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Evidence-Based Diabetes Management March/April
The Controversial Question of Metabolic Syndrome
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Brice Labruzzo Mohundro, PharmD, BCACP
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Targeting Insulin Resistance: The Ongoing Paradigm Shift in Diabetes Prevention
Tara Dall, MD; Dawn Thiselton, PhD; and Stephen Varvel, PhD
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Kim Farina, PhD
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Teresa L. Pearson, MS, RN, CDE
Measuring the Value of Better Diabetes Management
Darius N. Lakdawalla, PhD; Michael R. Eber, BSE; Felicia M. Forma, BSc; Jeffrey Sullivan, MS; Pierre-Carl Michaud, PhD; Lily A. Bradley, MBA; and Dana P. Goldman, PhD

Targeting Insulin Resistance: The Ongoing Paradigm Shift in Diabetes Prevention

Tara Dall, MD; Dawn Thiselton, PhD; and Stephen Varvel, PhD
The Cardiometabolic Epidemic Prevalence of diabetes has reached epidemic proportions, affecting over 25 million people in the United States alone. In 2010, 8.3% of adult Americans had diagnosed diabetes, 3.5% had undiagnosed diabetes, and 38.2% had prediabetes.1 What’s more, the situation appears to be   getting worse—with the annual rate of new cases more than tripling over the past 20 years (Figure), the Centers for Disease Control and Prevention estimates   that as many as 1 in 3 individuals will develop diabetes by 2050 if current trends continue.2 The dramatic increase in diabetes prevalence over time has    paralleled the increase in prevalence of overweight and obesity.1 On the basis of National Health and Nutrition Examination Survey 2003-2006 data, about  one-third of men and women have metabolic syndrome (MetS), a cluster of major cardiovascular risk factors related to overweight/obesity and insulin resistance.1

Heart disease and stroke are serious complications of diabetes. Although death rates for heart attack and stroke have been decreasing, adults with diabetes are  still twice as likely to die from these diseases as people who do not have diabetes.2,3 Vascular complications are responsible for the bulk of the costs, and are  the main cause of suffering and death, for patients with diabetes. Key studies such as the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study have established beyond question that better blood glucose control can dramatically reduce these complications in  diabetic patients.4,5 However, the chronic vascular disease and inflammation that leads to such devastating complications begins years before the hyperglycemic  threshold necessary for diabetes to be diagnosed. Here, the root of the damage lies in insulin resistance— often a result of obesity and inactivity—characterized  by impaired tissue responsiveness to the metabolic effects of insulin in the liver, skeletal muscle, and adipose tissue. Insulin resistance can, for a while, be  tolerated by increased production of insulin from the pancreas, while putting the pancreatic beta cells under considerable strain in the process. Insulin resistance alone, aside from predisposing to diabetes, is associated with early cardiovascular mortality, renal dysfunction, deterioration of the retina, and neuropathy.6 In fact, the importance of obesity as a risk factor for heart disease is related to its promotion of the insulin-resistant state. Furthermore, people with MetS have a 2-fold increased risk of cardiovascular outcomes and a 1.5-fold increased risk of death.7

Prediabetes affects more than 87 million US adults (38%) aged 20 years or over, with a lifetime risk for conversion to diabetes of 30% to 50%.1,8 By the time prediabetes has developed, untreated patients are at very high risk of developing full-blown diabetes, with even higher risk of cardiovascular events,  complications, and death. Lastly, 20% to 30% of adults in the general population in Western countries have non-alcoholic fatty liver disease (NAFLD), a condition associated with insulin resistance that confers increased risk for fibrosis and cirrhosis of the liver, liver cancer, and heart disease, with prevalence as  high as 70% to 90% of people who are obese or who have diabetes.9,10

The healthcare costs associated with diabetes are staggering: the American Diabetes Association (ADA) estimates that managing diabetes for just 1 year costs an average of $6649 per person, though costs can climb much higher when complications occur, and type 2 diabetes is projected to cost $500 billion a  year by 2020.11,12 Moreover, over the last decade, the cost of cardiovascular disease (including hypertension, heart failure, and stroke) has accounted for ~15% of increased medical spending and has increased at an average rate of 6% annually.1 Individuals with MetS experience about $2000 greater  healthcare expenditures annually and have higher utilization of inpatient, primary care, other outpatient, and pharmacy services than persons without MetS  factors, even over the short time frame of 2 years.13 Healthcare costs for patients with NAFLD have also been shown to be 26% higher, at 5-year follow-up,  than costs for patients without the disease.14

Insulin Resistance as a Therapeutic Target

Part of the reason why our medical system has failed to stem this tide has been the fact that current approaches diagnose diabetes too late—by the time frank diabetes is evident, 80% of beta cell function has already been lost.15,16 However, a paradigm shift is under way, changing the way we think of the disease. We now know that diabetes is the final stage of a long pathogenic process that starts with insulin resistance and increased strain on pancreatic beta  cells, progressing to an impaired ability to control blood sugar (ie, prediabetes), and only develops into fullblown diabetes once pancreatic beta cell death  has reached a point where natural insulin can no longer control fluctuations in blood glucose. At this point, extensive (and costly) efforts are directed toward  managing the disease and minimizing occurrence of micro- and macrovascular complications.Just as the fight against heart disease has been revolutionized by recognizing that heart attacks and strokes are the end result of atherosclerotic disease that has progressed over many years (hence the  logical necessity for early prevention of atherosclerosis with medical treatment and lifestyle changes), the battle against diabetes will only be won when we  ecognize that the disease we need to identify and aggressively treat is insulin resistance. Diabetes is the end stage to be prevented, not the jumping-on point for our medical system.

New Tools to Diagnose

The first step in preventing diabetes is identifying who is at greatest risk, and therefore most in need of aggressive lifestyle intervention and perhaps medical treatment. Several traditional risk factors such as age, sex, body mass index, blood pressure, and family history have long been understood to be related to  diabetes risk. Validation of various risk models has shown that the predictive value can be enhanced with biochemical measures, most often fasting glucose or glycated hemoglobin (A1C).17 However, traditional fasting blood measures alone will miss a substantial proportion of the prediabetic population who  have become so due to a dysregulated ability to control spikes in blood glucose after a meal (impaired glucose tolerance). A significant step forward was  made when the ADA specified diagnostic criteria for prediabetes that included impaired glucose tolerance (IGT), defined as a 2-hour post-load glucose level  uring an oral glucose tolerance test (OGTT) of 140 to 200 mg/dL, along with fasting glucose levels of 100 to 125 mg/dL (impaired fasting glucose) or  A1C level of 5.7% to 6.4%.

Blood tests for fasting levels of A1C and glucose are easy, cheap, and often performed as point-of-care tests. Unfortunately, the OGTT is often impractical in  the clinical setting and so, too often, IGT goes undiagnosed. Furthermore, these criteria only identify prediabetes once the underlying insulin resistance and  beta cell strain have progressed to the point of being unable to adequately control blood glucose levels. Thus, there is a great need for simple diagnostic tests that can identify early signs of insulin resistance and IGT from fasting blood samples, while remaining sufficiently cost-effective to be employed in the large at-risk population.

Fortunately, as our understanding of the pathophysiology of cardiometabolic risk has advanced, a variety of biomarkers have been identified with potential clinical utility in detecting early signs of insulin resistance (eg, characteristic changes in lipoprotein metabolism).18 Increases in total and small low-density  lipoprotein (LDL) particles, large very lowdensity lipoprotein (VLDL) particles, and average VLDL size, along with decreases in average LDL particle size, high-density lipoprotein (HDL) particles, and average HDL size have been associated with glucose clearance in the “gold standard” measure of insulin  resistance, the hyperinsulinemic clamp procedure, and also with incident diabetes in the Insulin Resistance Atherosclerosis Study.19,20 Increases in fasting  serum free fatty acid levels are known to be involved at an early stage of the disease process.21,22 Importantly, indicators of adipose tissue dysfunction, such  as increased release of leptin (which may indicate leptin resistance) or decreased release of adiponectin, have been shown to precede development of  diabetes in many individuals. 23,24 Furthermore, novel biomarkers such as alpha-hydroxybutyrate and linoleoyl-glycerophosphocholine have recently been  discovered via metabolic profiling to be independently associated with insulin resistance and predictive of progression from normal glycemia to prediabetes.25,26 While additional trials are necessary to fully validate these and other novel markers, these tools are increasingly available now to  clinicians who understand the importance of early detection.

New Approaches to Treatment

Alongside our growing understanding of how to identify early signs of insulin resistance has been development of new treatment options, and a burgeoning  sophistication in how to direct optimal treatment and lifestyle advice at the personal level based on ndividual biomarker profile. Recent ADA treatment  recommendations support this approach.27 Lifestyle recommendations form the cornerstone of diabetes prevention efforts (eg, reduced intake of  carbohydrates [especially refined ones] and increased daily activity). Several large trials have demonstrated that intensive lifestyle interventions consisting of  programs directed at weight loss (7% reduction from baseline) and exercise (150 min/ week) are remarkably effective in preventing diabetes in those at  high risk, reducing 3-year diabetes incidence by over 50%.28-32 Often, insulin sensitizers and weight loss through diet and exercise will improve key components of MetS.33 NAFLD can also be reversed with changes in dietary habits aimed at modest weight loss (approximately 10% of initial weight) and blood pressure regulation, with a consequent decrease in insulin resistance.34,35

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