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00019616-200305001-00001Miscellaneous-ArticleThe EndocrinologistThe Endocrinologist© 2003 Lippincott Williams & Wilkins, Inc.13May 2003 p S1–S21Trends in Management of Type 2 DiabetesRole of ThiazolidinedionesSupplementWyne, Kathleen L. MD, PHD; Bell, David S.H. MB, FACE, FACP; Braunstein, Seth MD, PHD; Drexler, Andrew J. MD; Miller, Jeffrey L. MD, FACP, FACE; Nuckolls, James G. MD, FACPAddress correspondence and reprint requests to: Kathleen L. Wyne, MD, PhD, Assistant Professor, Division of Endocrinology and Metabolism, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Rm J6-110B, Dallas, TX 75390-8857. Tel: 214-648-3494; Fax: 214-648-8917; E-mail: [email protected] 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 DIABETESDuring 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 TrialThe 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 StudyThe 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 StudyThe 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), sulfonylurea (chlorpropamide, glyburide, or glipizide) (N = 1,573), or to conventional dietary treatment (N = 1,138) (Fig. 1). Patients who were overweight also had the opportunity to be randomly assigned to treatment with metformin (N = 342).JOURNAL/endst/04.03/00019616-200305001-00001/figure1-1/v/2021-02-17T201712Z/r/image-jpeg Design of the United Kingdom Prospective Diabetes Study: primary randomization. FPG = fasting plasma glucose. Reprinted with permission from UK Prospective Diabetes Study [23] (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837-53.During the first 10 years, not only did intensive treatment lower HbA1c values more than conventional treatment (7.0% vs 7.9%; P<0.0001), but the risk of microvascular complications was significantly reduced by 25% in the intensive-treatment group compared with the conventional group (P=0.0099) (Fig. 2). For each 1% decrease in HbA1c, there was a 43% reduction in peripheral vascular disease, a 37% decrease in microvascular disease, and a 12% reduction in stroke [27]. In terms of cardiovascular end points, there was a 14% risk reduction in nonfatal and fatal myocardial infarctions. Data are being collected for an additional 5 years to establish whether improved glycemic control will significantly reduce macrovascular complications [23]. Analysis of the relationship of HbA1c to the occurrence of any diabetes-related end point showed a linear decrease such that maximal decrease in events occurred when the HbA1c was in the normal range. Notably, there was no threshold for this decrease in events, suggesting that the therapeutic glycemic goal should be a normal HbA1c in the same range as that for individuals without diabetes. However, very few individuals were able to maintain HbA1c in or near the normal range.JOURNAL/endst/04.03/00019616-200305001-00001/figure2-1/v/2021-02-17T201712Z/r/image-jpeg Risk reduction for complications in patients with type 2 diabetes who received intensive treatment versus conventional treatment: results of the United Kingdom Prospective Diabetes Study. [23] MI = myocardial infarction.In the UKPDS, 342 overweight patients were assigned to intensive treatment with metformin and were compared with 411 overweight patients who followed conventional treatment [24]. During the 10 years of follow-up, the median HbA1c was 7.4% in the metformin group and 8.0% in the conventional group. Interestingly, the metformin group had a 39% lower risk (P=0.010) of myocardial infarction than the conventional-treatment group. The patients treated with metformin also had significant risk reductions for any diabetes-related end point (32%; P=0.002), diabetes-related death (42%; P=0.017), and allcause mortality (36%; P=0.011) compared with the conventional group.The UKPDS also found that tight blood-pressure control (goal of <150/85 mm Hg) with use of captopril or atenolol significantly reduced the risk of certain diabetic complications compared with less tight control (goal of 180/105 mm Hg) [25]. Patients assigned to the tight control group had a significant reduction in microvascular complications (P=0.0092), reduction in any diabetes-related end point (P=0.0046), and decrease in mortality related to diabetes (P=0.019). Similar to the glycemic effect on the risk of any diabetes-related end point, decreasing systolic blood pressure into the normal range maximally decreased the occurrence of diabetes-related end points. Overall, the UKPDS established that aggressive treatment of diabetes can decrease the morbidity and mortality of the disease by decreasing its chronic complications, and proved that metabolic control is valuable.Diabetes Prevention ProgramA large, randomized, clinical trial was conducted by the Diabetes Prevention Program Research Group [28] enrolling adults in the United States who were at high risk for the development of type 2 diabetes (i.e., they had elevated fasting and postload plasma glucose concentrations). A total of 3,234 nondiabetic individuals were randomized to placebo, metformin 850 mg twice daily, or a lifestylemodification plan, which had as goals at least a 7% weight loss and at least 150 minutes of physical activity per week. Participants were followed for an average of 2.8 years (range, 1.8-4.6 years) and evaluated for the development of type 2 diabetes. The incidence of diabetes in the lifestyleintervention group was reduced by 58%, and metformin reduced the incidence of diabetes by 31% compared with placebo. The beneficial effect of lifestyle intervention, which may improve insulin sensitivity, was seen in men and women, in all racial and ethnic groups, and in participants both young and old.Troglitazone in the Prevention of DiabetesTreatment with thiazolidinediones also may prevent the development of type 2 diabetes in high-risk patients. In the Troglitazone in the Prevention of Diabetes (TRIPOD) study, women who had a history of gestational diabetes were randomized to treatment with troglitazone or placebo within 4 years of completion of their pregnancy [29]. After a mean follow-up of 30 months, the annual incidence of diabetes was 12.1% in the placebo group and 5.4% in the troglitazone-treated group; onset of diabetes was reduced by 56% in troglitazone-treated patients. Notably, the women treated with troglitazone experienced a reduction in endogenous insulin production that was associated with decreased insulin resistance and preservation of β-cell function. In a double-blind, pilot trial, treatment with rosiglitazone had similar effects [30]. The effect of rosiglitazone was compared with that of placebo in 18 nondiabetic patients with persistent impaired glucose tolerance. After 12 weeks of treatment, four of nine patients who received rosiglitazone had normal glucose tolerance. These studies suggest that thiazolidinediones can improve insulin sensitivity and may delay or prevent the development of type 2 diabetes (based on the 1997 American Diabetes Association criteria). Data from ongoing clinical trials, such as the Diabetes REduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) study and the A Diabetes Outcome Progression Trial (ADOPT), will provide crucial information regarding the ability of thiazolidinediones to prevent the development or slow the progression of diabetes in high-risk patients [31].INSULIN RESISTANCE AND THE METABOLIC (INSULIN RESISTANCE) SYNDROMEInsulin resistance is the inability of target tissues (especially muscle and liver) to respond to normal circulating concentrations of insulin. Insulin resistance affects glucose disposal in muscle and fat and reduces insulin suppression of hepatic glucose output [9, 32, 33]. In response to insulin resistance, β cells in the pancreas secrete increased amounts of insulin to maintain euglycemia, and as a consequence, hyperinsulinemia results. In approximately 25% of individuals with insulin resistance, the β cells cannot maintain high rates of insulin secretion because of functional defects, thus glucose tolerance becomes impaired, and eventually postprandial and fasting hyperglycemia result [9].Insulin resistance is prevalent in nearly 25% of the population and in more than 40% of people older than 60 years of age [34]. Insulin resistance is the first measurable defect in patients destined to develop type 2 diabetes and can be detected in the early prediabetic stage of impaired fasting glucose (fasting plasma glucose of 110-125 mg/dl). Insulin resistance is found in many of the normoglycemic individuals who are family members of patients with type 2 diabetes. In patients who develop type 2 diabetes in their sixth or seventh decades of life, insulin resistance precedes the development of the disease by at least one to two decades [35].Pathogenesis of Insulin ResistanceDefects in muscle glycogen synthesis play a significant role in insulin resistance, and recent studies have shown that defects in insulin-stimulated muscle glycogen synthesis are responsible for most of the insulin resistance observed in the skeletal muscle of patients with type 2 diabetes [36–38]. This abnormality can be attributed to defects in insulin-stimulated muscle glucose transport activity. In addition, these abnormalities are strongly associated with increased lipid accumulation within muscle cells [39–41].Type 2 diabetes and obesity are associated with insulin resistance, oxidative stress, and inflammation [42, 43]. It has been suggested that insulin resistance may be mediated by a series of proinflammatory cytokines and inflammatory mediators [42]. Inflammatory mediators (e.g., interleukin-6, tumor necrosis factor-α) are elevated in individuals with type 2 diabetes and in obese people [44–47], as is plasminogen activator inhibitor-1 (PAI-1), an inflammatory product [48]. Elevations of inflammatory mediators may contribute to the pathogenesis of atherosclerosis in these individuals. Atherosclerosis is recognized as an inflammatory process within the arterial wall [49]. Thus, inflammation triggered by proinflammatory factors can account for the evolution of the process of atherosclerosis, plaque rupture, and the thrombotic process.Metabolic (Insulin Resistance) SyndromeThe metabolic (or insulin resistance) syndrome consists of a set of metabolic abnormalities that cluster around insulin resistance. In guidelines published by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), factors characteristic of the metabolic syndrome include atherogenic dyslipidemia (elevated triglyceride, low high-density lipoprotein [HDL] cholesterol, and seemingly normal levels of low-density lipoprotein [LDL] cholesterol, which consists mostly of the more atherogenic small, dense LDL particles), hypertension, abdominal obesity, and prothrombotic and proinflammatory states (Table 1) [52]. The diagnosis of the metabolic syndrome is made when three or more of the five risk determinants (shown in Table 2) are present, although some data indicate that obesity cut-off points may be lower in the Asian population who have more slender builds [53].JOURNAL/endst/04.03/00019616-200305001-00001/table1-1/v/2021-02-17T201712Z/r/image-jpeg Components of the Metabolic Syndrome [50]JOURNAL/endst/04.03/00019616-200305001-00001/table2-1/v/2021-02-17T201712Z/r/image-jpeg Risk Determinants for the Diagnosis of the Metabolic Syndrome Defined by ATP IIIInsulin Resistance and Cardiovascular DiseaseSeveral studies have shown that insulin resistance is associated with an increased incidence of coronary artery disease [54–59], and the NCEP ATP III identified the metabolic syndrome as a constellation of risk factors for coronary heart disease [52]. Individuals with the metabolic syndrome clearly are at increased risk for coronary heart disease, myocardial infarction, and stroke. The prevalence of cardiovascular morbidity and mortality associated with the metabolic syndrome was determined in more than 4,000 high-risk Scandinavians [60]. The metabolic syndrome was present in only 10% of subjects with normal glucose tolerance, whereas more than 80% of patients with type 2 diabetes met criteria for the metabolic syndrome. The risk of coronary heart disease and stroke was increased by 3-fold (P<0.001) in individuals with the metabolic syndrome. Furthermore, cardiovascular mortality was markedly higher in persons with the metabolic syndrome (12%) than in those without the metabolic syndrome (2.2%; P<0.001).The Paris Prospective Study and the Helsinki Policemen Study both found a positive correlation between insulin resistance and the incidence of coronary events [54–57]. Two recent, large studies also evaluated the relationship between insulin resistance and cardiovascular disease [61, 62] and showed that improving insulin sensitivity in patients with type 2 diabetes led to beneficial effects on cardiovascular risk factors as well as on glucose control. These data have led to the hypothesis that if treatment of insulin resistance is begun before significant vascular damage has occurred, then the development of cardiovascular disease is likely to be slowed or eliminated.Dyslipidemia Associated with Insulin ResistanceMost lipid studies have focused on the benefits of lowering elevated LDL cholesterol. However, mean LDL cholesterol levels in insulin-resistant individuals with or without type 2 diabetes are the same as levels in the normal population, yet the prevalence of cardiovascular disease is approximately 4-fold greater in those with insulin resistance [63, 64]. The increased risk of cardiovascular disease in insulin-resistant individuals is attributed to abnormal lipoprotein metabolism and a characteristic dyslipidemia consisting of low levels of HDL cholesterol, often seemingly normal LDL cholesterol levels, and high triglyceride concentrations. However, insulin-resistant individuals often have qualitative changes in lipoproteins with an increase in small and dense LDL particles (Pattern B), which are easily oxidized and are more atherogenic than larger, more buoyant LDL particles [64–67]. Low levels of HDL cholesterol, small dense LDL particles, and elevated triglyceride levels are each independent risk factors for cardiovascular disease [55, 68] and represent a set of lipoprotein abnormalities that promote atherosclerosis [69]. Modifying the dyslipidemia associated with insulin resistance will lead to improved cardiovascular outcomes [70, 71].Other Components of the Metabolic SyndromeHypertensionInsulin resistance and hypertension are also closely associated. Patients with type 2 diabetes are almost twice as likely to have hypertension as are patients without diabetes [66]. Approximately 50% of patients with hypertension are insulin-resistant and hyperinsulinemic [64, 72]. Evidence suggests that in obese and insulin-resistant individuals, overactivity of the sympathetic nervous system may contribute in some degree to hypertension [64, 72]. Insulin also exerts direct effects on the kidney to increase sodium reabsorption, which can further contribute to hypertension [72].ObesityObesity, insulin resistance, and hyperinsulinemia are characteristic of the prediabetic phase [73], and recent data indicate that the prevalence of obesity and diabetes continues to increase among adults in the United States [2]. Central obesity, a condition in which fat is preferentially distributed in the abdomen as opposed to peripheral subcutaneous distribution, promotes the development of insulin resistance and type 2 diabetes. Central obesity also is an independent significant predictor of CHD morbidity and mortality [54, 65, 74]. In addition, central obesity has a stronger correlation with insulin resistance than does body mass index [75].Impaired Hemostatic FunctionInsulin-resistant individuals often have evidence of alterations in coagulation that predispose to arterial thrombosis [69, 76]. One of these alterations is elevated levels of PAI-1. Normally, PAI-1 blocks the action of tissue plasminogen activator (tPA) and is the primary inhibitor of endogenous fibrinolysis [65]. Increased PAI-1 concentrations are associated with cardiovascular disease and seem to play a role in the pathogenesis of thrombosis and myocardial infarction. PAI-1 concentrations are elevated in individuals with type 2 diabetes and in nondiabetic persons with insulin resistance, and there is a significant direct correlation between PAI-1 concentrations and insulin resistance [66]. Thus, insulin resistance and hyperinsulinemia may increase the risk of cardiovascular disease by impairing hemostatic function and enhancing the potential for acute thrombosis.Vascular AbnormalitiesThe endothelium regulates vascular tone by balancing vasodilator and vasoconstrictor effects, has effects on thrombogenesis, and modulates inflammatory responses [77]. Normally, insulin exerts anti-inflammatory and vasodilatory effects on the vasculature, effects that are diminished in the presence of insulin resistance [78–80]. Numerous studies have shown that in the presence of insulin resistance, insulin-mediated effects on nitric oxide and vasodilation are blunted [79, 81]. Similarly, insulin-mediated vasodilation is disrupted in obese individuals and in those with type 2 diabetes [80, 82, 83]. Factors that can cause endothelial dysfunction and promote atherosclerosis include hyperglycemia, hyperinsulinemia, and hypertension. Thus, vascular abnormalities and impaired endothelial function are common in patients with insulin resistance.BENEFICIAL EFFECTS OF THIAZOLIDINEDIONES IN INSULIN RESISTANCE AND TYPE 2 DIABETESThiazolidinediones are selective and potent agonists of peroxisome proliferator-activated receptor-γ (PPAR-γ), an intranuclear transcription factor that is expressed in target tissues for insulin action, including adipose tissue, skeletal muscle, and the liver [84–86]. The thiazolidinediones bind to sites on PPAR-γ, which is then activated and attaches to genes. These genes are involved in modulating lipid metabolism, adipose tissue differentiation, and insulin action [87].The thiazolidinediones have a unique mechanism of action in that they directly target insulin resistance by increasing insulin sensitivity in muscle, liver, and adipose tissue and by improving peripheral glucose disposal [85, 88–90], and these agents have been shown to effectively lower blood glucose levels in patients with type 2 diabetes [91–95]. In addition, PPAR-γ is present in a variety of cells that play an important role in atherosclerosis, such as endothelial cells, vascular smooth-muscle cells, monocytes, and macrophages [66]. The thiazolidinediones have several actions that may provide significant benefits in the highly atherogenic insulin-resistance syndrome and in type 2 diabetes.Cardiovascular BenefitsConsiderable data have accumulated recently to show that thiazolidinediones may have beneficial effects on the atherogenic process within the vessel wall [42]. Thiazolidinediones exert positive effects on endothelial function, monocyte/macrophage function, lipid abnormalities, smooth-muscle-cell migration, and fibrinolysis. All of these functions are believed to be abnormal as a part of insulin resistance. In addition to these effects, thiazolidinediones possess anti-inflammatory properties [96].Elevated C-reactive protein levels commonly seen in insulin-resistant individuals are reduced by thiazolidinedione therapy (Fig. 3) [97, 98]. This may reflect a decrease in arterial inflammation that is part of the atherosclerotic process. Treatment with thiazolidinediones restores the endothelium-mediated vasodilatory response to stimuli that is often diminished in patients with type 2 diabetes who are insulin-resistant [99, 100]. Thickening of the intimalmedia layer of the artery reflects early atherosclerotic processes. The thiazolidinediones decrease intimal-media thickness of the carotid arteries as measured by B-mode ultrasound [101, 102].JOURNAL/endst/04.03/00019616-200305001-00001/figure3-1/v/2021-02-17T201712Z/r/image-jpeg Effects of rosiglitazone on C-reactive protein (CRP). Percentages represent 1 subtracted from antilogs of mean difference between baseline and week 26 log-transformed levels. Both rosiglitazone treatment groups showed significant mean percentage reductions in CRP levels from baseline and placebo (P<0.05). CI = confidence interval. Adapted with permission from Haffner SM, Greenberg AS, Weston WM, et al.: Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002; 106: 679-84.Thiazolidinediones also have been shown to reduce PAI-1 levels, the primary inhibitor of endogenous fibrinolysis [103–105]. In a double-blind study, 114 patients with type 2 diabetes were randomly assigned to treatment with glyburide 10 mg twice daily alone or in combination with rosiglitazone 4 mg twice daily [105]. After 26 weeks of treatment, the combination of rosiglitazone plus glyburide was associated with a 21.8% decrease in PAI-1 antigen (P=0.031) and a 33.8% decrease in PAI-1 activity (P=0.006); both of these markers of hemostatic function increased in the group taking glyburide alone. Similar decreases in PAI-1 have been reported in patients treated with troglitazone [104]. These studies suggest that by treating insulin resistance with a thiazolidinedione, endothelial function recovers, hemostasis improves, and atherosclerotic disease is likely to be reduced.Effects on Blood PressurePatients with type 2 diabetes are nearly twice as likely as people without diabetes are to have hypertension [106]. The thiazolidinedione rosiglitazone has been shown to lower blood pressure in patients with type 2 diabetes. A total of 203 patients were randomized to treatment with rosiglitazone 4 mg twice daily or glyburide [107]. After 52 weeks of treatment, patients treated with rosiglitazone had significantly reduced ambulatory blood pressure compared with glyburide-treated patients. Similarly, diastolic blood pressure was significantly lowered in troglitazonetreated patients, whereas no significant changes in blood pressure were observed in glyburide-treated patients [108]. Reductions in blood pressure by thiazolidinediones may help to prevent vascular complications in patients with type 2 diabetes.Beneficial Effects on Lipid ParametersBy improving insulin sensitivity, thiazolidinediones may ameliorate the consequences of the dyslipidemia associated with type 2 diabetes and the metabolic syndrome. Rosiglitazone increases HDL cholesterol by at least 10% to 30%, changes LDL particles from predominantly small and dense to larger, more buoyant particles, which are less atherogenic, and decreases triglycerides in patients who have high baseline triglyceride levels [109–112]. In one study, treatment with rosiglitazone 4 mg twice daily was associated with a significant increase in LDL particle size in 71% of patients who had a predominance of small, dense, LDL particles (Fig. 4). Additionally, the more atheroprotective HDL2 subfraction increased by 12.6% in the rosiglitazone treatment group [109]. In another analysis, treatment with rosiglitazone was associated with a 24% increase in the HDL2 subfraction [112]. Similarly beneficial effects on dyslipidemia have been observed with pioglitazone [113], indicating that the thiazolidinediones exert beneficial effects on the dyslipidemic profile associated with insulin resistance.JOURNAL/endst/04.03/00019616-200305001-00001/figure4-1/v/2021-02-17T201712Z/r/image-jpeg Change in the proportion of patients with low-density lipoprotein (LDL) peak fraction <0.2632 (small, dense, more atherogenic subfraction) and ≥0.2632 (large, buoyant, less atherogenic subfraction) at study entry and after 8 weeks of treatment with rosiglitazone. Rf = relative flotation. Reprinted with permission from Freed MI, Ratner R, Marcovina SM, et al.: Effects of rosiglitazone alone and in combination with atorvastatin on the metabolic abnormalities of type 2 diabetes mellitus. Am J Cardiol 2002; 90: 947-52.Effects on Fat DistributionSeveral studies have shown that improving insulin sensitivity with thiazolidinediones favorably alters fat distribution by increasing subcutaneous peripheral fat mass and reducing intrahepatic and visceral fat [114–120]. Changes in fat distribution were evaluated in 33 patients with type 2 diabetes (baseline HbA1c of 7.1-7.8%), who were treated with rosiglitazone 8 mg per day or placebo [121]. After 16 weeks, subcutaneous fat area increased by 8% (P=0.02) and intrahepatic fat decreased by 45% (P=0.04); no changes in intra-abdominal fat were detected. Kelley et al. [117] randomized 23 obese patients with type 2 diabetes to metformin 2 g daily or rosiglitazone 8 mg daily. Patients treated with rosiglitazone experienced significantly improved insulin sensitivity (P<0.01), which correlated with a 10% decrease in visceral fat. Similar effects were demonstrated by Virtanen et al. [120] in a population of newly diagnosed patients with type 2 diabetes. In another study, 13 patients with type 2 diabetes, who were receiving stable doses of a sulfonylurea or were managed with diet alone, were treated with pioglitazone 45 mg daily and a sulfonylurea or pioglitazone 45 mg daily alone [119]. After 16 weeks of treatment, visceral fat was significantly reduced (P<0.05) and subcutaneous fat was significantly increased (P<0.01) with pioglitazone in all patients. Thus, thiazolidinediones improve insulin sensitivity and reduce fat distribution in the visceral abdominal cavity.Benefits of Thiazolidinediones on the Pancreatic β CellThere is a growing body of evidence that thiazolidinediones improve and may rejuvenate β-cell function. In rodent models of type 2 diabetes, investigators have shown that free fatty acids have a role in β-cell apoptosis, and thiazolidinediones may prevent β-cell death by reducing free fatty acids [122–124]. Thiazolidinediones restored β-cell insulin content in pancreatic islets of diabetes-prone mice [125]. After 28 days of treatment with rosiglitazone, metformin, or glyburide, only rosiglitazone-treated mice had significantly increased plasma and pancreatic insulin concentrations. In obese Zucker diabetic rats, rosiglitazone maintained β-cell proliferation, thus preventing loss of β-cell mass [126].Elevated concentrations of free fatty acids are associated with insulin resistance and contribute to the development of hyperglycemia [127]. The thiazolidinediones modify this response through improvements in insulin resistance and changing the pattern of free fatty acids present in patients with type 2 diabetes. After 26 weeks of rosiglitazone therapy (4 or 8 mg/day), free fatty acid concentrations decreased from baseline by 7% to 19%, compared with a 4% increase with placebo [128]. After 26 weeks of rosiglitazone 4 or 8 mg per day plus metformin, free fatty acids were significantly reduced (P<0.001) from baseline by 14% and 23%, respectively [91]. With metformin alone, free fatty acids were decreased by only 0.5% (P≤0.0003 vs. rosiglitazone plus metformin).In type 2 diabetes, as the β cell is failing, more of the precursor proinsulin is produced and the proinsulin-to-insulin ratio increases [129]. Improvements in proinsulin-toinsulin ratio may reflect decreased workload on the β cell. Treatment with rosiglitazone significantly reduces the proinsulin-to-insulin ratio, along with the total amount of circulating insulin, compared with placebo or glyburide [130] or when added to a regimen of metformin and sulfonylurea that is failing [131]. However, this effect has not been observed with pioglitazone [132]. Evidence of β-cell rejuvenation also has been reported in patients with type 2 diabetes who are receiving thiazolidinedione therapy [131, 133, 134].PHARMACOLOGIC APPROACH TO THE TREATMENT OF TYPE 2 DIABETESThe American Diabetes Association (ADA) most recently revised their guidelines for the diagnosis and classification of diabetes in 1997 (Table 3) [8]. Glycemic treatment goals recommended by the ADA include preprandial plasma glucose levels of 90-130 mg/dl, peak postprandial plasma glucose levels less than 180 mg/dl, and HbA1c levels less than 7% [8]. Adult, nonpregnant patients should receive aggressive treatment to achieve an HbA1c of less than 7%. In light of the data discussed earlier, the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology have issued guidelines that are even more rigorous than the ADA guidelines, recommending that patients be treated to an HbA1c level of less than 6.5% [135].JOURNAL/endst/04.03/00019616-200305001-00001/table3-1/v/2021-02-17T201712Z/r/image-jpeg Diagnostic Criteria for Type 2 Diabetes* [8]Nonpharmacologic therapies (i.e., diet and exercise) are the cornerstone for successful management of type 2 diabetes [8]. Caloric restriction, weight loss, and exercise can enhance insulin sensitivity and glycemic control. Specific treatment goals have been established for patients with type 2 diabetes (Table 4). For most patients, weight reduction and increased physical activity will improve insulin resistance, hyperglycemia, hypertension, and lipid profiles. However, when nonpharmacologic measures alone are not effective at lowering HbA1c levels to target, oral hypoglycemic agents should be added to nonpharmacologic therapy.JOURNAL/endst/04.03/00019616-200305001-00001/table4-1/v/2021-02-17T201712Z/r/image-jpeg Treatment Goals for Patients with Type 2 Diabetes [8]There are five classes of oral antidiabetic agents (Table 5) [136–150] that target the various pathophysiologic mechanisms of type 2 diabetes (Fig. 5). The oral agents reduce plasma glucose levels by targeting one of four processes: (1) stimulation of pancreatic β cells to produce more insulin (sulfonylureas, nonsulfonylurea secretagogues); (2) stimulation of glucose uptake by muscle and adipose tissues (thiazolidinediones, biguanides); (3) reduction of glucose output by the liver (biguanides, thiazolidinediones); and (4) reduction of glucose absorption by the gut (α-glucosidase inhibitors) [151, 152]. Mechanism of action, nonhypoglycemic effects, and adverse-effect profiles should be taken into consideration when choosing oral antidiabetic therapy for patients with type 2 diabetes. Additionally, patients with diabetes who are insulin resistant will benefit from initiation of treatment with an insulinsensitizing agent, such as the thiazolidinediones.JOURNAL/endst/04.03/00019616-200305001-00001/table5-1/v/2021-02-17T201712Z/r/image-jpeg Oral Antidiabetic Agents and Their FDA-approved Indications and Uses [136–150]JOURNAL/endst/04.03/00019616-200305001-00001/figure5-1/v/2021-02-17T201712Z/r/image-jpeg Pathogenesis of type 2 diabetes and targets of action for oral antidiabetic agents. Adapted with permission from Inzucchi SE: Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002; 287: 360-72.ThiazolidinedionesRosiglitazone and pioglitazone are the two currently available thiazolidinediones in the United States [136, 138]. Both of these agents are effective at lowering blood glucose and are indicated as monotherapy in patients with type 2 diabetes [92–94] or as combination therapy with a sulfonylurea or a biguanide [91, 95] (Table 5). Low- and mediumdose pioglitazone and the 4-mg dose of rosiglitazone also are indicated for use in combination with insulin [136, 138].The thiazolidinediones, sulfonylureas, and biguanides are equally effective as monotherapy for lowering blood glucose, each leading to a mean decrease in HbA1c of approximately 1% to 2% [151]. However, monotherapy with a sulfonylurea or metformin does not provide long-lasting glycemic control [23, 24]. Only the thiazolidinediones have been shown to preserve β-cell function [29, 131, 153]. Longterm studies of thiazolidinediones alone and in combination with other agents are underway to confirm the sustainability of glycemic control achievable with thiazolidinediones.In clinical trials, rosiglitazone and pioglitazone have been proven safe and effective for long-term therapy of type 2 diabetes. The thiazolidinediones are generally well tolerated with a low incidence of adverse effects. Consistent with their mechanism of action, thiazolidinediones do not cause hypoglycemia when administered as monotherapy or with metformin [154]. Thiazolidinediones may cause weight gain and fluid retention when initiated at high doses [151], although this effect is not observed in all patients [155, 156]. These agents have not been studied in patients with New York Heart Association class 3 or 4 cardiac status [136, 138]. The combination of a thiazolidinedione, particularly at medium-to-high doses, with insulin may increase the incidence of fluid retention [157].Troglitazone, an older thiazolidinedione, was removed from the market because of an idiosyncratic hepatotoxicity. Because of this, it is recommended that liver enzymes be measured at the start of therapy with a thiazolidinedione and be monitored every 2 months for the first 12 months and periodically thereafter [136, 138]. Recent data have shown that hepatotoxicity is not a class effect with these agents [158, 159]. The hepatotoxicity associated with troglitazone may have been related to properties specific to that molecule (e.g., side chains, metabolic pathway) and not to the common thiazolidine-2-4-dione structure shared with rosiglitazone and pioglitazone. In clinical trials, the incidence of liver abnormalities in rosiglitazonetreated patients was 0.32%, which is comparable with that seen in placebo-treated patients (0.17%) [158]. Very low rates of liver abnormalities also have been observed in patients treated with pioglitazone [160].BiguanidesBiguanides inhibit hepatic gluconeogenesis and have no direct effect on β-cell function [141, 151]. Metformin is the only biguanide available in the United States and is indicated as an adjunct to diet to lower blood glucose in patients with type 2 diabetes. Metformin also can be used as monotherapy or in combination therapy, and it provides glycemic control that is similar to that provided by sulfonylureas without stimulating insulin secretion [161].Hypoglycemia is generally not associated with metformin because this agent does not increase pancreatic insulin secretion. The most common adverse effects associated with metformin include abdominal pain, nausea, and diarrhea. However, lactic acidosis, a serious metabolic complication, has been reported with the use of metformin, particularly in individuals with renal dysfunction or advancing age [161]. By following prescribing guidelines for metformin, the incidence of lactic acidosis may be minimized [141, 162]. Metformin is contraindicated in individuals with renal disease or renal dysfunction [141].α-Glucosidase InhibitorsAcarbose and miglitol are α-glucosidase inhibitors that act by delaying and partially preventing carbohydrate absorption in the small intestine, thereby decreasing postprandial glucose levels [151]. These agents are approved for use as monotherapy or combination therapy [152, 157]. The primary advantages of these agents include minimal systemic absorption and low incidences of hypoglycemia or weight gain. However, the α-glucosidase inhibitors typically only lower HbA1c levels by approximately 0.5% to 1%, making them considerably less effective than thiazolidinediones, biguanides, or sulfonylureas. Adverse gastrointestinal effects associated with α-glucosidase inhibitors occur in approximately 30% of patients and include increased intestinal gas formation, loose stools, and abdominal discomfort [152]. Because of their mechanism of action and adverse-effect profile, these drugs are contraindicated in patients with diseases of the gastrointestinal tract (e.g., inflammatory bowel disease).SecretagoguesAntidiabetic drugs that act by increasing insulin secretion are called secretagogues, and they can be separated into two groups: sulfonylureas and nonsulfonylurea secretagogues. Sulfonylureas are by far the oldest of the oral antidiabetic agents. Sulfonylureas stimulate insulin release by binding to the sulfonylurea receptor on pancreatic β cells and increasing basal and postprandial insulin secretion [151, 152]. Sulfonylureas decrease HbA1c by approximately 1% to 2% [151]. These agents are approved for use as monotherapy or combination therapy.All agents that stimulate release of endogenous insulin can cause weight gain and hypoglycemia. This is a direct result of the increase in insulin production. The potential for clinically significant hypoglycemia with sulfonylureas, particularly with use of the longer-acting agents, chlorpropamide and glyburide, limits their use to some extent [163]. Predisposing factors for hypoglycemia include increased age, restricted carbohydrate intake, and renal or hepatic dysfunction. Sulfonylurea-induced hypoglycemia is more common in elderly, debilitated, or malnourished patients [164].Nonsulfonylurea SecretagoguesThe nonsulfonylurea secretagogues are a newer class and include two currently available products, nateglinide and repaglinide. Both products are approved for use as monotherapy or in combination with metformin, and repaglinide is approved for use with the thiazolidinediones. Both repaglinide and nateglinide are taken before meals and primarily affect postprandial glucose levels. The mechanism of action of these agents is similar to that of sulfonylureas; however, they are distinguished by their short metabolic half-lives [151]. These agents may be the preferred secretagogue in patients with a tendency toward developing hypoglycemia when taking long-acting secretagogues, such as patients with irregular meal times, those with renal insufficiency or failure, and elderly patients.InsulinPatients who remain hyperglycemic despite adequate therapy with oral antidiabetic agents, or individuals who present with severe hyperglycemia, may require insulin therapy. Data from the UKPDS indicate that because of the progressive nature of diabetes and the associated β-cell deterioration, most patients with type 2 diabetes will eventually need exogenous insulin [165]. As β-cell function diminishes to the point that the amount of endogenous insulin become inadequate, exogenous insulin administration becomes necessary. Numerous insulin preparations are currently available. For rapid onset and short duration of effect, insulin lispro and aspart may be used, whereas insulin glargine may be selected for longer duration of action. Several premixed insulins also may be useful in helping patients achieve better glycemic control.AN ALGORITHM FOR MANAGING TYPE 2 DIABETES: ROLE OF THIAZOLIDINEDIONESWhen treating a patient with type 2 diabetes, a treatment plan should be individualized based on the patient's characteristics and severity of disease. Therapeutic regimens should include lifestyle modifications and pharmacologic therapy as indicated. Treatment algorithms can be used as an initial guide for management, and we have previously proposed algorithms for managing patients with mild, moderate, and severe type 2 diabetes (Figs. 6–8) [166]. The following proposed treatment algorithm (Fig. 9) is designed to aid the practitioner in the management of patients with type 2 diabetes. If patients do not respond to treatment or remain acutely hyperglycemic during therapy, referral to a diabetes specialist may be appropriate. Patients should have an HbA1c level measured initially and every 3 months during therapy. The goal of treatment is to reduce HbA1c levels to 7% or lower [8, 135].JOURNAL/endst/04.03/00019616-200305001-00001/figure6-1/v/2021-02-17T201712Z/r/image-jpeg Proposed algorithm for the treatment of mild type 2 diabetes. At any point, consider referral to an endocrinologist for more intensive treatment. Biguanides are contraindicated in patients with renal disease or dysfunction (as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females], or abnormal creatinine clearance), congestive heart failure requiring pharmacologic treatment, and acute or chronic metabolic acidosis. Thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Reprinted with permission from Wyne KL, Drexler AJ, Miller JL, et al.: Constructing an algorithm for managing type 2 diabetes: focus on role of the thiazolidinediones. Postgrad Med Special Report 2003; May: 63-72.HbA1c = glycosylated hemoglobin.*Sulfonylureas may potentiate or cause hypoglycemia and their use should therefore be reserved, whereas thiazolidinediones and biguanides, alone or in combination with each other, have rarely been shown to cause hypoglycemia.†If hypoglycemia occurs, back-titrate or discontinue the secretagogue.‡Reassess in 3 months, if HbA1c >7%, discontinue secretagogue and initiate split-dose, mixed insulin regimen.JOURNAL/endst/04.03/00019616-200305001-00001/figure7-1/v/2021-02-17T201712Z/r/image-jpeg Proposed algorithm for the treatment of moderate type 2 diabetes. At any point, consider referral to an endocrinologist for more intensive treatment. Biguanides are contraindicated in patients with renal disease or dysfunction (as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females], or abnormal creatinine clearance), congestive heart failure requiring pharmacologic treatment, and acute or chronic metabolic acidosis. Thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Reprinted with permission from Wyne KL, Drexler AJ, Miller JL, et al.: Constructing an algorithm for managing type 2 diabetes: focus on role of the thiazolidinediones. Postgrad Med Special Report 2003; May: 63-72.HbA1c = glycosylated hemoglobin.*Sulfonylureas may potentiate or cause hypoglycemia and their use should therefore be reserved, whereas thiazolidinediones and biguanides, alone or in combination with each other, have rarely been shown to cause hypoglycemia.†If hypoglycemia occurs, back-titrate or discontinue the secretagogue.‡Reassess in 3 months, if HbA1c >7%, discontinue secretagogue and initiate split-dose, mixed insulin regimen.§If biguanide is contraindicated, add basal insulin, taper off secretagogue, and introduce bolus insulin as needed.JOURNAL/endst/04.03/00019616-200305001-00001/figure8-1/v/2021-02-17T201712Z/r/image-jpeg Proposed algorithm for the treatment of severe type 2 diabetes. At any point, consider referral to an endocrinologist for more intensive treatment. Biguanides are contraindicated in patients with renal disease or dysfunction (as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females], or abnormal creatinine clearance), congestive heart failure requiring pharmacologic treatment, and acute or chronic metabolic acidosis. Thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Reprinted with permission from Wyne KL, Drexler AJ, Miller JL, et al.: Constructing an algorithm for managing type 2 diabetes: focus on role of the thiazolidinediones. Postgrad Med Special Report 2003; May:63-72.FPG = fasting plasma glucose; HbA1c = glycosylated hemoglobin.*Sulfonylureas may potentiate or cause hypoglycemia and their use should therefore be reserved, whereas thiazolidinediones and biguanides, alone or in combination with each other, have rarely been shown to cause hypoglycemia.†If hypoglycemia occurs, back-titrate or discontinue the secretagogue.‡Reassess in 3 months, if HbA1c >7%, discontinue secretagogue and initiate split-dose, mixed insulin regimen.§If biguanide is contraindicated, add basal insulin, taper off secretagogue, and introduce bolus insulin as needed.#If at any time the patient is symptomatic or acutely ill, consider aggressive, empiric insulin therapy with appropriate guidance.¶For patients who remain symptomatic, consider initiating split-dose, mixed insulin regimen and discontinuing secretagogue (if on a secretagogue) or adding bedtime NPH or glargine insulin and continuing secretagogue (if on a secretagogue).JOURNAL/endst/04.03/00019616-200305001-00001/figure9-1/v/2021-02-17T201712Z/r/image-jpeg Proposed treatment algorithm for the management of patients with type 2 diabetes that is inadequately controlled with diet and exercise. FPG = fasting plasma glucose; HbA1c = glycosylated hemoglobin. *Sulfonylureas may potentiate or cause hypoglycemia and their use should therefore be reserved. †Increase to maximum effective doses. If hypoglycemia occurs, backtitrate or discontinue the nonthiazolidinedione agent.In patients who fail to respond to lifestyle modifications and need pharmacotherapy, treatment of insulin resistance should be the initial consideration. Two classes of antidiabetic agents that treat insulin resistance are the thiazolidinediones and biguanides; therefore, first-line oral therapy may include one of these agents. The choice between these agents should be based primarily on their pharmacologic and adverse-effect profiles. Because thiazolidinediones effectively lower blood-glucose levels, treat many of the components of the metabolic syndrome, may reduce cardiovascular complications, are likely to preserve β-cell function, and improve insulin sensitivity, a thiazolidinedione may be selected as first-line therapy unless otherwise contraindicated.There are a number of factors that support the early use of a thiazolidinedione in the management of patients with type 2 diabetes (Table 6). Because insulin resistance and the atherogenic pattern of cardiovascular risk factors precede the onset of clinical diabetes [73], it may be advantageous to begin therapy with a thiazolidinedione early in the course of the disease. Thiazolidinediones are potent insulin-sensitizing agents that act on the underlying pathophysiology of type 2 diabetes; they reduce hyperinsulinemia, provide durable glycemic control, and have an impact on insulin resistance in part because of their effect on visceral fat [118, 119, 168–170]. The thiazolidinediones decrease insulin resistance and plasma glucose concentrations as a consequence of fat relocation from the viscera, where the adipocytes are highly metabolically active, to subcutaneous sites in the body, where the adipocytes are much less metabolically active [171]. Use of thiazolidinediones early in the course of treatment also is beneficial because of the anti-inflammatory actions of these agents [66, 97, 172].JOURNAL/endst/04.03/00019616-200305001-00001/table6-1/v/2021-02-17T201712Z/r/image-jpeg Rationale for Early Use of Thiazolidinediones in Managing Patients with Type 2 Diabetes Mellitus [167]Data from the Paris Prospective Study [54] and the Quebec Cardiovascular Study [173] also support early use of a thiazolidinedione in the treatment of type 2 diabetes. Plasma-insulin concentration is an independent predictor of cardiovascular mortality. As insulin concentrations increase, the incidence of atherosclerosis and the risk of CHD mortality increase. An insulin-sensitizing agent that improves insulin resistance and minimizes hyperinsulinemia, such as a thiazolidinedione, is a logical choice over agents that promote increased insulin secretion and endogenous hyperinsulinemia, such as the sulfonylureas. The 20-year follow-up of the Paris Prospective Study revealed that elevated free fatty acids are associated with an increased risk of sudden death [174], and thiazolidinediones reduce free fatty acids [168].Another important benefit of using thiazolidinediones early in the treatment of type 2 diabetes is their ability to preserve β-cell function [154, 167]. Studies suggest that thiazolidinediones increase the responsiveness of β cells by reducing circulating glucose and free fatty acids that impair insulin secretion [29, 126, 175]. One study found that treatment with rosiglitazone 8 mg per day reduced insulin resistance by 33% and improved β-cell function by 65% in patients with type 2 diabetes [92]; similar results were noted when rosiglitazone was combined with a sulfonylurea or metformin [95, 176]. Treatment with thiazolidinediones significantly reduces the proinsulin-toinsulin and circulating insulin levels, which indicates improved β-cell function [130]. Thiazolidinediones also may exert direct effects on β-cell recovery [131, 153].If HbA1c levels remain above 7% with monotherapy, then combination therapy may be initiated. Combination therapy with a thiazolidinedione and metformin offers several benefits. One major advantage with this combination is the absence of clinically significant hypoglycemia, a significant problem with the sulfonylureas. In addition, because these agents reduce insulin sensitivity and lower blood glucose through complementary pathways [85, 177], an additive effect on blood glucose control may be achieved. The combination of rosiglitazone and metformin has been shown to significantly reduce fasting plasmaglucose concentrations and HbA1c compared with metformin alone [91, 178]. For most patients with type 2 diabetes, the combination of a thiazolidinedione and metformin will reduce hyperglycemia, hyperinsulinemia, and insulin resistance, preserve β-cell function, and improve other components of the metabolic syndrome (e.g., dyslipidemia, hypertension, central obesity). Furthermore, there is evidence that the combination of a thiazolidinedione with metformin attenuates the weight gain associated with thiazolidinedione monotherapy [91, 178]. By initiating combination therapy early in the course of the disease, it is hoped that many of the vascular complications associated with insulin resistance and type 2 diabetes can be delayed or avoided.Secretagogues should be reserved for second- or third-line therapy because these agents do not treat the underlying insulin resistance. Indeed, the secretagogues cause additional insulin to be secreted by β cells, which are already functionally compromised. It is unlikely that β-cell function would be prolonged with such an approach or that glycemic control would be durable. However, if combination thiazolidinedione/biguanide therapy at maximum effective doses does not reduce HbA1c levels to below 7%, then the addition of a low-dose secretagogue is justified. Recent studies indicate that triple oral therapy with a thiazolidinedione, biguanide, and sulfonylurea significantly improves glycemic control and is well tolerated [133, 134, 179]. After an adequate period of time, if the patient does not respond to oral triple therapy, a regimen including bedtime insulin or a mixed/split dose should be started. The thiazolidinedione/biguanide should be continued, and as daytime glucose levels fall in response to insulin, the sulfonylurea eventually can be discontinued.CONCLUSIONSType 2 diabetes mellitus is a devastating disease that affects a significant portion of the population. Patients with diabetes suffer from substantial morbidity and mortality associated with microvascular and macrovascular complications. However, aggressive intervention may prevent or delay the onset and progression of complications. During the past several decades, our understanding of the relationship between insulin resistance, hyperglycemia, and diabetic complications has crystallized, and we can use that knowledge to develop optimal treatment plans.Insulin resistance, frequently seen in obese patients and patients with type 2 diabetes, plays a multifaceted role in the development of cardiovascular disease. Insulin resistance is associated with an atherogenic dyslipidemia, vascular endothelial dysfunction, and alterations in hemostasis. Thiazolidinediones enhance insulin sensitivity, and evidence suggests that thiazolidinediones improve the cardiovascular risk factors associated with insulin resistance. The thiazolidinediones improve lipid parameters with an increase in HDL cholesterol levels and an increase in LDL cholesterol particle size with a shift to larger, more buoyant, less atherogenic LDL particles. After treatment with thiazolidinediones, diastolic blood pressure is lowered, endothelial-dependent vascular response is improved, and PAI-1 levels are reduced. The collective benefits of reduced insulin resistance may reduce the cardiovascular complications associated with type 2 diabetes. Furthermore, there is evidence that thiazolidinediones improve and preserve β-cell function.A treatment regimen for type 2 diabetes that does not include an agent to improve insulin resistance and preserve β-cell function is incomplete. Although all oral agents are effective at lowering blood glucose, insulin resistance is a core defect that must be addressed. Early use of a thiazolidinedione to improve insulin sensitivity and β-cell function is recommended from the onset of therapy. First-line, oral therapy for type 2 diabetes should include a thiazolidinedione and/or metformin, as monotherapy or combination therapy. Patients with more severe type 2 diabetes or symptomatic hyperglycemia should be closely monitored and may require triple therapy with a thiazolidinedione, biguanide, and a secretagogue from the onset. Insulin may be needed if glycemic goals are not met on triple oral therapy.In conclusion, thiazolidinediones are an excellent option for the first-line treatment of type 2 diabetes, alone or in combination with other agents. The early use of thiazolidinediones improves insulin sensitivity, one of the underlying pathologic defects associated with type 2 diabetes, and may preserve the integrity of the β cell. Aggressive and appropriate management of patients with type 2 diabetes will slow the progression of disease, reduce the development of diabetic complications, and improve clinical outcomes.REFERENCES1. 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FPG = fasting plasma glucose. Reprinted with permission from UK Prospective Diabetes Study [23] (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837-53. Risk reduction for complications in patients with type 2 diabetes who received intensive treatment versus conventional treatment: results of the United Kingdom Prospective Diabetes Study. [23] MI = myocardial infarction. Components of the Metabolic Syndrome [50] Risk Determinants for the Diagnosis of the Metabolic Syndrome Defined by ATP III Effects of rosiglitazone on C-reactive protein (CRP). Percentages represent 1 subtracted from antilogs of mean difference between baseline and week 26 log-transformed levels. Both rosiglitazone treatment groups showed significant mean percentage reductions in CRP levels from baseline and placebo (P<0.05). CI = confidence interval. Adapted with permission from Haffner SM, Greenberg AS, Weston WM, et al.: Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002; 106: 679-84. Change in the proportion of patients with low-density lipoprotein (LDL) peak fraction <0.2632 (small, dense, more atherogenic subfraction) and ≥0.2632 (large, buoyant, less atherogenic subfraction) at study entry and after 8 weeks of treatment with rosiglitazone. Rf = relative flotation. Reprinted with permission from Freed MI, Ratner R, Marcovina SM, et al.: Effects of rosiglitazone alone and in combination with atorvastatin on the metabolic abnormalities of type 2 diabetes mellitus. Am J Cardiol 2002; 90: 947-52. Diagnostic Criteria for Type 2 Diabetes* [8] Treatment Goals for Patients with Type 2 Diabetes [8] Oral Antidiabetic Agents and Their FDA-approved Indications and Uses [136–150] Pathogenesis of type 2 diabetes and targets of action for oral antidiabetic agents. Adapted with permission from Inzucchi SE: Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002; 287: 360-72. Proposed algorithm for the treatment of mild type 2 diabetes. At any point, consider referral to an endocrinologist for more intensive treatment. Biguanides are contraindicated in patients with renal disease or dysfunction (as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females], or abnormal creatinine clearance), congestive heart failure requiring pharmacologic treatment, and acute or chronic metabolic acidosis. Thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Reprinted with permission from Wyne KL, Drexler AJ, Miller JL, et al.: Constructing an algorithm for managing type 2 diabetes: focus on role of the thiazolidinediones. Postgrad Med Special Report 2003; May: 63-72.HbA1c = glycosylated hemoglobin.*Sulfonylureas may potentiate or cause hypoglycemia and their use should therefore be reserved, whereas thiazolidinediones and biguanides, alone or in combination with each other, have rarely been shown to cause hypoglycemia.†If hypoglycemia occurs, back-titrate or discontinue the secretagogue.‡Reassess in 3 months, if HbA1c >7%, discontinue secretagogue and initiate split-dose, mixed insulin regimen. Proposed algorithm for the treatment of moderate type 2 diabetes. At any point, consider referral to an endocrinologist for more intensive treatment. Biguanides are contraindicated in patients with renal disease or dysfunction (as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females], or abnormal creatinine clearance), congestive heart failure requiring pharmacologic treatment, and acute or chronic metabolic acidosis. Thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Reprinted with permission from Wyne KL, Drexler AJ, Miller JL, et al.: Constructing an algorithm for managing type 2 diabetes: focus on role of the thiazolidinediones. Postgrad Med Special Report 2003; May: 63-72.HbA1c = glycosylated hemoglobin.*Sulfonylureas may potentiate or cause hypoglycemia and their use should therefore be reserved, whereas thiazolidinediones and biguanides, alone or in combination with each other, have rarely been shown to cause hypoglycemia.†If hypoglycemia occurs, back-titrate or discontinue the secretagogue.‡Reassess in 3 months, if HbA1c >7%, discontinue secretagogue and initiate split-dose, mixed insulin regimen.§If biguanide is contraindicated, add basal insulin, taper off secretagogue, and introduce bolus insulin as needed. Proposed algorithm for the treatment of severe type 2 diabetes. At any point, consider referral to an endocrinologist for more intensive treatment. Biguanides are contraindicated in patients with renal disease or dysfunction (as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females], or abnormal creatinine clearance), congestive heart failure requiring pharmacologic treatment, and acute or chronic metabolic acidosis. Thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Reprinted with permission from Wyne KL, Drexler AJ, Miller JL, et al.: Constructing an algorithm for managing type 2 diabetes: focus on role of the thiazolidinediones. Postgrad Med Special Report 2003; May:63-72.FPG = fasting plasma glucose; HbA1c = glycosylated hemoglobin.*Sulfonylureas may potentiate or cause hypoglycemia and their use should therefore be reserved, whereas thiazolidinediones and biguanides, alone or in combination with each other, have rarely been shown to cause hypoglycemia.†If hypoglycemia occurs, back-titrate or discontinue the secretagogue.‡Reassess in 3 months, if HbA1c >7%, discontinue secretagogue and initiate split-dose, mixed insulin regimen.§If biguanide is contraindicated, add basal insulin, taper off secretagogue, and introduce bolus insulin as needed.#If at any time the patient is symptomatic or acutely ill, consider aggressive, empiric insulin therapy with appropriate guidance.¶For patients who remain symptomatic, consider initiating split-dose, mixed insulin regimen and discontinuing secretagogue (if on a secretagogue) or adding bedtime NPH or glargine insulin and continuing secretagogue (if on a secretagogue). Proposed treatment algorithm for the management of patients with type 2 diabetes that is inadequately controlled with diet and exercise. FPG = fasting plasma glucose; HbA1c = glycosylated hemoglobin. *Sulfonylureas may potentiate or cause hypoglycemia and their use should therefore be reserved. †Increase to maximum effective doses. If hypoglycemia occurs, backtitrate or discontinue the nonthiazolidinedione agent. Rationale for Early Use of Thiazolidinediones in Managing Patients with Type 2 Diabetes Mellitus [167]<strong xmlns:mrws="http://webservices.ovid.com/mrws/1.0">Trends in Management of Type 2 Diabetes</strong>: <strong xmlns:mrws="http://webservices.ovid.com/mrws/1.0">Role of Thiazolidinediones</strong>Wyne Kathleen L. MD PHD; Bell, David S.H. MB, FACE, FACP; Braunstein, Seth MD, PHD; Drexler, Andrew J. MD; Miller, Jeffrey L. MD, FACP, FACE; Nuckolls, James G. MD, FACPSupplementSupplement13p S1-S21