Trends in Management of Type 2 Diabetes

INTRODUCTION Diabetes mellitus is a chronic disease that affects at least 16 million American adults [1]. The prevalence of diabetes continues to increase, from 4.9% in 1990 to 7.3% in 2000-a 49% increase over 10 years [2]. Interestingly, the largest increase in prevalence was noted in the 30- to 39-year-old age group. Type 2 diabetes is nearing epidemic proportions because there are an increased number of older Americans and a greater prevalence of obesity and sedentary lifestyles. Complications associated with type 2 diabetes cause profound morbidity and substantial mortality. Not surprisingly, diabetes is the sixth deadliest disease in the United States [3, 4], with approximately 450,000 deaths occurring in 1999 among adults with diabetes [5]. Type 2 diabetes is a significant risk factor for cardiovascular disease, and cardiovascular diseases represent the leading cause of death in patients with type 2 diabetes [6]. Microvascular complications, such as retinopathy, nephropathy, and neuropathy, can significantly impact patients' lives as well. Diabetic retinopathy is a major cause of adult blindness, and diabetes is the most common single cause of end-stage renal disease in the United States [7, 8]. Type 2 diabetes results from two defects: insulin resistance in multiple tissues, including liver and fat, and the inability to produce enough insulin to overcome this resistance [9]. Therapy for type 2 diabetes should address all aspects of both of the defects. During the past decade, treatment of patients with type 2 diabetes has been transformed because of new information about the pathogenesis of the disease, a better understanding of the complications, and the availability of several new classes of antidiabetic agents. In this supplement, we will review some landmark studies in patients with diabetes, discuss the role insulin resistance and other metabolic abnormalities play in the development and progression of type 2 diabetes and its complications, and outline currently available oral medications for the treatment of type 2 diabetes. Based on this information, we will describe our approach to the treatment of patients with type 2 diabetes with a focus on the exciting newer class of antidiabetic agents, the thiazolidinediones. IMPLICATIONS OF THE LANDMARK TRIALS OF TYPE 2 DIABETES During the past few decades, various observational, epidemiologic, and interventional trials have revealed valuable information about the risk of complications in patients with diabetes and the importance of glycemic control. Data collected during several decades from the Framingham Heart Study have shown that diabetes is a risk factor for all types of cardiovascular disease [10–12]. Furthermore, patients with diabetes are more likely to have coronary heart disease (CHD) and more likely to die from it than are individuals without diabetes [13]. Investigators have found that control of diabetes, measured by glycosylated hemoglobin A1c (HbA1c) levels, was the most important predictor of CHD [14] and that increased HbA1c was significantly associated with mortality from all [15]. The incidence and progression of microvascular complications associated with type 2 diabetes is strongly related to glycemic control. The prevalence of diabetic retinopathy, nephropathy, and neuropathy increase as HbA1c values increase [16–19]. Diabetes Control and Complications Trial The Diabetes Control and Complications Trial (DCCT) was a randomized, multicenter trial that examined the impact of intensive insulin treatment (with the goal of normalization of blood glucose) on the vascular and neurologic complications of type 1 diabetes [20]. Nearly 1,500 patients with type 1 diabetes were enrolled and treated with intensive insulin therapy (an external pump or at least three injections daily guided by frequent blood glucose monitoring) or conventional therapy with one or two insulin injections daily. Development and progression of retinopathy and other complications were evaluated at regular intervals for an average of 6.5 years. At the end of the study, the group treated with intensive insulin therapy had a significantly lower median HbA1c (7.2%) than the conventional-therapy group (9.1%; P<0.001). Intensive insulin therapy reduced the risk for development of retinopathy by 76%, slowed the progression of retinopathy by 54%, and reduced the occurrence of microalbuminuria by 39% and that of clinical neuropathy by 60%. Clearly, glycemic control strongly influenced the development of diabetic complications in patients with type 1 diabetes. Kumamoto Study The Kumamoto Study assessed the impact of intensive insulin treatment on the microvascular complications of type 2 diabetes in patients who had diabetes for 6 to 10 years before entry into the trial [21, 22]. A total of 110 patients were randomized to conventional insulin therapy, or to more intensive multiple insulin-injection therapy, and thereafter were assessed every 6 months for a total of 8 years of ongoing follow-up. Similar to patients in the DCCT, which studied type 1 diabetes, patients in the Kumamoto Study who received intensive insulin therapy had better glycemic control (HbA1c = 7.1%) than those in the conventional-treatment group (HbA1c = 9.4%). Improved glycemic control reduced the risk of development or progression of retinopathy by 75% and that of microalbuminuria by 62%. The glycemic threshold for prevention of onset or progression of microvascular complications was associated with an HbA1c of less than 6.5% [22]. Data from this study and from the DCCT demonstrate that intensive glycemic control to near normoglycemia in patients with type 1 or type 2 diabetes reduces the risk of microvascular complications. United Kingdom Prospective Diabetes Study The United Kingdom Prospective Diabetes Study (UKPDS) is one of the most important studies conducted in patients with type 2 diabetes [23–26]. The UKPDS was designed to determine whether pharmacologic therapy for type 2 diabetes reduces the risk of complications, and specifically, whether sulfonylurea, metformin, or insulin has specific advantages or disadvantages. A substudy was added after the investigators realized that the patients with hypertension diagnosed before entry into the study had increased morbidity and mortality. The substudy was designed to address the question of whether tight blood pressure control reduces the risk of complications, and whether use of an angiotensin-converting enzyme (ACE) inhibitor or β-blocker offers particular therapeutic advantages or disadvantages. From 1977 to 1991, 5,102 individuals with newly diagnosed type 2 diabetes were enrolled into the UKPDS. After a 3-month dietary run-in, patients were randomly assigned to intensive treatment with insulin (N = 1,156), or (N = or to conventional dietary treatment (N = who were had the to randomly assigned to treatment with (N = of the United Kingdom Prospective Diabetes = with from Prospective Diabetes Study (UKPDS) Intensive control with or insulin with conventional treatment and risk of complications in patients with type 2 diabetes the 10 intensive treatment lower HbA1c values more than conventional treatment the risk of microvascular complications was significantly reduced by in the group with the conventional group in there was a in vascular disease, a in microvascular disease, and a in In of cardiovascular end there was a risk in and Data are collected for an years to whether glycemic control will significantly complications of the of HbA1c to the occurrence of end a such that in the HbA1c was in the there was threshold for this in that the therapeutic glycemic goal should a HbA1c in the as that for individuals without diabetes. few individuals were to HbA1c in or near the for complications in patients with type 2 diabetes who received intensive treatment conventional results of the United Kingdom Prospective Diabetes = the patients were assigned to intensive treatment with and were with patients who conventional treatment During the 10 years of the median HbA1c was in the group and in the conventional group. Interestingly, the group had a 39% lower risk of than the conventional-treatment group. The patients treated with had significant risk for end death and mortality with the conventional group. The UKPDS found that tight control of with use of or significantly reduced the risk of diabetic complications with less tight control of assigned to the tight control group had a significant in microvascular complications in end and in mortality related to diabetes Similar to the glycemic on the risk of end blood pressure into the the occurrence of end the UKPDS that treatment of diabetes can the morbidity and mortality of the disease by its chronic complications, and that metabolic control is Diabetes A randomized, clinical trial was conducted by the Diabetes adults in the United States who were at risk for the development of type 2 diabetes had and glucose A total of individuals were randomized to or a which had as at least a and at least of were for an average of years and evaluated for the development of type 2 diabetes. 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The use of insulin one of the associated with type 2 diabetes, and the of the and of patients with type 2 diabetes will the progression of disease, the development of diabetic complications, and clinical