The Effect of a Thiazolidinedione Drug, Troglitazone, on Glycemia in Patients with Type 2 Diabetes Mellitus Poorly Controlled with Sulfonylurea and Metformin: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Persistent hyperglycemia secondary to insulin resistance and eventual insufficient insulin secretory capacity is the hallmark of type 2 diabetes mellitus. Resistance to insulin-stimulated glucose uptake is present in most patients with this disease (1). Treatment is aimed at reducing blood glucose levels to normal or near-normal values (2, 3). Diet and exercise are the first treatments of choice for patients with type 2 diabetes mellitus. However, as many as 95% of those with newly diagnosed diabetes do not achieve adequate blood glucose control after a 3-month dietary intervention (4), and initiation with oral antidiabetes therapy is then advocated. On the basis of patient profile and level of glycemic control, first-line monotherapy typically begins with sulfonylurea (an insulin secretagogue) or metformin, which inhibits hepatic gluconeogenesis (5). When monotherapy fails to achieve optimal glycemic control, these agents are frequently prescribed in combination (6). However, many patients continue to experience suboptimal control, resisting health professionals' ultimate recommendation to begin insulin injection therapy (7-9). Thiazolidinediones are a class of peroxisome proliferator-activated receptor- drugs that, unlike sulfonylureas and metformin, stimulate increased peripheral glucose disposal and reduce insulin resistance in the muscle, liver, and adipose tissue (10-15). Studies have shown that troglitazone used as monotherapy or in combination with sulfonylurea and insulin improves glucose control (16-18). The addition of an insulin-sensitizing agent, such as troglitazone, to complement the insulin-stimulatory and hepatic glucosesuppressive effects of sulfonylurea and metformin has been considered an attractive therapeutic alternative to insulin. However, whether a thiazolidinedione would be efficient at a stage of the disease when -cell secretion is failing (19) remains to be demonstrated. The current trial (which was completed before troglitazone was withdrawn from the U.S. market because of hepatotoxicity) was conducted to determine whether the addition of a thiazolidinedione, troglitazone, could decrease hemoglobin A1c levels and thereby delay or eliminate the need for insulin treatment in patients who did not achieve adequate glucose control despite combined therapy with sulfonylurea and metformin. Methods Patients This multicenter study was conducted at 16 sites in Canada. Study participants were required to be at least 40 years of age and to have type 2 diabetes mellitus according to the National Diabetes Data Group criteria (20). Inadequate glycemic control was defined as having a hemoglobin A1c level of at least 0.085 (8.5%) despite undergoing at least 8 weeks of stable treatment with maximum tolerable doses of oral sulfonylurea and metformin. Patients treated with less than 20 mg of glyburide and less than 1500 mg of metformin were included only if documentation of intolerance to higher doses was available. Patients were ineligible if they had previously received long-term insulin treatment ( 3 days of treatment was allowed) or were currently using fenfluramine or glucocorticoids (these patients were excluded because of the negative effects of these drugs on insulin sensitivity). Patients were also ineligible if they had any of the following: serum creatinine concentration greater than 180 mol/L (2.0 mg/dL), alanine aminotransferase (ALT) level more than 2 times the upper limit of normal, uncontrolled hypertension, anemia, symptomatic angina, cardiac insufficiency, body mass index greater than 40 kg/m2, or active cancer within 5 years of screening. Contraceptive use was required for women of childbearing potential. Patient volunteers gave written informed consent to participate in the study. An ethics committeeinstitutional review board at each study center approved the protocol. Study Design Patients were recruited if they had received a diagnosis of type 2 diabetes mellitus and were currently taking maximum-dose sulfonylurea and metformin. Patients at each study site who met the inclusion criteria were invited to participate. Upon acceptance, they entered a 4-week lead-in period and received placebo in addition to their current regimen of sulfonylurea and metformin. Patients were then randomly assigned to receive, in a double-blind fashion, troglitazone, 400 mg/d, or a matching placebo of similar appearance and taste once daily for 24 weeks, in addition to current treatment with sulfonylurea and metformin. Random assignment of patients occurred sequentially, following a single computer-generated randomization schedule for the entire study with a block size of four. Medication was packaged according to the randomization schedule and was allocated to centers in blocks of four. Investigators, patients, and the sponsor were blinded to treatment and primary glycemic measures. After 24 weeks of double-blind treatment, an open-label phase followed in which placebo recipients began taking troglitazone, 400 mg/d, and patients previously treated with troglitazone continued to receive it for an additional 24 weeks. Fasting plasma glucose level and biochemical measures of safety, including chemistry tests (ALT and aspartate aminotransferase levels), hematologic tests, and urinalysis were performed at 4-week intervals throughout the study. Hemoglobin A1c level, total plasma insulin level, and lipid levels were measured at randomization and at 4-week intervals beginning at week 12. Self-monitoring of blood glucose level was encouraged, and glucose meters were provided to all patients. Symptomatic hypoglycemic events were characterized by the type of intervention required to alleviate the event and by severity (on the basis of a self-monitored blood glucose value obtained when symptomatic hypoglycemia was present). Physical examination and 12-lead electrocardiography were performed for each patient as additional safety assessments before randomization and at the end of the double-blind and open-label studies. Patients were to be withdrawn at their own discretion or if a clinician judged that their glucose levels were acutely deleterious, if they did not adhere to the protocol (that is, if they were <80% adherent to the study drug regimen), or if they had an intolerable adverse event. A central clinical laboratory (Medical Research Laboratories, Highland Heights, Kentucky) performed all biochemical measurements for all study centers. Hemoglobin A1c levels were measured by automated ion-exchange high-performance liquid chromatography (Bio-Rad Labs, Hercules, California), and insulin was measured by using a two-site immunoenzymometric assay (sensitivity, 8 pmol/L). Triglyceride, total cholesterol, and plasma glucose levels (hexokinase) were measured by using enzymatic methods with a Hitachi 747 analyzer (Hitachi Instruments, Inc., San Jose, California). High-density lipoprotein cholesterol was isolated by chemical precipitation and was measured in the same way as total cholesterol. Low-density lipoprotein cholesterol level was calculated by using the equation of Friedewald and colleagues (21). Statistical Analysis The sample calculation was based on a two-sided t-test, with a P value less than 0.05 indicating significance. Assuming that the standard deviation of hemoglobin A1c level was 0.017 (1.7%), 62 patients per treatment group were needed to detect at least a 1% difference between troglitazone-treated patients and placebo recipients at a power of 0.9. Assuming a 25% loss due to dropout, our goal was to randomly assign a minimum of 85 patients to each treatment group. The analyses of efficacy for the double-blind study were performed according to the intention-to-treat method and included all patients who received at least one dose of troglitazone or placebo and had at least one follow-up visit. The last observations for patients were carried forward to impute missing values. The safety analyses also included all patients. The analyses of efficacy for the open-label study were performed by using summary statistics inclusive of all available data for patients who entered the open-label study. Statistical analyses were performed by using SAS software, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Changes in levels of hemoglobin A1c, fasting plasma glucose, insulin, triglycerides, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol from randomization to the end of the double-blind study were analyzed by using analysis of covariance, with treatment and study center as factors and the baseline value as the covariate. All statistical tests were two-sided ( = 0.05). Exploratory analyses to investigate the effects of age, sex, menopausal status, and ethnicity were also conducted by using analysis of covariance, with center and treatment as factors and the baseline value as the covariate. The proportion of patients achieving American Diabetes Association glycemic control targets in the two treatment groups was compared by using the Fisher exact test with data pooled across study centers because some centers had insufficient data. Safety variables were evaluated by using summary statistics. Role of the Funding Source Parke-Davis provided funding and facilitated the data collection and analysis for this study and approved submission of the manuscript for publication. The authors had final authority over the decision to submit the manuscript for publication. Results Patients Baseline demographic and disease-related characteristics were similar for the two treatment groups (Table 1). Two hundred patients were randomly assigned, and 178 patients (92 in the troglitazone group and 86 in the placebo group) completed the double-blind study (Figure 1). A small percentage of patients withdrew early, but these withdrawals were not concentrated at any study center and were evenly distributed across the two treatment groups. The only noted difference was in patient with