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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with type 2 diabetes mellitus and/or the metabolic syndrome have considerable cardiovascular risk. Treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and with antihypertensive and some antihyperglycemic agents reduces this risk, but residual macrovascular morbidity and mortality persist, even in patients assigned to intensive multifactorial intervention programs. Therapeutic strategies that target inflammation and lipid abnormalities not well addressed by statins may offer additional opportunities for improving the prognosis of these patients. Inflammation, a key mechanism of atherogenesis, appears to have particular relevance to diabetic vascular complications, as well as in the development of diabetes itself. Oxidative stress and hyperglycemia also figure among the pathogenic factors that promote cardiovascular complications in patients with the metabolic syndrome and/or diabetes and may augment the ongoing inflammation. Peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma, members of the nuclear receptor family, form ligand-activated transcription factors that regulate key important metabolic pathways. PPARs have become therapeutic targets through the use of the fibrate class of antidyslipidemic drugs (PPAR-alpha) and the insulin-sensitizing thiazolidinediones (PPAR-gamma). The activation of these PPARs may also suppress inflammation and atherosclerosis. Recent clinical trials (Fenofibrate Intervention and Event Lowering in Diabetes [FIELD], Prospective Pioglitazone Clinical Trial in Macrovascular Events [PROactive]) have considered the impact of these PPAR agonists on cardiovascular disease, with mixed effects that require careful analysis, especially given ongoing trials and additional PPAR agonists in development.
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PMID:Inflammation in diabetes mellitus: role of peroxisome proliferator-activated receptor-alpha and peroxisome proliferator-activated receptor-gamma agonists. 1730 56

Type 2 diabetes mellitus is a significant risk factor for cardiovascular disease and is associated with significant cardiovascular morbidity and mortality. Current guidelines suggest lifestyle modification and at least a 30%-40% reduction of low-density lipoprotein (LDL) cholesterol with drug therapy, to a target level of <100 mg/dL. Additional secondary therapeutic targets include increasing high-density lipoprotein (HDL) cholesterol and lowering triglycerides. Although the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) remain first-line therapy, combination therapy with statins and fibrates or niacin is often needed to achieve target levels in patients with diabetes. Statins significantly lower LDL and decrease the relative risk for nonfatal myocardial infarction (MI) or coronary artery disease death. Clinical trials have demonstrated that in high-risk patients, such as those with diabetes, monotherapy with statins reduces overall cardiovascular events by 30%-40%. Fibrates have modest effects to lower LDL, but they significantly increase HDL and reduce triglycerides, they may improve glucose tolerance, and they have been shown to reduce nonfatal MI by 25%. Although data are limited, the combination of a statin and fenofibrate significantly reduced LDL, reduced triglycerides, and increased HDL compared with a statin alone. It is hoped that ongoing trials will demonstrate the clinical outcomes benefits of combination therapy in patients with diabetes.
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PMID:Clinical significance of recent lipid trials on reducing risk in patients with type 2 diabetes mellitus. 1730 65

The prominent use of fibric acid derivatives has lessened over the years because of unimpressive results in major clinical trials, safety concerns, and the emergence of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Clofibrate was widely used in the 1970s, but after publication of results from two major trials demonstrating only modest reductions in the rate of coronary heart disease (CHD) and concerns regarding an increase in the frequency of gallstones and overall mortality, its use subsided dramatically. With the introduction of gemfibrozil in the 1980s came a renewed interest in the class, which was also supported by the published results of the Helsinki Heart Study; however, despite a significant reduction in CHD events and a sound safety profile, overall mortality was comparable to that with placebo. Again, in the 1990s, awareness of the fibrates was heightened with the availability of fenofibrate and the findings of another major trial using gemfibrozil, the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT), which demonstrated impressive results in reducing cardiovascular events. To further strengthen the VA-HIT results, numerous post hoc analyses were performed on the data of major trials of fibrate therapy among patients with mixed dyslipidemia, with similar findings. Recently, however, data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study were published, indicating mixed results. Nearly 40 years after the introduction of the fibrates, practitioners are still contemplating the role of these agents in the treatment of CHD.
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PMID:Fibrates: what have we learned in the past 40 years? 1731 52

The use of fibrates in the management of lipoprotein disorders has a history dating back to the mid-1960s. This group of drugs has now been tested in several large long-term trials with cardiovascular end points. Overall, there is good evidence for the reduction of cardiovascular disease in primary prevention studies and in those of subjects with manifest disease. More recent trials have suffered from high interference due to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) introduction, particularly in their placebo control groups. However, there is very good evidence for overall safety from a combined study of >20,000 patients in these controlled clinical trials lasting approximately 5 years. Abdominal pain has been observed more frequently in the statin vs placebo group. Myopathy, liver enzyme elevations, and cholecystitis have been potential adverse reactions of interest. However, these have occurred at a very low rate and are rarely found to be statistically more frequent in the active-treatment group compared with the subjects taking placebo. The recent Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study found a slightly higher incidence of pancreatitis, deep venous thrombosis, and pulmonary embolism. Small creatinine and homocysteine elevations are observed in many patients taking fibrates, and the effect of this on long-term outcomes is under study. The FIELD study also described a significant reduction in the rates of progression of proteinuria and vascular retinopathy with fibrate therapy. To date, there has been no study exclusive to patients with elevated triglycerides, raising the question of the potential benefit of these drugs in patients with the lipid abnormalities most effectively treated with fibrates.
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PMID:Expert commentary: the safety of fibrates in lipid-lowering therapy. 1736 73

Niacin has beneficial effects on plasma lipoproteins and has demonstrated clinical benefits in reducing cardiovascular events and atherosclerosis progression. The side effects of niacin, however, have limited its use in general clinical practice. An understanding of cutaneous flushing based on the best available evidence should enhance patient education efforts and improve adherence. Although serious hepatic toxicity from niacin administration has been reported, it is largely confined to the use of slow-release formulations given as unregulated nutritional supplements. Niacin has been shown to induce insulin resistance in short-term trials, but the glycemic response in subjects with and without diabetes is usually minor. Niacin can be used safely in patients with diabetes. Despite a few case reports of myopathy associated with niacin-statin (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) combination therapy, 2 decades of clinical evidence since the introduction of statins do not support a general myopathic effect of niacin either alone or in combination with statins. Rare, less well-defined side effects of niacin include blurred vision due to cystoid macular edema, nausea and vomiting, and the exacerbation of peptic ulcers. Laboratory abnormalities that are usually small (< or =10%) and clinically unimportant include increased prothrombin time, increased uric acid, and decreases in platelet count and serum phosphorus. Overall, the perception of niacin side effects is often greater than the reality. As a result, a valuable medication for cardiovascular risk is underused.
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PMID:Safety considerations with niacin therapy. 1736 76

Most patients with type 2 diabetes mellitus develop cardiovascular disease (CVD), with substantial loss of life expectancy. Nonfatal CVD contributes greatly to excess healthcare costs and decreased quality of life in patients with diabetes. The current epidemic of obesity has raised expectations that CVD associated with type 2 diabetes will become an even greater public health challenge. Despite the importance of this health problem, there is a lack of definitive data on the effects of the intensive control of glycemia and other CVD risk factors on CVD event rates in patients with type 2 diabetes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is a randomized, multicenter, double 2 x 2 factorial design study involving 10,251 middle-aged and older participants with type 2 diabetes who are at high risk for CVD events because of existing CVD or additional risk factors. ACCORD is testing the effects of 3 medical treatment strategies to reduce CVD morbidity and mortality. All participants are in the glycemia trial, which is testing the hypothesis that a therapeutic strategy that targets a glycosylated hemoglobin (HbA1c) level of <6.0% will reduce the rate of CVD events more than a strategy that targets an HbA1c level of 7.0%-7.9%. The lipid trial includes 5,518 of the participants, who receive either fenofibrate or placebo in a double-masked fashion to test the hypothesis of whether, in the context of good glycemic control, a therapeutic strategy that uses a fibrate to increase high-density lipoprotein cholesterol and lower triglyceride levels together with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) to lower low-density lipoprotein cholesterol will reduce the rate of CVD events compared with a strategy that uses a statin plus a placebo. The blood pressure trial includes the remaining 4,733 participants and tests the hypothesis that a therapeutic strategy that targets a systolic blood pressure of <120 mm Hg in the context of good glycemic control will reduce the rate of CVD events compared with a strategy that targets a systolic blood pressure of <140 mm Hg. The primary outcome measure for all 3 research questions is the first occurrence of a major CVD event, specifically nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Upon the expected completion of participant follow-up in 2009, the ACCORD trial should document for the first time the benefits and risks of intensive glucose control, intensive blood pressure control, and the combination of fibrate and statin drugs in managing blood lipids in high-risk patients with type 2 diabetes.
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PMID:Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. 1759 22

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial aims to test whether a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) plus a fibrate is more efficacious in reducing cardiovascular events than a statin plus placebo in patients with type 2 diabetes mellitus with defined glycemic control. This is a blinded component in a 5,518-patient subset of the ACCORD cohort. These participants were randomized to either be (1) treated with simvastatin (titrated to 40 mg/day if necessary to achieve a goal low-density lipoprotein [LDL] cholesterol level of <2.59 mmol/L [100 mg/dL]) plus placebo or (2) treated to the same goal LDL cholesterol level with the statin plus active fenofibrate 160 mg/day or its bioequivalent (or 54 mg/day if the estimated glomerular filtration rate ranges from 30 to <50 mL/min per 1.73 m2). Setting an upper limit of LDL cholesterol qualifying for randomization excluded patients who would not likely achieve the LDL cholesterol goal. Recruitment for ACCORD began in January 2001, and follow-up is scheduled to end in June 2009. Since recruitment began, several clinical trials and consensus statements have been published that led to changes in the details of the lipid treatment algorithm and protocol. This report describes the design of the lipid protocol and modifications to the protocol during the course of the study in response to and in anticipation of these developments. The current protocol is designed to provide an ethically justifiable test of combined statin plus fibrate treatment consistent with the highest level of safety and lipid treatment standards of care.
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PMID:Evolution of the lipid trial protocol of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. 1759 26

Patients with type 2 diabetes mellitus are at increased risk for macrovascular disease complications. Hyperglycemia and atherosclerotic disease clearlyare associated, andbiologic intermediates mediated by hyperglycemia exist. Our understanding of the pathobiology linking hyperglycemia and atherosclerotic disease continues to evolve. Modulation of the advanced glycation end product (AGE) receptor for AGE (RAGE)/soluble RAGE (sRAGE) system, the thromboxane receptor, and C-peptide comprise just a few of the plausible links between dysglycemia and atherosclerosis. It seems intuitive, therefore, that therapeutic management of blood glucose in patients with diabetes should reduce macrovascular disease and related deaths. However, studies of glucose-lowering therapies performed to date yield qualitatively and quantitatively different results. No definitive proof of the concept is yet available, although it remains probable, with investigations presently under way. Numerous interventions extending beyond glucose control, including lifestyle modification, pharmacologic therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), aspirin, and angiotensin-converting enzyme inhibitors, as well as aggressive blood pressure control independent of blood pressure levels, have proved to be of cardiovascular benefit in the high-risk population of patients with diabetes. Thus, all of these interventions should be used in addition to glucose management in all patients with diabetes who are at increased risk for cardiovascular disease.
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PMID:Preventing macrovascular complications in type 2 diabetes mellitus: glucose control and beyond. 1766 47

Individuals with diabetes mellitus are at considerably higher risk for coronary artery disease compared with individuals without diabetes. In the United States, diabetes is the most prevalent factor putting patients at risk for coronary events. Intensive control of blood glucose has been demonstrated to reduce the risk for cardiovascular disease in patients with type 1 diabetes, but this has yet to be proved in patients with type 2 diabetes. Aggressive management of established cardiovascular risk factors using blood pressure-lowering and lipid-lowering therapies (particularly the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins) has been conclusively shown to reduce cardiovascular risk in patients with type 2 diabetes. Patients with type 2 diabetes remain at residual excess risk compared with individuals without diabetes, such that there is still a need for novel therapeutic approaches. Thiazolidinediones (TZDs) may have beneficial effects on cardiovascular disease in diabetes beyond improving blood glucose control. Although the evidence regarding rosiglitazone is yet to mature, completed and ongoing clinical trials with pioglitazone suggest that this TZD may be a novel treatment for managing cardiovascular risk in patients with diabetes. Addition of pioglitazone to existing therapy in high-risk patients with diabetes and atherosclerotic disease improves cardiovascular outcomes, and may be particularly beneficial for patients with previous myocardial infarction or stroke.
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PMID:Prevention of macrovascular disease in patients with diabetes mellitus: opportunities for intervention. 1782 43

This article presents a series of take-home statements, compiled by a multidisciplinary steering committee, concerning significant aspects of macrovascular disease in patients with diabetes mellitus, including the extent of risk, pathogenetic mechanisms, and optimal management for risk reduction. The discussion focuses in particular on the impact of diabetes medications beyond blood glucose control. In summary, these statements are as follows: (1) Patients with diabetes have an increased risk for cardiovascular disease that contributes to decreased life expectancy; (2) prognosis after a cardiovascular event is poorer in patients with diabetes; (3) pathogenetic mechanisms include insulin resistance, endothelial dysfunction, dyslipidemia, chronic inflammation, procoagulability, and impaired fibrinolysis; (4) management of established cardiovascular risk factors, for example with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and antihypertensive therapy, reduces cardiovascular event rates in diabetes; (5) correction of hyperglycemia can reduce macrovascular event rates, but the coupling to hyperglycemia is less tight for macrovascular events than it is for reduction of microvascular complications; (6) patients with diabetes should be screened for additional cardiovascular risk factors and appropriate interventions should be initiated; (7) results of observational and interventional studies have indicated that some insulin sensitizers appear to reduce the incidence of cardiovascular events and improve survival; (8) thiazolidinediones have beneficial effects on metabolism that may improve cardiovascular risk, and a randomized clinical trial in patients with advanced atherosclerosis indicates that addition of pioglitazone to therapy for hyperglycemia may reduce the incidence of cardiovascular events such as myocardial infarction and stroke.
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PMID:Optimizing cardiovascular outcomes in diabetes mellitus. 1782 44


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