Comparison of Glyburide

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.