... REPORT... The Metabolic Syndrome, Type 2 Diabetes, and Cardiovascular Disease: Understanding the Role of Insulin Resistance

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1 ... REPORT... The Metabolic Syndrome, Type 2 Diabetes, and Cardiovascular Disease: Understanding the Role of Insulin Resistance David M. Kendall, MD; Anne Peters Harmel, MD Abstract The most common and clinically important complication in adults with diabetes is cardiovascular disease (CVD), which includes coronary heart disease, peripheral vascular disease, and stroke. Both type 2 diabetes and the insulin resistance syndrome are associated with a marked increase in the risk for CVD. The metabolic syndrome and the closely related insulin resistance syndrome have recently been recognized as important disorders, each being associated with an increase in CVD risk even in the absence of glucose intolerance. Given the significant public health burden of CVD, risk reduction has emerged as a significant clinical challenge for most practitioners. Diabetes and the insulin resistance syndrome are closely related disorders, with insulin resistance being more than a key pathogenic defect in type 2 diabetes. Even in the absence of glucose intolerance, these 2 disorders are both associated with a number of distinct pathologic findings, including hypertension, atherogenic dyslipidemia, a prothrombotic environment, and significant vascular and hemodynamic abnormalities that result from endothelial cell dysfunction. Insulin resistance is now recognized to be closely associated with the development of each of these risk factors. This article uses a case-based approach to discuss the unique features of insulin resistance and type 2 diabetes considered to be key contributors to CVD risk. A systematic approach to both evaluation and management is proposed, with priority given to therapies of demonstrated clinical benefit. Because of its critical and central role in the development of many CVD risk factors, targeted treatment of insulin resistance will also be discussed as such therapy may prove to be a critical component of care in years to come. (Am J Manag Care. 2002;8:S635-S653) Case Study Jerry, a 50-year-old man, has been referred for endocrine evaluation by his primary care physician for management of cardiovascular disease (CVD) and recent development of an elevated fasting blood glucose level. He was diagnosed with dyslipidemia and hypertension 8 years ago, and definitive antihypertensive therapy was initiated thereafter. He has a family history of CVD; his sister had documented coronary artery disease (CAD) with prior myocardial infarction at age 51, and his father developed angina and underwent coronary artery bypass (CAB) in his 60s. In addition, his father and a paternal uncle both have a history of type 2 diabetes mellitus. He is not aware of a family history of hypertension or lipid disorders. He does not smoke and does not exercise on a regular basis. At the time of initial presentation, he had chest pain with significant electrocardiographic (ECG) changes noted. He was diagnosed with unstable angina, and coronary angiography was performed. Initial images suggested no definite flow-limiting or critical lesions, although diffuse angiographic evidence of atherosclerosis was noted, with multiple lesions showing greater than 50% stenosis. Medical therapy was initiated, including simvastatin 40 mg daily for his elevated low-density lipoprotein cholesterol (LDL-C) level, aspirin 325 mg daily, and atenolol 100 mg daily for control of symptomatic angina. The patient was readmitted 5 months later with recurrent refractory chest pain, VOL. 8, NO. 20, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S635

2 REPORT and ECG at this time showed inferior wall ischemia. Because the symptoms had progressed for the 5 months since his last visit, repeat coronary angiography was performed, revealing 2 lesions with greater than 70% stenosis. Because of these changes, coronary artery bypass grafting was performed. In addition to the medications he was taking prior to the procedure, an angiotensin-converting enzyme inhibitor (ACEI), lisinopril 20 mg daily, was initiated in the postoperative period and continued at the time of hospital discharge. Clinical Issues The Metabolic Syndrome and Insulin Resistance This clinical case represents an increasingly common clinical problem: the presence of multiple cardiovascular risk factors and established coronary heart disease in a patient with abnormal glucose tolerance. Such patients can now be identified and treated before they manifest overt CVD, and many will likely benefit from therapies designed to prevent or delay the development of either glucose intolerance or diabetes. Clinicians are becoming increasingly aware of the metabolic syndrome, a disorder of increased cardiovascular risk defined by the presence of a number of distinct cardiovascular risk factors. 1-4 The case presented here describes many of the classic features of the metabolic syndrome: glucose intolerance, dyslipidemia, hypertension, and an increased likelihood of having significant insulin resistance. This individual is at high risk for both subsequent CVD events and the development of type 2 diabetes. This paper will clarify the definition of the metabolic syndrome and discuss its relationship to the more specific disorder of insulin resistance. The role of both of these conditions in the development of type 2 diabetes and increased cardiovascular risk is emphasized, and the clinical management of such patients is reviewed. The Metabolic Syndrome. The metabolic syndrome is a recently defined and rapidly evolving area of clinical and basic research and clinical care. 1-4 Many aspects of the metabolic syndrome are yet to be fully defined, and all of the interrelationships particularly with insulin resistance are not fully understood. 5-7 Perhaps the most important feature of both the metabolic syndrome and insulin resistance syndrome is the understanding that these disorders serve to identify patients at significant risk for development of both CVD and type 2 diabetes. The metabolic syndrome has been described by a number of investigators for many years. As early as the 1920s, Swedish physician and investigator Eskil Kylin described a disorder characterized by the presence of hypertension, hyperglycemia, and hyperuricemia. 8 Reaven et al, 5 as well as other investigators, 5 have described in detail the features of the now-named metabolic syndrome, or syndrome X. 1,2,5,6 These authors were among the first to suggest the relationship to the generalized disorder of insulin resistance. With increasing awareness of the significant CVD risk associated with this disorder, 9,10 formal definitions of the metabolic syndrome have been proposed by several organizations including the World Health Organization (WHO), 1 the National Cholesterol Education Program (NCEP), 2 and the American Association of Clinical Endocrinology (AACE). 3 Each of these working definitions is summarized in Table 1, listing both pertinent defining and pathophysiologic characteristics of the disorder. These descriptions are primarily aimed at defining the syndrome rather than presenting clinically oriented criteria for establishing a diagnosis or guiding therapy. In addition, these definitions do not necessarily differentiate between the causes of the syndrome and its potential clinical consequences. One of the most recent descriptions of the metabolic syndrome was put forth in the NCEP Third Adult Treatment Panel (ATP III); this description provides a clinically oriented set of criteria for identifying highrisk individuals. 3 These criteria describe the metabolic syndrome as: a constellation of lipid and nonlipid CVD risk factors of metabolic origin closely linked to the generalized metabolic disorder [of] insulin S636 THE AMERICAN JOURNAL OF MANAGED CARE DECEMBER 2002

3 The Metabolic Syndrome, Type 2 Diabetes, and Cardiovascular Disease resistance. 3 While this description provides a clinically useful definition, it also raises again the issue of the interrelationship of the metabolic syndrome and insulin resistance. AACE has now provided a definition of the metabolic syndrome and has championed the development of a specific International Classification of Diseases code for this disorder. 2 The criteria used most uniformly are those described in the ATP III guidelines, although each of the descriptions offers unique and useful information in helping clinicians identify this disorder. The metabolic syndrome is being diagnosed with increasing frequency and is becoming an important public health concern. A recent report derived from the third National Health and Nutrition Examination Survey database (NHANES III) assessed the prevalence of the syndrome in the US population using the ATP III guidelines for defining the metabolic syndrome. 4 Based on these criteria, the age-adjusted prevalence of the metabolic syndrome was estimated to be 23.7% among adults in the United States. Rates were similar between males and females and increased with age. Among specific population groups, Mexican Americans had the highest age-adjusted prevalence of the syndrome (31.9%). Based on current census data, as many as 47 million people living in the United Table 1. Current Criteria for the Diagnosis of the Metabolic Syndome WHO NCEP ATP III AACE Hypertension Current antihypertensive therapy Current antihypertensive therapy Hypertension and/or BP >140/90 mm Hg or BP >130/85 mm Hg Dyslipidemia Plasma triglyceride level >1.7 mmol/l Plasma triglyceride level >150 mg/dl, Dyslipidemia (HDL-C (150 mg/dl) and/or HDL-C level HDL-C level <40 mg/dl in men, level <35 mg/dl in men, <0.9 mmol/l (35 mg/dl) in men, HDL-C level <50 mg/dl in women. <45 mg/dl in women, <1.0 mmol/l (<40 mg/dl) or triglyceride level in women >150 mg/dl) Obesity BMI >30 kg/m 2 and/or waist/hip Waist circumference >40 inches in Waist circumference ratio >0.90 in men, >0.85 in women men and >35 inches in women >102 cm (40 in) in men and >88 cm (35 in) in women Glucose Type 2 diabetes or IGT Fasting blood glucose level Impaired fasting blood >110 mg/dl glucose level (>110 mg/dl) or type 2 diabetes Other Microalbuminuria (overnight urinary Insulin resistance albumin excretion rate >20 mg/min (hyperinsulinemia relative [30 mg/g Cr]) to glucose levels) or acanthosis nigricans Requirements Confirmed type 2 diabetes or IGT Any 3 of the above disorders Consider any minor criteria for Diagnosis and any 2 of the above criteria. If including hypercoagulability, normal glucose tolerance, must PCOS, vascular or endodemonstrate 3 of the above criteria thelial dysfunction, microalbuminuria, and coronary heart disease WHO indicates World Health Organization; NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III; AACE, American Association of Clinical Endocrinology; BMI, body mass index; BP, blood pressure; Cr, creatinine; HDL-C, high-density lipoprotein cholesterol; IGT, impaired glucose tolerance; PCOS, polycystic ovary syndrome. VOL. 8, NO. 20, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S637

4 REPORT Figure 1. Contributing Factors and Metabolic, Vascular, and Clinical Consequences of Insulin Resistance Factors Contributing to Insulin Resistance Metabolic and Vascular Abnormalities Clinical Consequences Central obesity Hemostatic abnormalities Hypertension Stroke Vascular inflammation Hyperuricemia Atherosclerosis PVD Genetic factors Family history Population groups Sedentary lifestyle Reduced physical activity Increasing age Insulin Resistance Abnormal vascular behavior Abnormal FFA and VLDL metabolism and visceral fat deposition Impaired glucose homeostasis High TG Low HDL Impaired glucose tolerance IGT-IFG PCOS NASH CAD Diabetes CAD indicates coronary artery disease; FFA, free fatty acids; HDL, high-density lipoprotein; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; NASH, nonalcoholic steatohepatitis; PCOS, polycystic ovary syndrome; PVD, peripheral vascular disease; TG, triglyceride; VLDL, very low-density lipoprotein. States are estimated to have the metabolic syndrome. Despite increasing understanding of the definitions and consequences of the metabolic syndrome, significant confusion still exists regarding the clinical importance of the disorder and its distinction from the insulin resistance syndrome. The metabolic syndrome is associated with a marked increase in CVD risk and as such represents an important set of criteria for identifying individuals that should be targeted for CVD risk reduction. 9,10 Given the higher prevalence of glucose intolerance in this population, individuals with the metabolic syndrome are also likely to be at significantly higher risk for development of type 2 diabetes. Both CVD risk reduction efforts and diabetes prevention can and should be considered for all patients with the metabolic syndrome. Because of the large numbers of individuals affected, such efforts will undoubtedly have a significant public health impact. A recent case-based review outlines many of the definitions of the metabolic syndrome and its potential therapies. 11 With an increased appreciation for the role of insulin resistance in the development of the metabolic syndrome and a better understanding of the role of insulin resistance in both CVD risk and the risk for diabetes, many clinicians are now focusing on defining and treating insulin resistance more specifically. How does insulin resistance contribute to CVD risk? What potential impact will therapies for insulin resistance have on CVD risk and the future risk for type 2 diabetes? The remainder of this review will focus more specifically on the recently proposed definition of the insulin resistance syndrome S638 THE AMERICAN JOURNAL OF MANAGED CARE DECEMBER 2002

5 The Metabolic Syndrome, Type 2 Diabetes, and Cardiovascular Disease and will discuss specific therapies for CVD risk, glucose intolerance, and insulin resistance. The Insulin Resistance Syndrome. Insulin resistance is a metabolic disorder characterized by diminished tissue sensitivity to insulin. The specific pathophysiologic determinants of insulin resistance are still only partly understood, but insulin resistance likely results from specific physical and behavioral characteristics, such as obesity and physical inactivity in individuals with significant genetic predisposition. A summary of the proposed origins of insulin resistance and metabolic, vascular, and clinical consequences that develop in the setting of insulin resistance are detailed in Figure 1. As noted in this figure, insulin resistance generally develops in individuals who have some degree of genetic risk. Both obesity and physical inactivity contribute significantly to this risk and specific populations, as a consequence of still poorly defined genetic factors, are also at increased risk for developing insulin resistance. Once present, insulin resistance results in impaired insulin action in insulin-sensitive tissues such as muscle, fat, and liver, and insulin resistance is associated with abnormalities of blood vessel biology. 12 Insulin resistance results in abnormalities of glucose metabolism, with reduced peripheral disposal of glucose in muscle and increased hepatic glucose output in the fasting state. 5 Insulin resistance also results in impaired handling of plasma triglycerides and free fatty acids. 13 In addition, individuals with insulin resistance often manifest a number of changes in the behavior of large blood vessels, with characteristic abnormalities in vascular reactivity, changes in several key regulators of thrombolysis, and an increased risk for vascular inflammation The specific ways in which insulin resistance and insulin action per se regulate each of these features is currently being investigated and is beyond the scope of this review. The insulin resistance syndrome should not be confused with insulin resistance itself, nor can the syndrome be considered a specific disease. Rather, the insulin resistance syndrome is a specific collection of clinical features that occur with greater prevalence in insulin-resistant individuals, and this syndrome, just as with the metabolic syndrome, identifies individuals who are at increased risk for both type 2 diabetes and CVD. 11 Limited clinical and experimental data would suggest either a single criterion or specific criteria for the diagnosis of the insulin resistance syndrome. In addition, an important point to understand is that a syndrome itself is not a disease but rather a collection of clinical characteristics that suggest a critical role for a single process in this case, insulin resistance in a greater disease process. The recent American College of Endocrinology (ACE)/AACE Insulin Resistance Syndrome conference extended the concept of the metabolic syndrome by specifically addressing the role of insulin resistance as a pathophysiologic contributor to both CVD and diabetes risk. 18 The consensus committee also looked to recognize additional associated disorders of insulin resistance, such as polycystic ovary syndrome, which affects 1 in 10 US women of childbearing age, and nonalcoholic fatty-liver disease (steatohepatitis, or nonalcoholic steatohepatitis). In addition, the guidelines suggested by the AACE task force are designed to increase clinicians understanding and improve the methods for detection of the insulin resistance syndrome by emphasizing the use of the 2- hour postglucose challenge as the most sensitive clinically available test for insulin resistance. The AACE definition itself does not clearly differentiate between factors that increase the risk of insulin resistance and the consequences of insulin resistance. Figure 1 is primarily based on the recommendations of the AACE Insulin Resistance Task Force. This figure is presented to better clarify and distinguish between factors that contribute to the development of insulin resistance and its clinical consequences. In this figure, the metabolic and vascular abnormalities are specifically differentiat- VOL. 8, NO. 20, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S639

6 REPORT Table 2. Clinical Signs of Insulin Resistance Syndrome as Defined by the ACE/AACE Task Force Components Table of Risk Factors* Abnormal Parameters Overweight/obesity BMI 25 kg/m 2 High triglyceride levels Low HDL-C levels High blood pressure 2-hour postglucose challenge Fasting blood glucose level 150 mg/dl (1.69 mmol/l) <40 mg/dl (1.04 mmol/l) in men <50 mg/dl (1.29 mmol/l) in women 130/85 mm Hg >140 mg/dl Between 110 mg/dl and 126 mg/dl *Other risk factors include family history of type 2 diabetes, hypertension or cardiovascular disease (CVD), polycystic ovarian syndrome, sedentary lifestyle, age, and ethnicity. Factors should be assessed and measured in people who are considered at risk for CVD, insulin resistance, and type 2 diabetes. ACE/AACE indicates American College of Endocrinology/American Association of Clinical Endocrinology; BMI, body mass index; HDL-C, highdensity lipoprotein cholesterol. ed from the ultimate clinical consequences of the syndrome. The goal of this description is to assist the clinician in delineating those features that identify the disorder from those that are consequences as well as to offer specific opportunities for intervention. An important point is that not all patients with the insulin resistance syndrome will develop all of the clinical features of the disorder. Furthermore, not all of these patients will develop the clinical consequences of the syndrome. In addition, each of these abnormalities can occur in virtually any chronological order. For many patients, atherosclerosis and CVD will develop before overt hyperglycemia is evident, as illustrated in the case study presented. Clinicians must understand the distinction between impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). IFG is defined simply as fasting blood glucose values in the range of 110 to 125 mg/dl, as defined by the American Diabetes Association (ADA). 19 Individuals with IFG are at increased risk for progressive deterioration in glucose metabolism and are at known increased risk for CVD IGT implies abnormalities in postchallenge glucose metabolism (postprandial blood glucose elevations) and is a more sensitive indicator of insulin resistance and perhaps the metabolic syndrome. In many studies, surprisingly little overlap is seen in these diagnoses. Regardless of the order in which these clinical abnormalities develop, significant opportunity remains for earlier diagnosis and earlier intervention in such patients. 22 Such intervention will be essential in order to significantly limit the risk of heart disease and reduce the future risk of type 2 diabetes. Features of the Insulin Resistance Syndrome. The insulin resistance syndrome is characteristically defined by the very risk factors for insulin resistance outlined by the AACE consensus committee. These risk factors are outlined in Figure 1 and in Table 2. As discussed, insulin resistance plays a central role in the pathogenesis of hypertension, dyslipidemia, and glucose intolerance. 5-7,11-18 In addition, many nonclassical CVD risk factors are closely linked to insulin resistance, including vascular inflammation, abnormal endothelial function, and a prothrombotic vascular milieu The central role of insulin resistance is further emphasized (Figure 2), and the close connection between adjacent components of the syndrome, for example, hypertension and abnormal vascular reactivity, is also noted. Each of the specific components is discussed in further detail, below. Insulin Resistance and Glucose Intolerance. Insulin resistance is present in the vast majority of patients with impaired glucose tolerance, impaired fasting glucose, and type 2 diabetes. 20 In healthy individuals, insulin resistance leads to a compensatory increase in insulin secretion; in those with inadequate pancreatic insulin response, insulin resistance results in glucose intolerance and ultimately, for many, the development of type 2 diabetes. The role of insulin resistance in the development of abnormal glucose metabolism has been well described. 5 S640 THE AMERICAN JOURNAL OF MANAGED CARE DECEMBER 2002

7 The Metabolic Syndrome, Type 2 Diabetes, and Cardiovascular Disease Figure 2. Theoretical Relationship of Insulin Resistance to Other Features of the Insulin Resistance Syndrome Hyperglycemia IFG/IGT Type 2 Diabetes Dyslipidemia LDL-TG-HDL Hypertension Microalbuminuria Thrombotic Risk Inflammation PAI-1 Fibrinogen Platelet aggregation Insulin Resistance Vascular Inflammation CRP Abnormal Vascular Behavior Endothelial dysfunction Intimal thickening CRP indicates C-reactive protein; HDL, high-density lipoprotein; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; LDL, low-density lipoprotein; PAI-I, plasminogen activator inhibitor; TG, triglycerides. Source: International Diabetes Center All rights reserved. Reprinted with permission. Increasingly, clinicians appreciate that management of insulin resistance plays a critical role in the effective management of diabetes. Insulin resistance therapies have been shown to play an important role in diabetes prevention as well. The importance of glucose intolerance as a CVD risk factor is well described Extensive data support the relationship between increased blood glucose levels and increased CVD risk. Both IGT and IFG are associated with increased CVD In a population-based study from the Framingham cohort, the metabolic risk factors for coronary heart disease, including obesity, hypertension, decreased highdensity lipoprotein cholesterol (HDL-C) levels, elevated triglyceride levels, and hyperinsulinemia, demonstrated a continuous increase in CVD risk across the spectrum of glucose values in the nondiabetic range (between 90 and 125 mg/dl). This increase in risk was apparent even in the lowest quintiles of normal fasting glucose. 25 The recent European Prospective Investigation of Cancer and Nutrition (EPIC) study in Europe also demonstrated a marked increase in cardiovascular events in men without diabetes when comparing glycosylated hemoglobin A (HbA 1c ) levels in the highest quintile (5.0% to 5.4%) compared to those the lowest quintile (<5.0%). 26 Despite this evidence, no clinical trials to date have demonstrated a significant lowering of macrovascular disease risk when targeting glucose specifically in subjects with either IFG or IGT. Increasing blood glucose levels in those with diagnosed diabetes are also associated with an increasing CVD event rate. 27 While glucose lowering is known to significantly reduce the risk of microvascular complications in type 2 diabetes, 28,29 no trials to date have demonstrated a clear benefit of glucose lowering on CVD risk. Large clinical trials are now under way, including the National Institutes of Health Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial, that are designed to more clearly define the role of intensive glucose control in the management of CVD risk. At present, efforts to VOL. 8, NO. 20, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S641

8 REPORT diagnose glucose intolerance as early as possible must be emphasized in all patients with suspected insulin resistance syndromes. Insulin Resistance and Dyslipidemia. Insulin resistance results in specific and well-defined abnormalities of lipid metabolism. 13 The presence of these lipid disorders is one of the defining characteristics of the insulin resistance syndrome. The dyslipidemia of insulin resistance is characterized by elevated levels of plasma triglycerides and low HDL-C levels, although LDL-C levels in insulin-resistant subjects are usually not significantly elevated. However, an increased number of small, dense LDL-C particles (very lowdensity lipoprotein cholesterol [VLDL-C]) are often present. Insulin action is not limited to glucose disposal. Insulin regulates metabolism of free fatty acids and the production of triglyceride-rich VLDL-C particles. In an insulin-resistant individual, increased levels of free fatty acids (FFA) are liberated from peripheral fat tissue. This increased circulating level of FFA in turn stimulates synthesis of triglyceride-rich VLDL-C particles by the liver. The increase in levels of plasma VLDL-C in turn lowers plasma HDL-C and LDL-C concentrations because of the exchange of cholesterol ester and triglyceride (via cholesterol ester transfer protein) with circulating HDL-C and LDL-C particles. This ultimately results in reduced cholesterol concentration in both HDL-C and LDL-C particles. However, the triglyceride-rich LDL-C particles are subject to further lipolysis, which gives rise to the formation of small, dense LDL-C particles. The resultant dyslipidemia is highly atherogenic and accounts for at least part of the increase in CVD risk in insulin-resistant individuals. Insulin Resistance, Hypertension, and Abnormal Vascular Behavior. While data are currently limited, hypertension is estimated to occur in up to one third of those with the metabolic syndrome and is present in a significant percentage of those with evidence of insulin resistance. Insulin resistance has been directly tied to the development of both hypertension and other abnormalities of vascular behavior. 7 The interest in this relationship is increasing as evidence accumulates suggesting that insulin resistance can directly affect vascular signaling, primarily through mediators such as nitric oxide, and endothelial cell function. 12,16 Insulin resistance is associated with a number of changes in vascular endothelial and smooth muscle function. The potential mechanisms by which insulin resistance may cause hypertension include resistance to insulin-mediated vasodilation, abnormal endothelial signaling (via nitric oxide-dependent pathways), increased sympathetic nervous system activity, sodium retention, and enhanced growth factor production and activation leading to proliferation of smooth muscle cells in the vessel wall and increased rates of intimal expansion. 30 Insulin Resistance, Vascular Inflammation, and Prothrombotic Vascular Environment. Diabetes and the insulin syndrome are both disorders characterized by abnormalities of the vessel wall and circulating plasma that markedly increase thrombotic risk. This increase in thrombotic risk, when combined with an increase in rates of atherosclerosis, in great part accounts for the increase in rates of thrombotic CVD events. Factors contributing to a prothrombotic milieu include changes in the equilibrium between activators of plasminogen (primarily tissue-type plasminogen activator) and inhibitors of events such as plasminogen activator inhibitor type 1 (PAI-1). 14,15 Excessive inhibition of fibrinolysis increases the risk of abnormal coagulation and thrombosis. Plasma levels of PAI-1 are increased in insulin-resistant individuals, including obese subjects who may or may not have diabetes. 14 A number of studies suggest a mechanistic link between insulin resistance and these abnormal fibrinolytic features. 15 In addition, diabetes and insulin resistance are associated with increased platelet aggregation. These S642 THE AMERICAN JOURNAL OF MANAGED CARE DECEMBER 2002

9 The Metabolic Syndrome, Type 2 Diabetes, and Cardiovascular Disease observations suggest that antiplatelet therapy will play a critical role for patients with diabetes and insulin resistance. Case Study Continued At the time of consultation, Jerry and his wife both questioned the significance of his recent increase in glucose levels. While he denied ongoing cardiac symptoms, he was concerned with efforts to reduce CVD risk and questioned the need for many of his medications. He said he did not have a history of abnormal weight loss, polyuria, or polydipsia. At the time of outpatient follow-up, laboratory evaluation demonstrated an increased fasting glucose level of 112 mg/dl. On routine evaluation 1 year ago, his fasting glucose level was 96 mg/dl; on 2 subsequent evaluations since that time, it increased to 104 and 111 mg/dl, respectively. Review of hospital records demonstrated numerous elevated blood glucose levels following the bypass surgery with nonfasting values ranging from 131 to 188 mg/dl during the course of his hospitalization. His fasting lipid profile while on simvastatin therapy at this time showed total cholesterol level of 167 mg/dl, with an HDL-C level of 33 mg/dl, triglyceride level of 210 mg/dl, and LDL-C level of 92 mg/dl. The patient weighed 278 lb at this evaluation, with obvious central obesity. His body mass index was calculated at 34 kg/m 2. Waist circumference was not directly measured. Blood pressure was 144/92 mm Hg on multidrug antihypertensive therapy. Urinalysis revealed microalbuminuria (112 mg/g creatinine). Measurement of HbA 1c level at the time of bypass surgery was reported as normal at 5.7%, but repeat HbA 1c at follow-up was 6.3%. Given his family history, the significant glucose intolerance, and established CVD, the patient was considered to be at significant risk for development of type 2 diabetes. In addition, his complex history of CVD risk factors was discussed. He received instruction on the use of selfmonitored blood glucose testing and was instructed on the use of carbohydrate counting in an attempt to regulate postprandial blood glucose increases. He was also instructed on rational calorie restriction to assist with weight management, and he was encouraged to increase physical activity to 100 minutes or more per week with an initial weight loss goal of approximately 10% of his current weight, or about 28 lb. Because of the increased urinary protein excretion, the ACEI dose was increased to 40 mg daily and low-dose hydrochlorothiazide (HCTZ, 12.5 mg daily) was added to decrease systolic blood pressure to < 130 mm Hg. Dietary changes, including total saturated fat restriction, were also encouraged to assist with management of elevated triglycerides. Clinical Management of the Insulin Resistance Syndrome Management of the insulin resistance syndrome currently requires treatment of many of the individual metabolic consequences of this syndrome. Treatment is focused on abnormal glucose tolerance and the other CVD risk factors present. In those with both diabetes and CVD, comprehensive and aggressive therapy is required to limit both microvascular and macrovascular disease risk. In those with established CVD alone, treatment should clearly focus on CVD risk management. However, individuals with CVD and the insulin resistance syndrome may also benefit significantly from specific therapy for insulin resistance both to limit the impact of insulin resistance on the individual CVD risk factors and to reduce the future risk for type 2 diabetes. Over the past decade, a number of clinical trials have demonstrated the benefit of specific therapy for patients with CVD and diabetes. Treatment of lipid abnormalities, aggressive management of blood pressure, and the use of aspirin therapy are known to reduce the subsequent risk for CVD. Aggressive glucose lowering reduces the risk for microvascular complications of diabetes. 28,29 Patients with insulin resistance syndrome were most likely included in many of the clinical trials of non glucose-lowering therapies and, while not studied specifically in all VOL. 8, NO. 20, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S643

10 REPORT trials, they are very likely to benefit from many of the same therapies of established benefit in patients with diabetes. One approach to diagnosis and management of the distinct components of insulin resistance syndrome is described in Figure 3 and is further detailed in the section below. Therapeutic Lifestyle Interventions. Therapeutic lifestyle changes, including weight management, increased physical activity, interval assessment of dietary changes, and measurement of fasting and postprandial glucose, should be considered in all patients with insulin resistance just as they are for patients with type 2 diabetes. Careful instruction on the benefits of modest weight loss, restriction of carbohydrate and total fat intake, and an increase in physical activity are of established benefit. Obesity and physical inactivity are important risk factors for the development of insulin resistance and are associated with higher rates of development of cardiovascular risk factors. Central obesity is common in these individuals and is one of the specific markers used to identify those at risk for having insulin resistance (Table 2). Recent recommendations for management of diabetes 19 and the insulin resistance syndrome 18 clearly support the role of therapeutic lifestyle changes. Furthermore, such interventions can play an important role in managing the associated dyslipidemia, hypertension, and hyperglycemia seen in these conditions. Modest weight loss achieved through a reduction in total calorie and fat intake, when combined with an increase in physical activity, has also been shown to reduce the risk for type 2 diabetes by more than 50%. 31,32 Such prevention efforts can be anticipated to significantly reduce the future risk of both microvascular and macrovascular complications of diabetes, as well. Some of the benefits of both weight loss and increased physical activity in patients with the metabolic syndrome and diabetes are likely related to their favorable effect on insulin sensitivity. Weight reduction and changes in diet composition improve insulin sensitivity. 33,34 Dietary carbohydrate restriction lowers blood glucose and plasma triglyceride levels, often resulting in further improvements in insulin sensitivity, and is associated with weight loss in some individuals. 35 Physical activity increases insulin sensitivity by up to 25%. In addition, increased aerobic and resistance physical activity serves to lower blood pressure and increase levels of HDL-C. 33,34,36 At present, the greatest difficulty with regard to lifestyle interventions is to provide patients with both the incentive for change and the specific methods by which they can achieve and sustain these changes. Unquestionably, education of patients is essential. Lifestyle interventions and education are of demonstrated benefit in patients with diabetes. The results of the recent diabetes prevention trials 31,32 further underscore the need for supervised lifestyle interventions. Current challenges include: identifying appropriate activities and assuring access to a safe environment to perform such activities; providing group and provider support for the activities; and accountability to either a provider or coach. In addition, nutritional counseling will require supervision and follow-up to remain effective. This was demonstrated in the recent diabetes prevention trials 31,32 and has been shown in diabetes management. Current clinical evidence would suggest that modest weight loss (5% to 7% of current body weight) and an increase in physical activity of 100 to 150 minutes per week may be sufficient to provide metabolic benefit. At present, most healthcare insurance systems do not routinely provide financial coverage for lifestyle counseling or education for patients who do not have diabetes. Yet many patients with the insulin resistance syndrome will likely benefit significantly from education programs. Specific efforts to integrate educational and lifestyle interventions into the regular care of patients will be challenging but essential. Patients must be challenged to make every effort to establish these lifestyle changes. Doing so will not only limit the need for pharmacologic therapy but will S644 THE AMERICAN JOURNAL OF MANAGED CARE DECEMBER 2002

11 The Metabolic Syndrome, Type 2 Diabetes, and Cardiovascular Disease Figure 3. Proposed Treatment Approach to the Insulin Resistance Syndrome Insulin Resistance Syndrome Obesity (central) Dyslipidemia Hypertension Insulin resistance Glucose intolerance Established CVD Therapeutic Lifestyle Changes Weight management (5%-10% weight loss) Physical activity ( min/wk) Carbohydrate restriction Blood glucose monitoring ψ support Lipid Disorders TG HDL LDL Hypertension BP >130/80 Hyperglycemia Insulin resistance Fasting glucose >110 Additional Treatment Considerations Lipid Profile LDL <100 HDL >40 TG <150 Statin Fibrate Insulin sensitizers? Blood Pressure (every visit) Target BP <130/80 ACEI-based Rx Multidrug Rx Insulin sensitizers? Screening FPG (annual) Target = normal glucose tolerance Weight-loss activity? Metformin? Glitazones Background Therapy Aspirin ACEI Tobacco cessation Source: International Diabetes Center All rights reserved. Reprinted with permission. ACEI indicates angiotensin-converting enzyme inhibitor; BP, blood pressure; CVD, cardiovascular disease; FPG, fasting plasma glucose; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TG, triglyceride. also provide added value to any drug therapy employed. Glucose Control, Glycemic Control, and Cardiovascular Risk. Intensive glycemic control significantly reduces the risk for microvascular complications in patients with diagnosed diabetes. 28,29 However, the impact of intensive glucose lowering on CVD risk is, at present, unclear. Epidemiologic data support the assumption that lower blood glucose values will be associated with lower rates of CVD events and mortality and that maximal benefit will be achieved as glucose levels approach normal. 29 Which combination of glucose-lowering therapies will be of greatest benefit has not been determined, although some data support the use of metformin 28 and the insulin-sensitizing medications. 37 Long-term studies of glucose lowering and its impact on CVD risk will be essential in order to fully understand the role of intensive glycemic control in managing CVD. The benefit of intensive glycemic control has been demonstrated for patients hospitalized for treatment of an acute CVD event. 38 The Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial assessed the impact of early and aggressive glucose lowering by means of an insulin infusion on CVD risk and mortality. In this trial, intensive therapy using insulin infusion was associated with reductions in total mortality. 38 More recently, treatment of acutely ill nondiabetic patients with insulin infusion was shown to lower in-hospital mortality. 39 VOL. 8, NO. 20, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S645

12 REPORT Both studies suggest that intensive glucose lowering may indeed be necessary to limit CVD risk in the acute care setting. In contrast to those with diagnosed diabetes, patients with the insulin resistance syndrome often have only small elevations in plasma glucose. Data from several clinical studies confirm that even relatively modest changes in glucose tolerance may be associated with an increased risk for CVD As such, the goal of treatment for patients with the insulin resistance syndrome should be to maintain levels of blood glucose as near normal as possible, particularly in the acute care setting. Whether this will indeed reduce the risk of CVD will require data from additional long-term studies. Recent intervention trials have focused on the prevention of diabetes per se. In high-risk populations, such as those with impaired glucose tolerance or CVD, several interventions may retard the progression to frank type 2 diabetes. A number of studies have confirmed that lifestyle interventions such as those described above, including weight loss and physical activity, can significantly reduce the risk of type 2 diabetes in those with either IFG or IGT. 31,32 Whether such interventions will lower the risk of CVD complications is not known, but diabetes prevention can be anticipated to significantly limit the risk for microvascular complications. In the Diabetes Prevention Program, metformin therapy was also associated with a significant, albeit smaller, reduction in type 2 diabetes risk. 31 More recent data from Buchanan et al suggested that early treatment with the thiazolidinedione (TZD) troglitazone, when used in patients at higher risk for type 2 diabetes, reduced the risk of diabetes by more than 50% and limited rates of intimal medial thickening, a surrogate marker of CVD risk. 40 These findings suggest that such therapy has significant potential to limit CVD risk with therapies that both prevent diabetes and target insulin resistance. In addition, the potential benefit of sustained normoglycemia on future microvascular disease risk is obvious. Dyslipidemia. Interval measurement of plasma lipids is an essential part of CVD risk management in any patient at high risk for CVD. Lipid management must be considered a standard of care for patients with the insulin resistance syndrome. Early and aggressive use of statin therapy and judicious use of therapies for low HDL-C levels are interventions supported by clinical trial data. Alternative therapies may also be of considerable benefit in many patients. LDL-C treatment targets for high-risk patients, such as those with the metabolic syndrome or insulin resistance syndromes, should be less than 100 mg/dl. In the recent NCEP guidelines, management of HDL-C and triglyceride levels is also emphasized. 3 Lifestyle interventions are of significant benefit with increases in physical activity, reduction in dietary fat intake, and weight management all beneficial in raising HDL-C levels. Pharmacologic treatment should also be considered for any patient with HDL-C levels less than 40 mg/dl. This approach is supported by both epidemiologic data 41,42 and recent clinical trials. 43,44 In addition, specific therapy should be considered if triglyceride levels are greater than 150 mg/dl. LDL-C Levels. Based on data from numerous clinical trials, statin therapy should be considered in any insulin-resistant patient with established CVD to achieve LDL-C levels of less than 100 mg/dl. Such targets are also appropriate for any patient with either diabetes or the insulin resistance syndrome. In both secondary and primary prevention trials, statin treatment in patients with type 2 diabetes significantly reduced the risk of CVD Indeed, the benefit for patients with diabetes was often greater than in those without diabetes. Statin therapy administered even in those with normal LDL-C levels has been shown to further reduce CVD risk. 48 Whether statin therapy should be provided to all patients with diabetes and the insulin resistance syndrome remains to be determined. HDL-C and Triglyceride Levels. Despite significant benefits, decreasing LDL-C lev- S646 THE AMERICAN JOURNAL OF MANAGED CARE DECEMBER 2002

13 The Metabolic Syndrome, Type 2 Diabetes, and Cardiovascular Disease els does not address the most common lipid disorder present in individuals with the insulin resistance syndrome or type 2 diabetes. Recent clinical trials suggest that targeted treatment of low HDL-C levels is of significant benefit for patients with known CVD, type 2 diabetes, and evidence of insulin resistance. 43,44 The Veterans Affairs HDL Intervention Trial confirmed that use of gemfibrozil, a fibric acid derivative, in patients with evidence of heart disease and low HDL-C levels was associated with significant reductions in CVD risk. 43 The absolute risk reduction with fibrate therapy was approximately 4% to 5% in all patients and 8% in patients with diabetes. This absolute risk reduction is comparable to the 4% to 10% reduction in absolute risk of CVD in statintreated patients with modest elevations in LDL-C, such as those in the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) and Cholesterol and Recurrent Events (CARE) trials. 46 LDL-C reduction is also of established benefit in patients with low levels of HDL-C as demonstrated in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS) trial. 47 At present, which patients will benefit most from fibrate treatment for low HDL-C is not clear, either in lieu of or in combination with statin therapy for high LDL-C levels. Based on results of these studies, a growing number of patients are anticipated to actually benefit from combined treatment of both LDL-C and HDL-C disorders. Similarly, whether targeted treatment of HDL-C or triglyceride levels is of greater importance is not yet clear. At present, practitioners should consider the entire lipoprotein profile treating individual disorders with the understanding that indeed, the relative concentrations of HDL-C, LDL-C, and triglyceride levels are closely connected in patients with insulin resistance. Important treatment alternatives for patients with low HDL-C and high triglyceride levels include high-dose statin therapy, niacin, and the insulin-sensitizing medications. Niacin and the TZDs increase HDL-C levels by 20% or more. Niacin is associated with an increase in insulin resistance, although recent reports suggest that niacin can be used in patients with diabetes without significant negative impact on glucose control. 49 Because of the high incidence of mixed lipid disorders, multidrug therapy may be needed for many patients. Combination therapy with a statin-fibrate may be considered. However, such therapy is associated with an increased risk for drug-induced myositis. As such, these combinations should be considered only in those for whom subsequent risk for heart disease is considered high and the potential risks of therapy are outweighed by potential benefits. When using statin-fibrate combinations, lowerdose statin therapy is often preferred to limit the risk of myopathy. In addition, such therapeutic combinations should be avoided in patients with renal insufficiency or those on other drugs that may interfere with statin or fibrate metabolism, such as immunosuppressive drugs, macrolide antibiotics, and some antifungal medications. The potential benefit of such combination therapy is being further studied in the ongoing ACCORD trials. In selected patients, particularly those with the lowest levels of HDL-C, addition of insulin-sensitizing therapy or niacin may also be effective. Such therapy avoids the potential risk for myopathy from combined fibrate-statin use. Not surprisingly, therapies for insulin resistance may also improve lipid profiles in insulin-resistant patients. Both troglitazone and pioglitazone have been reported to significantly lower triglyceride levels, while all glitazones are known to increase HDL-C concentrations The specific mechanism by which these agents exert these unique effects is not currently known, but likely relates to the effect of these therapies on free fatty acid metabolism. 13 Both troglitazone and rosiglitazone have been associated with modest but significant increases in LDL-C levels while separate studies with pioglitazone demonstrate either no increase or increases that are comparable to those with placebo therapy. At present, glitazones are not indicated for the primary treatment of VOL. 8, NO. 20, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S647

14 REPORT lipid disorders. However, insulin-sensitizing agents may represent a clinically useful alternative in the management of patients with low HDL-C and high triglyceride levels in the setting of known glucose intolerance. Whether these agents will indeed provide sustained benefit on lipid levels requires additional study. Hypertension. As previously noted, hypertension is common in patients with either insulin resistance or type 2 diabetes. Regular blood pressure measurement is essential in the routine care of such patients. Blood pressure targets in these higher-risk patients are generally set at 130/80 mm Hg. Patients not achieving such targets should receive either nonpharmacologic or pharmacologic therapy to lower blood pressure readings. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends a blood pressure goal of less than 130/85 mm Hg. 53 Slightly lower targets (130/80 mm Hg) have been suggested by the ADA. Intensive treatment of blood pressure utilizing a wide variety of antihypertensive agents can reduce the risk for CVD in high-risk subjects. Treatment trials specifically in patients with diabetes have demonstrated a significant reduction in rates of both microvascular and macrovascular complications with intensive blood pressure management The use of nonpharmacologic interventions is again emphasized as first-line therapy and must include recommendations to increase physical activity, attempt prudent sodium restriction, and achieve even small degrees of weight loss. ACEIs are considered the preferred therapy for most patients with established CVD and should be considered as first-line therapy in any patient with diabetes or the insulin resistance syndrome ACEI therapy can reduce CVD risk to a greater degree than most other antihypertensive therapies. The Heart Outcomes Prevention Evaluation (HOPE) Trial demonstrated that even individuals with normal blood pressure but at high risk for CVD, such as those with diabetes and the insulin resistance syndrome, had fewer CVD events with the use of ramipril therapy. 57 From a practical perspective, ACEI therapy can and should be considered for any patient who has the insulin resistance syndrome with hypertension, renal disease or microalbuminuria, or a prior CVD event or established CVD, and in any patient with diabetes and evidence of microvascular complications. Both β-blockers 55 and angiotensin-2 receptor blockers have been shown to reduce CVD risk in patients with diabetes and should be considered appropriate alternatives to ACE-inhibitor therapy in these high-risk patients. 60,61 More aggressive treatment targets are likely to be appropriate in those with hypertension and the insulin resistance syndrome, just as they are for patients with diabetes. Such aggressive targets will often require the use of multidrug therapy. Because of the connection between insulin resistance and the development of hypertension, the potential for insulinsensitizing therapies to also lower blood pressure and improve other associated abnormalities of blood vessel behavior is not surprising. Treatment with glitazones has been shown to lower blood pressure, and the benefits of glitazone treatment on blood pressure appear to be greatest in those with baseline hypertension While the blood pressure reductions observed with glitazone therapy are often modest, these finding further support a central role for insulin resistance in the vascular disorders of diabetes and the insulin resistance syndrome. Thrombotic Risk. As noted above, acute thrombosis of a damaged vessel is now known to play a key role in triggering acute CVD events. These observations suggest that antiplatelet therapy has a critical role in patients with diabetes and insulin resistance. 66,67 Aspirin therapy is of recognized benefit. A dose of mg daily is currently recommended for all high-risk patients with diabetes who are older than 35 years of age. Similar abnormalities of platelet function and fibrinolysis are present in S648 THE AMERICAN JOURNAL OF MANAGED CARE DECEMBER 2002