Glycemic control and beyond: the ABCs of standards of care for type 2 diabetes and cardiovascular disease.

The phenomenal growth in the rate of type 2 diabetes presents an enormous burden to society. Diabetes and its complications cost billions and significantly impact quality of life in individuals with diabetes. Diabetes management has transitioned from focusing exclusively on glycemic control to an approach that addresses both glucose abnormalities and the chronic complications of the disease. Increased understanding of the underlying mechanisms of disease and the multifactorial basis of diabetes complications suggest the importance of early diagnosis and treatment of all diabetes complications. Preventive approaches emphasizing risk factor reduction strategies are essential. The American Diabetes Association Standards of Medical Care for People with Diabetes assist both the health care provider and the individual with diabetes to appreciate the comprehensive treatment goals in diabetes and provide specific guidelines for achieving these goals. This article presents these guidelines in an easy-to-remember ABC format.     

Managing atherosclerosis in patients with type 2 diabetes mellitus and metabolic syndrome

Diabetes mellitus with its increasing prevalence is a major global health problem in United States. Macrovascular complications, especially atherosclerosis, are the major cause of morbidity and mortality in patients with type 2 diabetes mellitus. Metabolic syndrome is considered to be a metabolic precursor of type 2 diabetes mellitus and is an independent risk factor in the pathogenesis of atherosclerosis. It is a constellation of proatherogenic metabolic abnormalities, which include obesity, hypertension, characteristic dyslipidemia, hyperglycemia, insulin resistance, and compensatory hyperinsulinemia. Recent epidemiological data have demonstrated a strong causal association between insulin resistance and coronary vascular disease independent of hyperglycemia associated with type 2 diabetes mellitus. Given the high prevalence of metabolic syndrome in the general population and its role in the pathogenesis of atherosclerosis, every attempt should be made to recognize early the metabolic syndrome and to modify the associated proatherogenic metabolic abnormalities. Management of atherosclerosis in insulin-resistant states like metabolic syndrome and type 2 diabetes is a multifactorial process involving nonpharmacological interventions like exercise, diet control, and pharmacological therapy directed at hypertension, hyperglycemia, and dyslipidemia. Further research is warranted to demonstrate the effects of these interventions unequivocally in preventing the progression of metabolic syndrome to overt type 2 diabetes mellitus with its associated macrovascular complications.     

Atherosclerosis in type 2 diabetes mellitus: the role of insulin resistance

Type 2 diabetes mellitus is associated with a marked increase in the risk of atherosclerotic diseases, including coronary heart disease, peripheral arterial disease, and cerebrovascular disease. Insulin resistance is a key factor in the pathogenesis of type 2 diabetes mellitus. Insulin resistance and its attendant metabolic abnormalities may cause much of the increased cardiovascular risk of type 2 diabetes mellitus. Among the abnormalities associated with insulin resistance are dyslipidemia, hypertension, systemic inflammation, and a prothrombotic state. This review discusses the role that each of these disorders plays in the cardiovascular risk of type 2 diabetes mellitus.     

Guidelines for the management of atherosclerotic diseases in diabetes mellitus

Diabetes mellitus is associated with a greater risk of developing atherosclerosis and its complications: myocardial infarction, stroke and peripheral vascular disease. In patients with diabetes, atherosclerosis represents a complex multifactorial disease with increased lesion progression and severity compared to the nondiabetic population. Several risk factors have been proposed to explain the increased risk of cardiovascular disease with diabetes. They include: hyperglycemia, hypertension, dyslipidemia, obesity and other factors. It is difficult to precisely establish the elements leading to diabetes-accelerated atherosclerosis by means of epidemiological studies because all these factors coexist in diabetic patients. Then, management of atherosclerosis in diabetes is a multifactorial process involving nonpharmacological interventions like exercise, diet control, and pharmacological therapy directed at hypertension, hyperglycemia, and dyslipidemia.     

Diabetic dyslipidaemia

Type 2 diabetic patients have an increased risk of cardiovascular disease and, although many factors contribute to this risk, it is likely that diabetic dyslipidaemia plays an important role. Dyslipidaemia in Type 2 diabetic patients is characterized by low levels of HDL cholesterol and high triglyceride levels. In Type 2 diabetes, the total amount of LDL cholesterol is the same as in healthy people, but there are qualitative changes, e.g. a shift to smaller, denser LDL particles and an increased susceptibility to oxidation. Oxidized LDL may promote the development of atherosclerosis. It is possible to modify the major abnormalities of diabetic dyslipidaemia by combining lifestyle modifications (e.g. increased physical activity, cessation of smoking and weight reduction) with improved glycaemic control and hypolipidaemic drugs to reduce the burden of CVD within this high-risk population.     

Insulin and insulin resistance: impact on blood pressure and cardiovascular disease

Cardiovascular disease is a major cause of mortality in individuals with diabetes. Many factors, including hypertension, contribute to the high prevalence of CVD in this population. Hypertension occurs approximately twice as frequently in patients with diabetes compared with patients without diabetes. Conversely, recent data suggest that hypertensive persons are more likely to develop diabetes than normotensive persons. In addition, up to 75% of CVD in patients with diabetes may be attributed to hypertension, leading to recommendations for more aggressive blood pressure control (ie, < 130/85 mm Hg) in persons with coexistent diabetes and hypertension. Increasing obesity further contributes to both diabetes and hypertension and significantly increases CVD morbidity and mortality. Other important risk factors for CVD in these patients include atherosclerosis, dyslipidemia, microalbuminuria, endothelial dysfunction, platelet hyperaggregability, coagulation abnormalities, and diabetic cardiomyopathy. The current knowledge regarding these risk factors has been reviewed, placing special emphasis on the metabolic syndrome, hypertension, microalbuminuria, and the role of obesity in these disorders. Although not discussed in detail, it is acknowledged that both hygienic measures (weight loss and aerobic exercise) and treatment strategies that include aspirin, statins, INS sensitizers, and antihypertensive agents that reduce renin-angiotensin-aldosterone system activity have been shown to reduce inflammation, coagulation abnormalities, endothelial function, proteinuria, and in some cases reduce CVD and renal disease progression. Additional therapeutic agents are currently being developed specifically to improve INS sensitivity and other CVD risk factors that are components of the cardiometabolic syndrome.     

Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions

Diabetes in humans accelerates cardiovascular disease caused by atherosclerosis. The relative contributions of hyperglycemia and dyslipidemia to atherosclerosis in patients with diabetes are not clear, largely because there is a lack of suitable animal models. We therefore have developed a transgenic mouse model that closely mimics atherosclerosis in humans with type 1 diabetes by breeding low-density lipoprotein receptor-deficient mice with transgenic mice in which type 1 diabetes can be induced at will. These mice express a viral protein under control of the insulin promoter and, when infected by the virus, develop an autoimmune attack on the insulin-producing beta cells and subsequently develop type 1 diabetes. When these mice are fed a cholesterol-free diet, diabetes, in the absence of associated lipid abnormalities, causes both accelerated lesion initiation and increased arterial macrophage accumulation. When diabetic mice are fed cholesterol-rich diets, on the other hand, they develop severe hypertriglyceridemia and advanced lesions, characterized by extensive intralesional hemorrhage. This progression to advanced lesions is largely dependent on diabetes-induced dyslipidemia, because hyperlipidemic diabetic and nondiabetic mice with similar plasma cholesterol levels show a similar extent of atherosclerosis. Thus, diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions.     

Pathophysiology of peripheral arterial disease and risk factors for its development

Peripheral arterial disease (PAD) is a systemic atherosclerotic process for which the major risk factors are similar to those for atherosclerosis in the carotid, coronary, and other vascular beds. Among the traditional risk factors for PAD, those with the strongest associations are advanced age, smoking, and diabetes mellitus. More recently, a number of nontraditional risk factors for PAD have also been recognized. This article briefly reviews the pathophysiology of PAD and the evidence supporting established and emerging risk factors for its development.     

Fenofibrate: treatment of hyperlipidemia and beyond

Fenofibrate is a PPAR-α agonist indicated for the treatment of hypertriglyceridemia and mixed dyslipidemia, and is approved for the treatment of hypercholesterolemia, lipid abnormalities commonly observed in patients at high risk of cardiovascular disease, including Type 2 diabetes and/or metabolic syndromes. Treatment with fenofibrate lowers triglycerides, raises HDL-cholesterol and decreases concentrations of small LDL-cholesterol particles and apolipoprotein B. Fenofibrate is particularly effective for reducing postprandial VLDL and LDL particle concentrations, and the increased oxidative stress and inflammatory response that occurs after a fatty meal. In addition, nonlipid pleiotropic effects mediated by PPAR-α are likely to contribute to the reduction in atherosclerosis progression and cardiovascular events, and have beneficial effects on diabetes-related microvascular diseases. While current approaches to treating dyslipidemia to prevent cardiovascular diseases focus on statin therapy, it is increasingly clear that substantial residual risk persists. The clinical significance of combination therapy with fenofibrate and a statin to macrovascular and microvascular risk is being evaluated in a large outcomes study.     

Diabetic nephropathy. Metabolic versus hemodynamic considerations.

Not all patients with diabetes develop clinically significant nephropathy and, for this reason, attention has begun to focus on the risk factors for development of this serious complication. These risk factors have not been quantified to the same degree as those factors associated with more common progressive vascular diseases, such as atherosclerosis. However, studies of pathogenesis and clinical and epidemiological surveys of diabetic nephropathy point to numerous risk categories. Glycemic control, genetic and familial predispositions, renal and glomerular enlargement, glomerular hyperfiltration, and capillary and systemic hypertension can be invoked as contributors to this disease process. This review focuses on hemodynamic alterations and their role in the development and progression of diabetic nephropathy. Increases in GFR, largely driven by increases in plasma flow and capillary pressure, appear in early IDDM and NIDDM. This abnormality of renal vascular control probably is derived from alterations in several vasoactive control systems. In addition, the elevations in capillary pressure may be damaging to the glomerular capillaries. Arterial hypertension is not necessarily present before clinical nephropathy appears; however, it is a usual concomitant of progressive diabetic renal disease. The strongest evidences for the roles of altered systemic and renal hemodynamics in the progression of diabetic renal disease are clinical and experimental studies demonstrating attenuation of the disease process by lowering systemic and capillary pressures with antihypertensive agents, and dietary and glycemic modifications. Thus, although multiple factors probably interact to determine risk for the development of diabetic nephropathy, hemodynamic forces are a particularly important contributor and are especially amenable to therapeutic intervention.     

Management of hypercholesterolaemia in the patient with diabetes

Coronary heart disease (CHD) is the leading cause of death in patients with type 2 diabetes. The hyperglycaemia that characterises this disease is often accompanied by a cluster of other risk factors, such as dyslipidaemia and hypertension, and effective management of the patient with diabetes requires treatment directed at correcting all of the abnormalities that increase cardiovascular risk. Approximately 90% of patients with diabetes have type 2 disease, and dyslipidaemia in these patients is characterised by elevated plasma triglycerides and very-low-density lipoproteins (VLDL), by reduced high-density lipoprotein cholesterol (HDL-C), and by a shift in LDL distribution towards small, dense particles. All of these lipid abnormalities are important risk factors for CHD. Retrospective subgroup analysis and prospective studies have shown that lipid-lowering therapy can slow the progression of atherosclerosis and reduce the risk for cardiovascular events in patients with diabetes, and both the National Cholesterol Education Program Adult Treatment Panel III and American Diabetes Association have established aggressive treatment goals for lipid-lowering therapy in these patients. All of the major medications used to treat hyperlipidaemia in other populations (niacin, fibrates, bile acid sequestrants and statins) have been used effectively to improve the plasma lipid profile in patients with diabetes. Statins are generally accepted as first-line treatment for these patients, although fibrates also have an important role in patients with pronounced hypertriglyceridaemia. Statins significantly reduce low-density lipoprotein cholesterol (LDL-C) in a broad range of patients. These agents also have substantial effects on plasma triglycerides and, in patients with hypertriglyceridaemia, lower very-low-density lipoprotein cholesterol (VLDL-C) to approximately the same extent as LDL-C. In this regard, the new agent rosuvastatin has been shown, in recent trials, to produce greater decreases in these lipoproteins than currently marketed compounds. Aggressive use of agents that attack the lipid abnormalities characteristic of patients with type 2 diabetes has the potential to significantly reduce CHD risk in these individuals.     

Microalbuminuria screening in patients with hypertension: recommendations for clinical practice

INTRODUCTION: Correlations between renal and cardiovascular (CV) pathologies in advanced kidney or heart disease are well characterised, but less clearly defined in the early stages. Microalbuminuria, in addition to being an early sign of kidney damage, is often found in patients with essential hypertension, suggesting that it may reflect early vascular abnormalities. EVIDENCE FROM LITERATURE: Studies have shown that even very low levels of microalbuminuria strongly correlate with CV risk: albumin excretion rates as low as 4.8 microg/min, well below the microalbuminuria thresholds stated in current clinical guidelines, are associated with increased risk of CV and cerebrovascular disease, independent of the presence of other risk factors. Increased microalbuminuria indicates endothelial dysfunction or developing atherosclerosis and predicts end-organ damage, major cardio or cerebrovascular events and death. CLINICAL ASPECTS: Available tests for screening microalbuminuria are sensitive, reliable and accessible; current European and US guidelines advocate annual screening in patients with diabetes and wherever possible in non-diabetic patients with hypertension. Early identification of high-risk patients through detection of microalbuminuria allows selection of aggressive treatment to slow disease progression. THERAPEUTIC IMPLICATIONS: Antihypertensive agents providing angiotensin II blockade are recommended for the treatment of hypertensive patients with microalbuminuria, regardless of diabetes and/or early or overt nephropathy. Treatment with angiotensin II receptor blockers provides effective reduction of microalbuminuria and blood pressure, and long-term prevention of CV events beyond blood pressure reduction. In addition, pharmacoeconomic studies have shown that these long-term benefits translate into a substantially reduced burden on healthcare resources.     

Abnormalities in renal hemodynamics

Chronic kidney disease (CKD) is a major risk factor for the development of cardiovascular disease (CVD). Abnormalities of renal hemodynamics are associated with CKD. Abnormalities in renal hemodynamics include blood flow into glomeruli, and tubulointerstitial tissue. Renin-angiotensin system, oxidative stress and NOS system affect abnormalities of renal hemodynamics in CKD. Further, intrarenal hemodynamic abnormalities are strongly associated with systemic arteriosclerosis. Appropriate regulation of renal hemodynamics and controls of hypertension and diabetes mellitus retard the progression of both CKD and CVD.     

Primary prevention of cardiovascular disease in people with dysglycemia

Cardiovascular disease accounts for a great majority of deaths in patients with type 2 diabetes. According to the World Health Organization, the prevalence of cardiovascular disease in diabetic patients ranges from 26 to 36%. Fatality rate after myocardial infarction is greater in diabetic patients, and overall prognosis after coronary heart disease is worse. Based on these observations, it has been proposed that diabetes should be considered as a coronary heart disease risk equivalent. If that is the case, prevention of diabetes and early intervention should be pursued. This view is supported by the notion that cardiovascular risk is already increased in people with impaired glucose tolerance. Moreover, higher-than-optimum blood glucose is a major cause of cardiovascular mortality in most world regions of the world. Whether dysglycemia is a marker for a more complex metabolic condition or may directly contribute to excess cardiovascular risk is still a matter of debate. However, experimental work has shown how increased glucose level can trigger multiple mechanisms of susceptibility to atherosclerosis, and diabetes prevention trials have indicated that along with reduction of the rate of conversion toward diabetes, significant improvement in cardiovascular risk factors occurs. Moreover, in the STOP-NIDDM trial, targeting postprandial glucose was associated with reduction in new cases of hypertension, myocardial infarction, and any cardiovascular events. In conclusion, dysglycemia should be included in the list of established cardiovascular risk factors and early treatment introduced in the attempt to improve cardiovascular morbidity and mortality.     

Using imaging for cardiovascular risk prediction: an overview.

Atherosclerosis is a systemic, silent, and deadly disease; however, primary risk reduction is very effective. Cost-effective risk modification relies on accurate and individualized risk stratification; however, traditional risk factor-based assessments fail to account for individual progression along the pathophysiologic continuum. Ultrasound and other imaging techniques that measure both anatomy and function provide well-validated surrogate markers for atherosclerosis that have incremental predictive power to that provided by risk factors, and may be useful in designing primary prevention strategies.     

Screening and risk stratification of patients with the metabolic syndrome and diabetes

The metabolic syndrome is a clustering of risk factors known to promote or increase the risk for development of cardiovascular disease. Recent estimates demonstrate that approximately one-third of the adult population of developed countries are characterized with metabolic syndrome by different definitions. Metabolic syndrome, even in the absence of diabetes, is associated with an increased risk of cardiovascular disease and total mortality, as well as an increased risk for the development of diabetes. Patients with diabetes are considered a cardiovascular risk equivalent, and warrant aggressive management of underlying risk factors to optimize prevention of cardiovascular disease. Initial evaluation of coronary heart disease risk involves global risk estimation using Framingham or other algorithms for risk prediction. Furthermore, consideration of screening for novel risk factors, such as C-reactive protein, as well as subclinical atherosclerosis (as assessed by carotid ultrasound, computed tomography or ankle–brachial index), can further refine the estimation of future cardiovascular disease risk. The presence of subclinical atherosclerosis or elevated levels of C-reactive protein can potentially modify recommended treatment goals for lipid and other cardiovascular risk factors.     

A practical "ABCDE" approach to the metabolic syndrome

The metabolic syndrome comprises a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus that are due to abdominal obesity and insulin resistance. This increasingly important proinflammatory condition remains both underrecognized and undertreated. To aid physicians in their approach to the metabolic syndrome, we assessed and synthesized the literature on cardiovascular risk assessment and early intervention for risk reduction. We performed a comprehensive search of MEDLINE and the Cochrane database for peer-reviewed clinical studies published from January 1, 1988, to December 31, 2007, augmented by consultation with content experts. We used the search terms metabolic syndrome, abdominal obesity, waist circumference, insulin resistance, cardiovascular disease, prediabetes, diabetes, treatment, prevention, aspirin, hypertension, cholesterol, atherogenic dyslipidemia, lifestyle therapy, diet, and exercise. Criteria used for study review were controlled study design, English language, relevance to clinicians, and validity based on experimental design and appropriateness of conclusions. Although growing evidence supports early intervention in patients with the metabolic syndrome, many physicians do not recognize the risk associated with this condition and fail to initiate early treatment. A comprehensive management plan can be assembled through an "ABCDE" approach: "A" for assessment of cardiovascular risk and aspirin therapy, "B" for blood pressure control, "C" for cholesterol management, "D" for diabetes prevention and diet therapy, and "E" for exercise therapy. This ABCDE approach provides a practical and systematic framework for encouraging metabolic syndrome recognition and for implementing a comprehensive, evidence-based management plan for the reduction of cardiovascular risk.     

Screening and risk stratification of patients with the metabolic syndrome and diabetes

The metabolic syndrome is a clustering of risk factors known to promote or increase the risk for development of cardiovascular disease. Recent estimates demonstrate that approximately one-third of the adult population of developed countries are characterized with metabolic syndrome by different definitions. Metabolic syndrome, even in the absence of diabetes, is associated with an increased risk of cardiovascular disease and total mortality, as well as an increased risk for the development of diabetes. Patients with diabetes are considered a cardiovascular risk equivalent, and warrant aggressive management of underlying risk factors to optimize prevention of cardiovascular disease. Initial evaluation of coronary heart disease risk involves global risk estimation using Framingham or other algorithms for risk prediction. Furthermore, consideration of screening for novel risk factors, such as C-reactive protein, as well as subclinical atherosclerosis (as assessed by carotid ultrasound, computed tomography or ankle-brachial index), can further refine the estimation of future cardiovascular disease risk. The presence of subclinical atherosclerosis or elevated levels of C-reactive protein can potentially modify recommended treatment goals for lipid and other cardiovascular risk factors.     

Dyslipidemia in insulin resistance: clinical challenges and adipocentric therapeutic frontiers

The ever-increasing rates of obesity and diabetes worldwide have the potential to further fuel the epidemic of cardiovascular disease that we are experiencing today. To slow this epidemic successfully, insulin resistance and associated lipid abnormalities that frequently accompany it are key clinical targets. Yet, we are still challenged to reach the mandated clinical goals for lipids that would minimize the development and progression of cardiovascular disease. Adoption of a comprehensive approach by clinicians, in line with recent recommendations for stricter treatment goals for the at-risk patient, is essential to achieving cardiovascular risk reduction. The challenge for clinicians is integrating strategies, approaches and treatments that address the multiple metabolic defects in patients with insulin resistance and dyslipidemia. New perspectives can help effectively meet this ongoing challenge. Emerging evidence suggests that adipose tissue is intimately involved in the inter-relationships between insulin resistance and dyslipidemia. The future probably involves therapeutic strategies that directly target adipose tissue to optimally reduce cardiometabolic risk.     

Dyslipidemia in insulin resistance: clinical challenges and adipocentric therapeutic frontiers

The ever-increasing rates of obesity and diabetes worldwide have the potential to further fuel the epidemic of cardiovascular disease that we are experiencing today. To slow this epidemic successfully, insulin resistance and associated lipid abnormalities that frequently accompany it are key clinical targets. Yet, we are still challenged to reach the mandated clinical goals for lipids that would minimize the development and progression of cardiovascular disease. Adoption of a comprehensive approach by clinicians, in line with recent recommendations for stricter treatment goals for the at-risk patient, is essential to achieving cardiovascular risk reduction. The challenge for clinicians is integrating strategies, approaches and treatments that address the multiple metabolic defects in patients with insulin resistance and dyslipidemia. New perspectives can help effectively meet this ongoing challenge. Emerging evidence suggests that adipose tissue is intimately involved in the inter-relationships between insulin resistance and dyslipidemia. The future probably involves therapeutic strategies that directly target adipose tissue to optimally reduce cardiometabolic risk.