) and 5 patients without MS (6%) had diabetes mellitus. The prevalence of each criterion was significantly higher (p <0.05) in the MS group. Average Framingham risk scores were 7.0 and 4.5 for patients with and without MS, respectively. The prevalence of smoking, male gender, and family history of premature coronary artery disease were the same for the 2 groups. In conclusion, MS was highly prevalent in this population of young patients with acute myocardial infarction.

Modifications of coronary risk factors.

In addition to the revascularization and glycemic management interventions assigned at random, the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) design includes the uniform control of major coronary artery disease risk factors, including dyslipidemia, hypertension, smoking, central obesity, and sedentary lifestyle. Target levels for risk factors were adjusted throughout the trial to comply with changes in recommended clinical practice guidelines. At present, the goals are low-density lipoprotein cholesterol <2.59 mmol/L (<100 mg/dL) with an optional goal of <1.81 mmol/L (<70 mg/dL); plasma triglyceride level <1.70 mmol/L (<150 mg/dL); blood pressure level <130 mm Hg systolic and <80 mm Hg diastolic; and smoking cessation treatment for all active smokers. Algorithms were developed for the pharmacologic management of dyslipidemia and hypertension. Dietary prescriptions for the management of glycemia, plasma lipid profiles, and blood pressure levels were adapted from existing clinical practice guidelines. Patients with a body mass index >25 were prescribed moderate caloric restriction; after the trial was under way, a lifestyle weight-management program was instituted. All patients were formally prescribed both endurance and resistance/flexibility exercises, individually adapted to their level of disability and fitness. Pedometers were distributed as a biofeedback strategy. Strategies to achieve the goals for risk factors were designed by BARI 2D working groups (lipid, cardiovascular and hypertension, and nonpharmacologic intervention) and the ongoing implementation of the strategies is monitored by lipid, hypertension, and lifestyle intervention management centers.

Prevalence of newly diagnosed diabetes in clinical settings.

A substantial number of patients being evaluated or treated for cardiovascular disease are found to have glucometabolic disorders. Identification of such patients is important because treatment for coronary artery disease and stroke needs to be individualized. Hyperglycemia on admission or during hospitalization regardless of whether diabetes mellitus is known to exist in these patients is associated with increased morbidity and mortality. Despite the fact that this has been known for some time, various strategies to reduce hyperglycemia have had mixed results in cardiac outcomes. Another important factor is that a new diagnosis of diabetes mellitus in these patients should result in the patient's triage to appropriate healthcare professionals to optimize glycemic control. The prevalence of hyperglycemia in patients admitted with acute cardiovascular disease and the effect of hyperglycemia on outcome are reviewed.

Glucose, insulin, and potassium for metabolic support in acute myocardial infarction: is the jury still out?

During ischemic and cardiomyopathic conditions, carbohydrate (glucose) metabolism in cardiomyocytes predominates over use of free fatty acids. The shift to glucose metabolism is a physiologic response to ischemia, which in many patients, particularly diabetics or those who are insulin-resistant, is blunted. Free fatty acid metabolism during ischemia produces higher levels of lactate and hydrogen ions within the ischemic cells. This in turn degrades myocardial contractility, induces diastolic dysfunction, and reduces the arrhythmogenic threshold of the cardiomyocyte. Suppression of free fatty acid uptake and oxidation by any means will increase myocardial glucose substrate utilization in ischemia. Theoretically, then, an insulin-glucose solution that can augment GLUT-1 and GLUT-4 translocation to the sarcolemmal membrane can assist cardiomyocyte survival during ischemia; however, study results have not supported metabolic therapy. It is essential for any investigation of glucose, insulin, potassium therapy to separate out the effect of hyperglycemia and glucose toxicity to make any meaningful comment on the effectiveness of metabolic support in myocardial infarction.

Antiplatelet therapy in populations at high risk of atherothrombosis.

Atherothrombosis is the most common cause of an acute ischemic event. Antiplatelet agents form the cornerstone of atherothrombosis prevention. The purpose of this article is to review the use of antiplatelet agents in patients that are at particularly high risk of atherothrombotic events. To undertake this review, we searched the literature to identify key studies on the use of antiplatelet agents in this group of patients. Antiplatelet agents, such as aspirin and clopidogrel, play a fundamental role in the treatment and management of secondary thrombotic events. The routine use of aspirin is recommended, as it has been shown to reduce the risk of thrombotic events by approximately 25%. Additional benefit has been demonstrated with clopidogrel, both as a monotherapy and in combination with aspirin. In the CAPRIE trial, 19,185 patients with atherosclerotic vascular disease were randomized to receive clopidogrel (75 mg/day) or aspirin (325 mg/day) for a mean duration of follow-up of 1.91 years. Clopidogrel provided an additional 8.7% relative risk reduction in the primary composite endpoint of ischemic stroke, myocardial infraction or vascular death compared with aspirin. In the CURE trial, the addition of clopidogrel to background aspirin was associated with a 20% relative risk reduction in a composite of death from cardiovascular causes, nonfatal myocardial infarction or stroke compared with aspirin alone. In patients undergoing PCI as part of the PCI-CURE substudy, clopidogrel was associated with a 30% relative reduction in the incidence of cardiovascular events in the first 30 days after intervention compared with aspirin. The benefits of antiplatelet therapy continue to be investigated. Whether dual antiplatelet therapy is superior to aspirin monotherapy for high-risk primary prevention is unknown. The ongoing CHARISMA trial aims to determine the relative efficacies of aspirin monotherapy and aspirin/clopidogrel combination therapy in a broad range of high-risk patient populations. In addition, the REACH registry, a worldwide survey of symptomatic and high-risk patients, has been set up to provide vital epidemiological information regarding the risks of atherothrombosis in order to contribute to the development of better preventive strategies and management regimens for at-risk patients.

Impact of glucose intolerance and insulin resistance on cardiac structure and function: sex-related differences in the Framingham Heart Study.

BACKGROUND: Although insulin resistance has been implicated in the pathogenesis of left ventricular (LV) hypertrophy, previous studies have yielded inconsistent results and are limited by referral bias. METHODS AND RESULTS: We examined the relations between echocardiographic LV measurements and glucose tolerance status in 2623 Framingham Study subjects (1514 women, mean age 53 years) free of myocardial infarction and heart failure. We also evaluated the relations of insulin resistance (homeostasis model, HOMA-IR) and LV and left atrial (LA) measures within the normal and abnormal glucose tolerance categories (the latter included impaired glucose tolerance, impaired fasting glucose, and newly diagnosed diabetes). LV mass (adjusted for age, height, heart rate, and systolic blood pressure) increased across categories of worsening glucose tolerance; the trend was more striking in women (P<0.001) compared with men (P=0.054). In subjects with normal (n=2022) and abnormal glucose tolerance (n=327), covariate-adjusted LV mass and LV wall thickness increased across HOMA-IR quartiles in women (P<0.001) but not men. In contrast, covariate-adjusted LA size increased with worsening glucose tolerance and across HOMA-IR quartiles in the normal and abnormal glucose tolerance groups in both sexes. Adjustment for body mass index considerably attenuated the relations of LV/LA measures and HOMA-IR, rendering them statistically nonsignificant in the normal glucose tolerance group. CONCLUSIONS: In our large community-based sample, LV mass and wall thickness increased with worsening glucose intolerance, an effect that was more striking in women compared with men. Insulin resistance was associated with increased LV mass in women alone, but this relation was largely accounted for by obesity.

Beyond low-density lipoprotein: addressing the atherogenic lipid triad in type 2 diabetes mellitus and the metabolic syndrome.

The metabolic syndrome and type 2 diabetes mellitus are both becoming more prevalent, and both increase the risk of cardiovascular disease. Many patients are not receiving appropriate treatment for the type of dyslipidemia that commonly occurs in these disorders--the so-called 'atherogenic lipid triad' of high serum triglyceride levels, low serum high-density lipoprotein cholesterol (HDL-C) levels, and a preponderance of small, dense, low-density lipoprotein cholesterol (LDL-C) particles. All of the processes involved in atherogenesis can be exacerbated by insulin resistance and/or the metabolic syndrome. Hypertriglyceridemia is a strong predictor of coronary heart disease. There is also an inverse relationship between serum levels of HDL-C and triglycerides in diabetic patients, with low serum HDL-C levels possibly representing an independent risk factor for cardiovascular disease. Small, dense, LDL-C particles are also highly atherogenic as they are more likely to form oxidized LDL and are less readily cleared. Insulin resistance, which is central to the metabolic syndrome and type 2 diabetes mellitus, leads to high levels of very low-density lipoprotein (VLDL), which contain a high concentration of triglycerides, resulting in high serum triglyceride levels and low serum HDL-C levels. Even though modification of the atherogenic lipid triad is probably one of the most effective methods of reducing cardiovascular risk, therapy for diabetic dyslipidemia is often directed to first lowering serum LDL-C levels with a HMG-CoA reductase inhibitor. This may leave substantial excess risk for cardiovascular disease in patients with these types of dyslipidemia. The results of recent trials evaluating HMG-CoA reductase inhibitors have been mixed, with two showing no significant effect on cardiovascular outcomes in subgroups of diabetic patients. The recent CARDS (Collaborative Atorvastatin Diabetes Study) showed that atorvastatin can reduce cardiovascular events in a trial specifically designed for a diabetic population, though the population had to have at least one other risk factor in addition to diabetes mellitus. Fibric acid derivatives, such as fenofibrate, bezafibrate and gemfibrozil, are potentially well suited to the treatment of dyslipidemia that is generally associated with type 2 diabetes mellitus and the metabolic syndrome, as they are usually more effective than HMG-CoA reductase inhibitors for normalizing serum levels of HDL-C and triglycerides. Promising results have been obtained from several trials of fibric acid derivatives including the BIP (Bezafibrate Infarction Prevention) study and the VA-HIT (Veterans Affairs Cooperative Studies Program HDL-C Intervention Trial; gemfibrozil). The FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) trial, a clinical outcomes trial specifically designed to evaluate fenofibrate in a large population of patients with type 2 diabetes mellitus, many of whom have the metabolic syndrome, is underway. The FIELD trial results should shed light on the efficacy and safety of fenofibrate in reducing cardiovascular morbidity in diabetic and metabolic syndrome patients and on the safety profile of combination therapy with fenofibrate and a HMG-CoA reductase inhibitor.