Long-term Safety of Pioglitazone versus Glyburide in Patients with Recently Diagnosed Type 2 Diabetes Mellitus

Rajeev Jain, MD; Kwame Osei, MD; Stuart Kupfer, MD; Alfonso T. Perez, MD; Jeff Zhang, MS

Pharmacotherapy. 2006;26(10):1388-1395. 

Abstract and Introduction

Abstract

Study Objective: To evaluate the long-term safety and efficacy of glyburide versus pioglitazone in patients with a recent diagnosis of type 2 diabetes mellitus.
Design: Prospective, randomized, multicenter, double-blind trial with a 16-week titration period and a 40-week maintenance period.
Setting: Sixty-five investigative sites in the United States and Puerto Rico.
Patients: Five hundred two subjects with a recent diagnosis of type 2 diabetes that was unsuccessfully treated with diet and exercise were randomly assigned to study treatment. Of the 251 patients in each treatment group, 128 (51.0%) glyburide-treated patients and 134 (53.4%) pioglitazone-treated patients completed the study.
Interventions: Dosages of randomly assigned glyburide and pioglitazone were titrated every 4 weeks for 16 weeks in 5-mg/day and 15-mg/day increments, respectively, until a fasting plasma glucose level between 69 and 141 mg/dl was achieved. The optimized regimen was maintained during the subsequent 40-week double-blind phase.
Measurements and Main Results: At week 56, glyburide and pioglitazone improved glucose control comparably (change in hemoglobin A1c -2.02% and -2.07%, respectively, p = 0.669). Withdrawal due to lack of efficacy or adverse events occurred more frequently with glyburide (20.8%) than pioglitazone (12.8%, p < 0.032). Significantly higher percentages of glyburide than pioglitazone treated patients had a hypoglycemic (24.3% vs 4.4%, p = 0.0001) or cardiac (8.8% vs 4.4%, p = 0.0478) event. Edema (4.8% vs 7.9%, p = 0.1443) and weight gain (4.4% vs 4.0%, p = 0.8238) did not differ significantly between the glyburide and pioglitazone groups. Only a few patients discontinued study drug because of weight gain (one glyburide, one pioglitazone), edema (one pioglitazone), or a cardiac event (two glyburide).
Conclusion: With long-term treatment, both glyburide and pioglitazone resulted in comparable glycemic control; however, pioglitazone was associated with less hypoglycemia and fewer withdrawals due to lack of efficacy or adverse events.

Introduction

Pioglitazone is an oral antidiabetic agent of the thiazolidinedione class indicated for use in patients with type 2 diabetes mellitus as an adjunct to diet and exercise or in combination with a sulfonylurea, metformin, or insulin when diet and exercise alone do not result in adequate glycemic control.[1] Thiazolidinediones act on peroxisome proliferator-activated receptors (PPARs),[2] which regulate glucose, lipid, and protein metabolism and influence cell proliferation, differentiation, and apoptosis.[3] Through selective agonism of PPAR-g receptors, thiazolidinediones inhibit hepatic glucogenesis and increase insulin sensitivity in muscle and adipose tissue, lowering glucose levels.3 Because thiazolidinediones do not stimulate insulin secretion but enhance the effects of circulating insulin, the antihyperglycemic effect can be achieved only in the presence of insulin.[1]

In addition to glycemic control, selected thiazolidinediones have been shown to have a beneficial effect on lipid profiles.[4] In support of these findings, several randomized controlled trials have demonstrated improved glycemic control and favorable lipid-altering effects with once-daily pioglitazone or with a combination of pioglitazone plus metformin, a sulfonylurea, repaglinide, or insulin.[4-9] In addition, a recent head-to-head comparison trial of the thiazolidinediones pioglitazone and rosiglitazone demonstrated comparable effects on glycemic control, although pioglitazone significantly lowered triglyceride levels, increased high-density lipoprotein cholesterol levels, and decreased the number of small, dense low-density lipoprotein cholesterol particles compared with rosiglitazone.[10]

Although thiazolidinediones have been associated with weight gain, edema, and slight reductions in hemoglobin and hematocrit levels (as a result of plasma volume expansion), several reports indicate that these adverse events are generally mild to moderate and infrequently lead to discontinuation of pioglitazone or rosiglitazone. Neither pioglitazone nor rosiglitazone has been associated with hepatotoxicity, which is linked to the thiazolidinedione troglitazone.[11]

Oral drugs of the sulfonylurea class, such as glyburide, stimulate insulin secretion by binding to and blocking adenosine 5¢-triphosphate- dependent potassium channels in β-cell membranes. This action increases intracellular calcium concentrations, inducing insulin secretion.[12] Because the therapeutic effect of sulfonylureas depends on their insulin secretory action, development of hypoglycemia is associated with their use.[13]

Type 2 diabetes mellitus is a lifelong disorder requiring long-term treatment. Because, to our knowledge, no long-term safety and efficacy data comparing glyburide with pioglitazone have been collected yet, this study was conducted to determine whether long-term treatment with glyburide versus pioglitazone is safe and effective in achieving and maintaining glycemic control in patients with recently diagnosed type 2 diabetes mellitus inadequately controlled with diet and exercise.

Methods

Patient Population

In this prospective, randomized, multicenter, double-blind, active comparator, parallel-group trial, we evaluated long-term glyburide versus pioglitazone use in patients with recently (≤ 2 yrs) diagnosed type 2 diabetes mellitus unsuccessfully treated with diet and exercise. This study was conducted in accordance with applicable United States Food and Drug Administration Code of Federal Regulations, the World Medical Association Declaration of Helsinki, and the International Conference on Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice. The institutional review board at each investigative site approved the protocol. Before enrollment, participants provided written informed consent.

Treatment-naïve men and nonpregnant, nonlactating women 18-80 years of age, from the United States or Puerto Rico, were eligible for enrollment. Treatment-naïve was defined as documented type 2 diabetes of less than 2 years' duration and not treated with the drugs listed below. At screening, patients were required to have hemoglobin A1c (A1C) between 7.5% and 11.5%, fasting C-peptide level of 1.0 ng/ml or greater, and fasting plasma glucose level above 120 mg/dl.

Any patient whose treatment had previously failed due to lack of efficacy or signs of intolerance, or who had recently (< 3 mo) undergone treatment with rosiglitazone, pioglitazone, or troglitazone could not participate in the study. Additional exclusion criteria included previous drug or alcohol abuse; previous treatment with any meglitinide analog, αglucosidase inhibitor, metformin, insulin, or sulfonylurea treatment for 3 months or more; use of hydrochlorothiazide greater than 25 mg/day, glucocorticoids, steroid joint injections, niacin greater than 250 mg/day, or antidiabetic agents other than the study drugs during the trial; concurrent participation or enrollment in another investigational study; serum creatinine level above 1.5 mg/dl for men and above 1.4 mg/dl for women; greater than 1+ dipstick proteinuria or equivalent; anemia with hemoglobin levels below 12 g/dl in men and below 10 g/dl in women; diastolic blood pressure above 100 mm Hg or systolic pressure above 180 mm Hg; body mass index below 20 or above 45; alanine aminotransferase (ALT) level more than 1.5 times the upper limit of normal or active liver disease or jaundice; or triglyceride level greater than 500 mg/dl. Patients were also excluded if they had a chronic condition expected to require recurrent glucocorticoid use, New York Heart Association class III or IV heart failure, an acute cardiovascular event within 6 months before screening including myocardial infarction, cerebrovascular accident, evidence of an ongoing cardiac disturbance, evidence of acute or unstable chronic pulmonary disease or lesions at chest radiography, or a history of cancer not in remission for at least 5 years.

After 2 weeks of screening patients for inclusion and exclusion criteria, patients were enrolled and randomly assigned 1:1 by means of a double-control design to receive pioglitazone 15 mg/day or glyburide 5 mg/day. Randomization was stratified according to use or nonuse of concomitant cholesterol-lowering drugs.

Protocol

At visit 1, all patients were instructed to take one tablet (pioglitazone or placebo) and one capsule (glyburide or placebo) each morning. During a 16-week titration period, glucose control was optimized by achieving and maintaining fasting plasma glucose levels between 69 and 141 mg/dl. Pioglitazone or glyburide dosages could be increased every 4 weeks in increments of 15 or 5 mg/day, respectively, to a maximum of pioglitazone 45 mg/day or glyburide 15 mg/day. After titration, patients began 40-week double-blind treatment in which the optimal study drug dosage was maintained for each patient. Patients were required to bring study drug containers to each visit, and tablets were counted to assess treatment compliance. The primary efficacy variable was mean change in A1C from baseline to week 56.

Adverse events, serious adverse events, and hypoglycemic events were recorded at each visit. Any untoward medical event concurrent with the use of the study drugs was considered an adverse event. A hypoglycemic event was reported if a patient had two or more usual symptoms of hypoglycemia concurrently, one symptom before ingesting a glucose or lactose containing substance, or a blood glucose level below 60 mg/dl (with home monitoring) or below 70 mg/dl (with clinical laboratory tests). Vital signs and weight were measured at all study visits. Clinical laboratory tests (hematology, serum chemistry, and urinalysis), 12-lead electrocardiography, and physical examinations were performed at screening and the final visit. Information on dietary intake and exercise was collected for each patient and could have been used by investigators for patient management, but these data were not used for statistical analyses.

Statistical Analyses

All statistical analyses were performed by using SAS version 8.0 or higher software (SAS Institute, Inc., 1990, Cary, NC) and were two-sided at a 0.05 significance level. All analyses were performed by using the intent-to-treat cohort, defined as any randomly assigned patient receiving one or more doses of study drug. The last observation carried forward was used for missing values in analyzing the difference from baseline to each measure after baseline.

Demographic and baseline characteristics, adverse events, serious adverse events, and laboratory examinations were summarized with use of descriptive statistics. Categoric data treatment comparisons were performed by using a Cochran-Mantel-Haenszel test controlling for pooled center. The primary efficacy measure was analyzed by using a two-way analysis of covariance (ANCOVA) with terms for treatment and center as the main effects, baseline as a covariate, and a treatment-by-center interaction term. The homogeneity of ANCOVA residual variances between treatment groups was checked with the Wilks-Shapiro test.

Results

A total of 502 patients from 65 investigative sites were enrolled and randomly assigned to receive pioglitazone 15 mg/day (251 patients) or glyburide 5 mg/day (251 patients). Of the 251 patients in each treatment group, 128 (51.0%) glyburide and 134 (53.4%) pioglitazone-treated patients completed the study. The mean treatment compliance rate was 96.8%.

Baseline demographic characteristics such as age, sex, and weight were comparable between groups (  ). In addition, no clinically relevant differences were noted between treatment groups in type of drugs taken or percentage of patients taking any concomitant drugs (glyburide 76.5%, pioglitazone 75.7%). During the 40-week maintenance period, the range of mean ± SD daily doses at each visit was 9.9 ± 4.33 to 10.5 ± 4.31 mg for glyburide and 34.9 ± 11.64 to 37.6 ± 11.30 mg for pioglitazone. The median daily dose at each visit was 10 mg for glyburide and 45 mg for pioglitazone.

Table 1.  Baseline Demographic Characteristics

Characteristic Glyburide Group (n=251) Pioglitazone Group (n=251) p Value
  No. (%) of Patients  
Sex 0.381
Male 141 (56.2) 133 (53.0)  
Female 110 (43.8) 118 (47.0)  
Race-ethnicity 0.335
Caucasian 165 (65.7) 153 (61.0)  
African-American 34 (13.5) 40 (15.9)  
Hispanic 50 (19.9) 52 (20.7)  
Asian 0 (0.0) 4 (1.6)  
Native American 1 (0.4) 1 (0.4)  
Other 1 (0.4) 1 (0.4)  
  Mean ± SD  
Age (yrs) 52.1 ± 12.39 52.1 ± 11.28 0.859
Height (cm) 169.5 ± 10.73 169.9 ± 10.01 0.678
Weight (kg) 94.3 ± 20.02 93.9 ± 19.67 0.828
Body mass index (kg/m2) 32.8 ± 5.71 32.5 ± 5.75 0.629
Waist:hip ratioa 0.94 ± 0.075 0.93 ± 0.073 0.360
Duration of diabetes (mo) 9.4 ± 15.18 9.6 ± 13.78 0.925
Hemoglobin A1c (%) 9.2 ± 1.26 9.2 ± 1.20 0.558
Fasting plasma glucose level (mg/dl) 183.8 ± 53.8 189.4 ± 51.5 0.267
C-peptide level (ng/ml) 3.74 ± 1.58 3.72 ± 1.59 0.989

 

an = 249 for the glyburide group, n = 250 for the pioglitazone group.

Long-term Efficacy

Treatment with glyburide or pioglitazone produced significant mean decreases in A1C from baseline by week 16 (-2.45% and -2.04%, respectively) for a mean treatment difference of 0.41% (p < 0.001; Figure 1). By week 56, however, glycemic control with glyburide had deteriorated (-2.02%), whereas it was maintained with pioglitazone (-2.07%) such that no difference in A1C was observed (mean treatment difference -0.05%, p = 0.669). Treatment responsiveness was also comparable with either treatment by week 56: 131 (88.5%) of 148 glyburide-treated patients and 129 (87.2%) of 148 pioglitazone-treated patients demonstrated an A1C less than or equal to normal range (4.3-6.1%) or a decrease of 0.65 units or more from baseline. Furthermore, the proportion of patients who achieved an A1C less than 7.0% by week 56 was also comparable between groups: 99 (66.9%) of 148 glyburide-treated patients and 102 (68.9%) of 148 pioglitazone-treated patients.

Figure

 

Mean change from baseline in hemoglobin A1c (A1C) through week 56 (last observation carried forward, intent-to-treat cohort). Results are least squares mean changes from baseline ± standard error. Baseline mean ± SD A1C values: glyburide (filled diamonds, n = 251) 9.16 ± 1.255%, pioglitazone (open squares, n = 251) 9.23 ± 1.196%. *p < 0.001, glyburide vs pioglitazone.

Reasons for withdrawal are displayed in  . Overall, the rate of early withdrawal before week 56 because of insufficient therapeutic efficacy or an adverse event was significantly higher with glyburide (20.8%, 44 patients) than with pioglitazone (12.8%, 25 patients; p = 0.032).

Table 2.  Reasons for Withdrawal from Treatment

Reason No. (%) of Patients p Value
Glyburide Group (n=251) Pioglitazone Group (n=251)
Lack of Efficacy 29 (11.6) 18 (7.2) 0.092
Adverse Events 25 (10.0) 14 (5.6) 0.067
   Hypoglycemia 9 (3.6) 0 (0.0) 0.004
Patient Noncompliance 15 (6.0) 14 (5.6) 0.848
Lost to Follow-up 21 (8.4) 22 (8.8) 0.873
Consent Withdrawal 21 (8.4) 28 (11.2) 0.293
Protocol Violation 8 (3.2) 14 (5.6) 0.191
Investigator Discretion 3 (1.2) 7 (2.8) 0.339
Site Closure 1 (0.4) 0 (0.0) 1.000
Total Patient Withdrawals 123 (49.0) 117 (46.6) 0.592

Safety

During 56 weeks of study drug exposure and 30 days after the final visit, 209 (83.3%) glyburide-treated and 205 (81.7%) pioglitazone-treated patients had one or more adverse events, most (69.7%) of which were mild to moderate. The rate of patient withdrawal due to an adverse event was higher in the glyburide (10.0% [25 of 251 patients]) than in the pioglitazone group (5.6% [14 of 251 patients];  ). On the basis of investigator determinations, 92 (36.7%) glyburide-treated and 69 (27.5%) pioglitazone-treated patients reported a treatment-related adverse event. The most frequently reported adverse events and serious adverse events are displayed in  .

Table 2.  Reasons for Withdrawal from Treatment

Reason No. (%) of Patients p Value
Glyburide Group (n=251) Pioglitazone Group (n=251)
Lack of Efficacy 29 (11.6) 18 (7.2) 0.092
Adverse Events 25 (10.0) 14 (5.6) 0.067
   Hypoglycemia 9 (3.6) 0 (0.0) 0.004
Patient Noncompliance 15 (6.0) 14 (5.6) 0.848
Lost to Follow-up 21 (8.4) 22 (8.8) 0.873
Consent Withdrawal 21 (8.4) 28 (11.2) 0.293
Protocol Violation 8 (3.2) 14 (5.6) 0.191
Investigator Discretion 3 (1.2) 7 (2.8) 0.339
Site Closure 1 (0.4) 0 (0.0) 1.000
Total Patient Withdrawals 123 (49.0) 117 (46.6) 0.592

Table 3.  Adverse Events with a Frequency of at Least 5% and Serious Adverse Events with a Frequency of at Least 0.5% in Either Treatment Group: Intent-to-Treat Cohort

MedDRA Preferred Term No. (%) of Patients
Glyburide Group (n=251) Pioglitazone Group (n=251)
Any adverse event 209 (83.3) 205 (81.7)
Hypoglycemia NOS 61 (24.3) 11 (4.4)
Upper respiratory tract infection NOS 31 (12.4) 32 (12.7)
Headache NOS 22 (8.8) 19 (7.6)
Sinusitis NOS 24 (9.6) 15 (6.0)
Arthralgia 19 (7.6) 13 (5.2)
Diarrhea NOS 16 (6.4) 15 (6.0)
Back pain 18 (7.2) 12 (4.8)
Bronchitis NOS 8 (3.2) 19 (7.6)
Pain in limb 14 (5.6) 10 (4.0)
Edema, lower limb 8 (3.2) 14 (5.6)
Any serious adverse event 22 (8.8) 23 (9.2)
Coronary artery disease NOS 4 (1.6) 0 (0.0)
Myocardial infarction 2 (0.8) 2 (0.8)
Chest pain NEC 2 (0.8) 1 (0.4)
Ankle fracture 2 (0.8) 0 (0.0)
Colon cancer stage IV 2 (0.8) 0 (0.0)

 

MedDRA = Medical Dictionary for Regulatory Activities, version 3.3; NOS = not otherwise specified; NEC = not elsewhere classified.

Two deaths were reported during the study, both in patients taking glyburide: one death was due to coronary artery disease (not otherwise specified), and the other was due to respiratory failure. Neither event was considered related to glyburide.

Overall, hypoglycemia was the most common adverse event; treatment with glyburide produced a significantly greater rate of hypoglycemia (24.3%) than that with pioglitazone (4.4%, p < 0.001;  ). In addition, the number of hypoglycemic episodes among glyburide-treated patients (176 episodes) was greater than 7-fold the number among pioglitazone-treated patients (24 episodes). Recurrent hypoglycemia (Ž 2 events) was significantly higher with glyburide (33 patients) than pioglitazone (six patients, p = 0.0001). These episodes caused nine patients (3.6%) in the glyburide group to discontinue treatment early; no patients in the pioglitazone group withdrew due to hypoglycemia.

Table 3.  Adverse Events with a Frequency of at Least 5% and Serious Adverse Events with a Frequency of at Least 0.5% in Either Treatment Group: Intent-to-Treat Cohort

MedDRA Preferred Term No. (%) of Patients
Glyburide Group (n=251) Pioglitazone Group (n=251)
Any adverse event 209 (83.3) 205 (81.7)
Hypoglycemia NOS 61 (24.3) 11 (4.4)
Upper respiratory tract infection NOS 31 (12.4) 32 (12.7)
Headache NOS 22 (8.8) 19 (7.6)
Sinusitis NOS 24 (9.6) 15 (6.0)
Arthralgia 19 (7.6) 13 (5.2)
Diarrhea NOS 16 (6.4) 15 (6.0)
Back pain 18 (7.2) 12 (4.8)
Bronchitis NOS 8 (3.2) 19 (7.6)
Pain in limb 14 (5.6) 10 (4.0)
Edema, lower limb 8 (3.2) 14 (5.6)
Any serious adverse event 22 (8.8) 23 (9.2)
Coronary artery disease NOS 4 (1.6) 0 (0.0)
Myocardial infarction 2 (0.8) 2 (0.8)
Chest pain NEC 2 (0.8) 1 (0.4)
Ankle fracture 2 (0.8) 0 (0.0)
Colon cancer stage IV 2 (0.8) 0 (0.0)

 

MedDRA = Medical Dictionary for Regulatory Activities, version 3.3; NOS = not otherwise specified; NEC = not elsewhere classified.

Two (0.8%) glyburide-treated patients withdrew due to a cardiovascular event: coronary artery disease (not otherwise specified) and myocardial infarction. The overall rate of cardiovascular events was 2-fold higher in glyburide-treated patients (8.8% [22 patients]) than in pioglitazone-treated patients (4.4% [11 patients], p = 0.0478); eight (3.2%) glyburide-treated patients and three (1.2%) pioglitazone-treated patients had a cardiac serious adverse event. The rate of congestive heart failure (0.4%) was similar with either treatment, occurring in one patient in each treatment group.

Edema occurred in 7.9% of patients (20 patients) taking pioglitazone and 4.8% of patients (12 patients) taking glyburide (p = 0.1443); these occurrences were constituted primarily by lower extremity edema (  ). Consequently, one (0.4%) pioglitazone-treated patient discontinued treatment early due to edema compared with none in the glyburide group.

Table 3.  Adverse Events with a Frequency of at Least 5% and Serious Adverse Events with a Frequency of at Least 0.5% in Either Treatment Group: Intent-to-Treat Cohort

MedDRA Preferred Term No. (%) of Patients
Glyburide Group (n=251) Pioglitazone Group (n=251)
Any adverse event 209 (83.3) 205 (81.7)
Hypoglycemia NOS 61 (24.3) 11 (4.4)
Upper respiratory tract infection NOS 31 (12.4) 32 (12.7)
Headache NOS 22 (8.8) 19 (7.6)
Sinusitis NOS 24 (9.6) 15 (6.0)
Arthralgia 19 (7.6) 13 (5.2)
Diarrhea NOS 16 (6.4) 15 (6.0)
Back pain 18 (7.2) 12 (4.8)
Bronchitis NOS 8 (3.2) 19 (7.6)
Pain in limb 14 (5.6) 10 (4.0)
Edema, lower limb 8 (3.2) 14 (5.6)
Any serious adverse event 22 (8.8) 23 (9.2)
Coronary artery disease NOS 4 (1.6) 0 (0.0)
Myocardial infarction 2 (0.8) 2 (0.8)
Chest pain NEC 2 (0.8) 1 (0.4)
Ankle fracture 2 (0.8) 0 (0.0)
Colon cancer stage IV 2 (0.8) 0 (0.0)

 

MedDRA = Medical Dictionary for Regulatory Activities, version 3.3; NOS = not otherwise specified; NEC = not elsewhere classified.

Increase in weight was reported as an adverse event with both glyburide and pioglitazone treatment and occurred at a similar rate in both groups (4.4% [11 patients] and 4.0% [10 patients], respectively, p = 0.8238). At the final visit, mean ± SD weight increase from baseline was significantly greater in the pioglitazone group than the glyburide group (3.66 ± 6.138 kg vs 1.95 ± 5.354 kg, p < 0.001). Weight increase led to study discontinuation for one glyburide- and one pioglitazone-treated patient. No clinically important changes in vital signs, electrocardiograms, or physical examination findings were reported.

At the final visit, mean ± SD ALT level decreased from baseline in both groups; a greater decrease was observed with pioglitazone (-6.3 ± 15.33 U/L) than glyburide (-1.4 ± 12.75 U/L). This result is consistent with observations that a higher proportion of glyburide-treated patients (25 [12.1%] of 206) than pioglitazone-treated patients (9 [4.3%] of 209, p = 0.008) exceeded the upper limit of normal for ALT at the final visit despite no difference at baseline. One patient discontinued pioglitazone treatment because of elevated ALT (>3 times the upper limit of normal). No other clinically relevant abnormal laboratory values or shifts in laboratory values were observed during this study.

Discussion

A direct comparison of glyburide and pioglitazone monotherapy among patients with recently diagnosed type 2 diabetes mellitus demonstrated that pioglitazone is a safe and effective first-line treatment for long-term use. The overall tolerability, adverse-effect profile, and improved level of glycemic control with glyburide and pioglitazone in this trial are consistent with those of previous reports that compared sulfonylureas and thiazolidinediones.[14-16]

After 56 weeks of treatment, glycemic control based on A1C was comparable between the glyburide and pioglitazone groups. However, the profile of A1C measurements from 16-56 weeks suggests a trend of deteriorating glycemic control in the glyburide group and sustained glycemic control in the pioglitazone group. Although these trends are subtle, this observation is consistent with that of reports comparing pioglitazone and gliclazide[14,15] as well as reports on sulfonylurea therapy in the United Kingdom Prospective Diabetes Study (UKPDS).[16] Because these trials enrolled only patients with recently diagnosed type 2 diabetes mellitus, one possibility for deteriorating glycemic control with sulfonylurea monotherapy may have been declining β-cell function with disease progression. The A1C profile from the current study suggests that pioglitazone sustains its efficacy over a longer time than do sulfonylureas and indicates possible β-cell-sparing effects with pioglitazone.[17] Consistent with this possibility, early discontinuation of treatment was greater with glyburide than pioglitazone monotherapy, which in part was attributable to lack of therapeutic efficacy.

The frequency of adverse events leading to study drug discontinuation was also higher with glyburide than pioglitazone. Not unexpectedly, hypoglycemia was the most common adverse event leading to glyburide treatment discontinuation. Adverse events typically attributed to thiazolidinedione therapy, such as edema and weight gain, were observed with both treatments during this trial. Although edema affecting the extremities was reported by more patients treated with pioglitazone than with glyburide, each event was classified as mild or moderate, except one case of severe edema in a pioglitazone-treated patient. The weight increase observed with either treatment is also consistent with results reported in other controlled clinical trials and is a known adverse effect of both drugs.[13] Several interrelated factors, including decreased glycosuria and caloric retention with improved glycemic control, expansion of the subcutaneous fat depot, and fluid retention have been suggested explanations for weight gain with thiazolidinediones.[18]

Overall, a greater mean decrease in ALT was noted with pioglitazone than with glyburide. In addition, a higher proportion of patients treated with glyburide exceeded the upper limit of normal for ALT at the final visit compared with patients treated with pioglitazone. Together these findings support previous reports that pioglitazone reduces hepatic fat content and is not associated with hepatotoxic adverse effects.19

Although this study was not powered to evaluate cardiac outcomes, the frequency of cardiac disorders was 2-fold greater in glyburide than pioglitazone treated patients. Of note, congestive heart failure was reported in only two patients in the trial, one in each treatment group. However, patients with New York Heart Association class III or IV cardiac disorders were not included in this trial.

Interpretation of the study results is limited by the high rate of patient withdrawal. However, the rate of attrition likely did not introduce a selection bias, as an equivalent number of subjects in each treatment group (glyburide 49.0%, pioglitazone 46.6%) withdrew from the study before week 56. Another limitation of this study is that patients were not treated with exactly comparable doses of pioglitazone and glyburide. Patients in the pioglitazone group were taking a mean daily dose of approximately 36 mg (maximum recommended dose 45 mg), whereas patients in the glyburide group were taking a mean daily dose of approximately 10 mg (maximum recommended dose 20 mg). However, since this study was designed as a treat-to-target study, investigators were instructed to adjust the study drug dosage as necessary to achieve and maintain a fasting plasma glucose level between 69 and 141 mg/dl. The observation that glycemic control was equivalent between groups indicates that the investigators complied with this objective.

Conclusion

Patients with type 2 diabetes mellitus achieve glycemic control safely and effectively with both pioglitazone and glyburide treatment; however, the results of this study suggest that long-term treatment with pioglitazone is superior to glyburide with respect to tolerability. Overall, pioglitazone treatment resulted in sustained glycemic control, fewer patient withdrawals due to lack of efficacy or hypoglycemia, and fewer cardiac events compared with glyburide.

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