Targeting Insulin Resistance: The Ongoing Paradigm Shift in Diabetes Prevention

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

To date, there are no medications with US Food and Drug Administration indication for use in prediabetes. There are, however, clinical trials showing safety and benefit of several classes of antidiabetic therapies in the setting of prediabetes and insulin resistance. Metformin has long been the frontline medical treatment for diabetes, and has been shown repeatedly to slow or prevent progression to diabetes in prediabetics by enhancing insulin sensitivity. ^36,37 Quick-release bromocriptine, a newly approved antidiabetic therapy with unique mechanism of action (a dopamine agonist), may also be effec tive in the setting of insulin resistance and prediabetes, as it helps correct the dyslipidemia, postprandial hyperglycemia, elevated free fatty acids, and effects due to increase in sympathetic tone.^38,39 Thiazolidinediones (TZDs) have proved to be very effective insulin sensitizers, and several large trials have shown reductions in progression from prediabetes to diabetes of 62% to 72%.^40,41 Further, GLP-1 agonists, DPP-4 inhibitors, or quick-release bromocriptine may be indicated when signs of beta cell stain are present.^42,43 Importantly, these medications can be safely used in prediabetes, as they do not cause hypoglycemia. While more randomized clinical trial data are needed before guidelines can be established, physicians are already using biomarker profiles to guide treatment approaches and are experiencing impressive success not only in preventing progression to diabetes but in actually reversing the underlying pathology. For example, a recent report described an approach that assigned patients in clinical practice to treatment with either metformin + pioglitazone or metformin + pioglitazone + exenatide based on indices of underlying insulin resistance and beta cell function. This approach sucdiabetes cessfully reverted more than 50% of prediabetics back to normal glycemic status.⁴⁴

Return on Investment

Not only does a focus on detection and therapeutic correction of insulin resistance hold the promise of reducing diabetes incidence and the devastating

impact this has on people’s lives, but it could also have a huge impact on efforts to reduce overall health expenditures. A recent analysis of the potential for cost savings estimates that reducing diabetes and hypertension prevalence by just 5% would result in annual savings of approximately $9 billion in the short term and up to $25 billion in the medium term.⁴⁵ The ADA recommends that such diabetes prevention programs be covered by third-party payers due to the potential cost savings. ⁴⁶

The largest diabetes prevention trial in the United States, the DPP, has shown that intensive lifestyle interventions or metformin treatment were cost-effective or cost saving during the 3-year intervention⁴⁷ and after 10 years of follow-up.⁴⁸ Further, economic modeling has suggested that when glycemic control is not achieved solely with lifestyle or metformin monotherapy, combination with a TZD is also costeffective. ^49,50 Cost analysis of individual A1C cutoffs suggests that the high-cost interventions used in the DPP should be cost-effective down to the current lower limit of prediabetes (A1C = 5.7%), and that intervening at even lower A1C values could also be cost-effective if the cost of the intervention were lowered.⁵¹ By diagnosing the early signs of insulin resistance, those who are not yet technically prediabetic but would still benefit from intervention (ie, are most likely to progress to diabetes) can be identified and treated appropriately. As our interventions become more efficient and effective, the large population of high-risk patients currently being missed can be identified and treated cost-effectively.

Conclusion

In order to achieve a better return on prevention efforts, 3 things must happen. First, patient screening must improve in order to better identify those at risk. Key to this is recognizing that the target is insulin resistance. Second, interventions must be more effective at not only slowing disease progression but in reversing disease itself—restoring normal insulin sensitivity and protecting against beta cell death. This will be achieved in part by recognizing that diabetes is a multifaceted disease and interventions should be tailored to the individual based on their particular underlying pathophysiology. Finally, only when a full cardiometabolic risk profile is evaluated on an individual basis can the most effective and efficient steps be taken to prevent diabetes and cardiovascular disease and promote future health in the population at large. EBDMAuthor Affiliation: From Advanced Lipidology (TD), Delafield, WI; Health Diagnostic Laboratory (HDL), Inc (DT, SV), Richmond, VA.

Funding Source: None.

Author Disclosures: Dr Dall reports employment with HDL, Inc, and has received invitations from a commercial sponsor, Santaris, to lecture. Drs Thiselton and Varvel report employment with Health Diagnostic Laboratory, Inc, which performs diagnostic testing of diabetes risk factors.

Authorship Information: Concept and design (DT, SV); acquisition of data (TD); analysis and interpretation of data (TD); drafting of the manuscript (TD, DT, SV); critical revision of the manuscript for important intellectual content (TD, DT, SV); provision of study materials or patients (TD); and administrative, technical, or logistic support (DT).

Address correspondence to: Stephen Varvel, PhD, Director of Clinical Trials, Health Diagnostic Laboratory, Inc, 737 N 5th St, Ste 103, Richmond, VA 23219. Email: svarvel@hdlabinc.com.References

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