Barry J. Goldstein, MD, PhD
The Growing Epidemic of Type 2 Diabetes
Type 2 diabetes mellitus is a progressive metabolic disease that is becoming increasingly common in the United States. The number of Americans with type 2 diabetes more than doubled from 1980 to 2004.[1] According to the American Diabetes Association (ADA), approximately 20.8 million children and adults in the United States — 7% of the population — have diabetes. Although an estimated 14.6 million people have been diagnosed with diabetes, approximately 6.2 million are unaware that they have the disease.[2] The potential causes of this growing epidemic include an aging population, lifestyle changes, limited physical activity, obesity, and high caloric intake. Type 2 diabetes is a costly healthcare burden and a major cause of morbidity and mortality. In terms of medical expenditures and lost productivity, the cost of type 2 diabetes was estimated to be about $132 billion in 2002.[3]
Insulin resistance accounts for more than 90% of all type 2 diabetes cases.[4] The National Health and Nutrition Examination Survey (NHANES) estimated that one third of the US population between the ages of 40 and 74 years is insulin-resistant.[5] Insulin resistance is at the core of the pathogenesis of the metabolic syndrome and leads not only to insulin-stimulated glucose uptake with glucose intolerance or frank diabetes, but also to high triglycerides, low high-density lipoprotein cholesterol (HDL-C), high blood pressure, and increased cardiovascular risk.[6] Elevated blood glucose levels are diagnostic of type 2 diabetes. Clinical studies have demonstrated that diabetes itself is one of the major risk factors for coronary heart disease and micro- and macrovascular complications.[7-9]
Obesity, a growing epidemic in both adults and children, is a metabolic abnormality that is highly associated with the development of type 2 diabetes. The NHANES data indicated that the prevalence of obesity is also on the rise. In 2003 and 2004, 17.1% of US children and adolescents were overweight.[10] These data indicated that the age-adjusted prevalence of overweight and obesity among adults has increased from a level of 23% in NHANES III to a new level of approximately 32%.[11] These high incidences of overweight among children and obesity among adults remain a major public health concern, because they can lead to subsequent type 2 diabetes and cardiovascular disease. A recent study showed that individuals with onset of diabetes in youth (especially at younger than 20 years of age) had a 3-fold higher death rate than nondiabetic participants, compared with a 1.4-fold increased rate in individuals with onset of diabetes occurring at an older age.[12]
Pathophysiology of Type 2 Diabetes: A Dual-Defect Disease
Type 2 diabetes is a dual-defect disease characterized by insulin resistance and impaired beta-cell function. Glucose derived from dietary carbohydrate and hepatic glucose production is tightly regulated by insulin. Type 2 diabetes results from an imbalance between insulin sensitivity and insulin secretion.[13] In the diabetic condition, glucose production fails to be adequately regulated by insulin, leading to hepatic glucose overproduction and diminished glucose uptake by muscle tissue. In addition, accelerated gastric emptying and excessive lipolysis in adipose tissue also contribute to developing type 2 diabetes.[13] Over time, pancreatic beta cells fail to maintain their high rate of insulin secretion, leading to glucose intolerance, insulin resistance, and overt type 2 diabetes.[13] Various clinical syndromes are associated with insulin resistance, including obesity, type 2 diabetes, cardiovascular disease, essential hypertension, polycystic ovary syndrome, nonalcoholic fatty liver disease, certain types of cancer, and sleep apnea.
Treatment Goals and Options for Type 2 Diabetes
Glycemic control remains fundamental to treating diabetes. The UK Prospective Diabetes Study (UKPDS) demonstrated that intensive glycemic control with antidiabetes drugs reduces microvascular complications.[8] The availability of sensitive and inexpensive home glucose monitors has made it possible for patients with type 2 diabetes to monitor long-term glycemic control. Diabetes treatment guidelines recommend vigorously lowering glucose levels to attain near-normal glycemia in order to reduce micro- and macrovascular complications. The most recent recommendations of the ADA suggest that although the glycated hemoglobin (A1C) goal for patients with all forms of diabetes is < 7%, the goal for an individual patient is an A1C as close to normal (< 6%) as possible, because this level can be safely achieved without significant hypoglycemia.[14] The American College of Endocrinology recommends a similar A1C goal of ≤ 6.5%.[15,16]
Patients with type 2 diabetes have various treatment options available to control their glucose levels. In addition to therapeutic lifestyle changes that include diet and exercise, several classes of medications with different mechanisms of action are currently available. Advances in our understanding of the pathophysiology of diabetes, identification of the targets of antidiabetes medications, and pivotal clinical trials have all contributed to the development of antidiabetes treatment strategies — both monotherapy and combination therapy.[17-20]
The goal of pharmacotherapy is to control hyperglycemia and delay the comorbidities that are associated with diabetes. For type 2 diabetes, drugs that increase circulating insulin levels or decrease insulin resistance are used. Important considerations include the additional effects of medications on biomarkers of cardiovascular risk, and safety and tolerability issues. The following drugs effectively control glucose levels by differing mechanisms of action.[21]
Sulfonylureas: Sulfonylureas (glipizide, glyburide, glimepiride) reduce glucose levels by stimulating insulin release from the pancreas. However, they tend to cause hypoglycemia and can become less effective over time.[22]
Meglitinides: Meglitinides (nateglinide, repaglinide) are insulin secretagogues and act by stimulating insulin release from the pancreas. They have a short half-life and restore insulin levels following meals. However, compliance is an issue because they must be taken 3 times a day with main meals.
Biguanide: Biguanide (metformin) primarily acts by inhibiting hepatic glucose production and controlling glucose levels. Although it tends to cause less weight gain, gastrointestinal side effects may be significant. Additionally, this agent may not be effective in the long-term control of this chronic disease state.
Alpha-glucosidase inhibitors: Alpha-glucosidase inhibitors (acarbose, miglitol) delay the postprandial digestion of complex carbohydrates and thus inhibit postprandial hyperglycemia. These agents are associated with severe gastrointestinal side effects and are limited by their relatively weak efficacy in lowering A1C levels.
Thiazolidinediones (TZDs): TZDs (rosiglitazone, pioglitazone) bind and activate peroxisome proliferator-activating receptor-gamma, thereby improving insulin sensitivity and reducing hepatic glucose levels. Additionally, these agents have been shown to improve estimates of beta-cell function and provide sustained glycemic control. Unlike sulfonylureas, TZDs do not cause hypoglycemia or stimulate insulin release. However, TZDs may cause fluid retention and weight gain.
Combinations: A variety of combination therapies are used to treat type 2 diabetes with 2 agents with complementary mechanisms of action. Many of these combinations have demonstrated clinical success by improving glycemic control to recommended goals while offering better tolerability profiles, in many cases due to a reduced dose of 1 or both agents. Sulfonylureas have been used in combination with insulin-sensitizing medications, including metformin and TZDs, and have demonstrated significantly improved glycemic control.[8,23] TZDs, such as rosiglitazone and pioglitazone, in combination with metformin have been shown to improve glycemic control, insulin sensitivity, and beta-cell function.[24,25]
Insulin: Insulin is required for the management of type 1 diabetes and in many patients at the more advanced stages of type 2 diabetes. Insulin is administered in long-acting (basal), short-acting (mealtime), and premix (long- and short-acting) formulations. Relatively peakless long-acting recombinant insulin analogs have been helpful in restoring basal insulin needs (glargine, detemir). New forms of rapid-acting insulin — called insulin analogs (lispro, aspart, glulisine) — have a faster onset and shorter duration of action than regular insulin. They are used to lower mealtime glucose excursions. Inhaled insulin, which only contains rapid-acting human insulin, is also available. This is also used for mealtime glucose control and is taken before a meal.
Incretin mimetics and dipeptidyl peptidase (DPP)-IV inhibitors: Incretins, including glucagon-like peptide (GLP)-1, are hormones secreted in the gut in response to the absorption of glucose and they have multiple glycoregulatory actions. GLP-1 levels are reduced in patients with type 2 diabetes. Exenatide, an agent that mimics the effects of naturally occurring GLP-1, has been proven effective in improving glucose control by restoring the impaired glucose-dependent insulin secretion by the islet beta cells and suppressing islet alpha-cell glucagon secretion, 2 effects that contribute to hyperglycemia in diabetes. Exenatide also slows gastric emptying, leading to a better match between food absorption and insulin secretion, which leads to improved postprandial glucose control. Exenatide administration is associated with moderate weight reduction. Side effects include nausea, especially during the first week or two of use. The drug is administered via injection twice daily, and it is costly. Longer-acting GLP-1 agonists are in development and may provide an improvement over exenatide because they would only need to be injected once daily or weekly.
Another approach to enhance the action of GLP-1 in the body, currently under US Food and Drug Administration (FDA) review, is via the DPP-IV inhibitors. DPP-IV is the enzyme responsible for the degradation of GLP-1 in the bloodstream, and blocking the action of DPP-IV significantly prolongs the blood levels of this incretin. Levels of another incretin, glucose-dependent insulinotropic polypeptide, are also enhanced when DPP-IV is inhibited. Two new oral medications, vildagliptin and sitagliptin, have shown similar glycemic benefits as exenatide via beta-cell-stimulated insulin secretion, islet alpha-cell glucagon suppression, and slowing of gastric emptying. Unfortunately, these agents have not shown a significant effect on weight reduction.
What Does the Future Hold?
Perhaps the most important goal in the management of diabetes is preventing long-term complications. One approach is the primary prevention of diabetes altogether. To that end, a number of prevention studies have shown that oral antidiabetic agents or lifestyle interventions can significantly reduce the progression of impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) to overt diabetes. Other studies have shown reduced primary or secondary cardiovascular events in patients with type 2 diabetes who were using various interventions, including statins, antihypertensives, and TZDs.[26] In patients with established cardiovascular disease, pioglitazone showed some improvement of secondary cardiovascular endpoints in the Prospective Pioglitazone Clinical Trial In Macrovascular Events Study, but outcomes data in patients treated at earlier stages of the development of atherosclerosis are lacking. Due to increasing evidence that the prevention of diabetes and its complications may ultimately be a therapeutic possibility, several large-scale studies are under way that will help establish the best clinical approach to this goal. Clinical outcomes include the impact of intensive glycemic control on progression to diabetes, the benefits of early intervention, reduction of cardiovascular complications, and the improvement of beta-cell function.
The Diabetes Reduction with Ramipril and Rosiglitazone Medication (DREAM) study is designed to determine whether rosiglitazone and/or ramipril can delay or prevent the development of type 2 diabetes in those who have IGT and/or IFG who are at high risk of developing diabetes.[27] The Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study is assessing the effect of valsartan and short-acting nateglinide in prediabetes patients.[28] The Actos Now for Prevention of Diabetes (ACT NOW) trial is evaluating the effect of pioglitazone in subjects with IGT and metabolic syndrome for improvement in insulin sensitivity, beta-cell function, body composition, and cardiovascular risk factors.[29] The A Diabetes Outcome Progression Trial (ADOPT) is designed to provide data on the differentiating effects of rosiglitazone, glyburide, and metformin on glycemic control, beta-cell function, and macrovascular disease risk.[30] These large-scale clinical trials may have a significant impact when their findings are reported over the next several years.
Conclusions
Type 2 diabetes is a major health problem in the United States. Consequently, the incidence of diabetes complications and cardiovascular diseases is also increasing and has a negative impact on public health and the economy. Therefore, it is important to control the growing epidemic of type 2 diabetes. Younger people are especially at risk for the long-term complications of diabetes when they acquire the disease at an early age. Glycemic control is one of the most important risk factors to contain the progression of type 2 diabetes and its associated microvascular complications, and glucose itself is likely to play a key role in macrovascular disease as well. In addition to therapeutic lifestyle changes, several pharmacologic options are available for the treatment of type 2 diabetes. Antidiabetes drugs effectively control glucose levels. Intensive glycemic control may be shown to help delay the progression of type 2 diabetes as well as to offer additional benefits, such as improved beta-cell function. Ultimately, we anticipate that type 2 diabetes and its complications will be effectively managed with a comprehensive treatment strategy that includes therapeutic lifestyle modifications and pharmacologic therapy aimed at glycemic control as well as reduction in cardiovascular risk.
