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Comparison of Pioglitazone and Gliclazide in Sustaining Glycemic Control Over 2 Years in Patients With Type 2 Diabetes

¹ Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana
² Isle of Wight Healthcare, National Health Service Trust, St. Mary’s Hospital, Newport, Isle of Wight, U.K
³ Second Department of Internal Medicine, Faculty Hospital, Comenius University, Mickiewiczona, Bratislava, Slovak Republic
⁴ NZOZ GCP Dobra Pratyka Lebarska, ul che-mi-ska, Grudzi-dz, Poland
⁵ Medyczyne Centrum, Diabetologiczno-Endokrynologia, Diabetologia Rusznikarska, Krakow, Poland
⁶ Takeda Europe Research and Development Centre, London, U.K

Address correspondence and reprint requests to Dr. Meng H. Tan, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285. E-mail: tan_meng{at}lilly.com

	ABSTRACT

TOP ABSTRACT INTRODUCTION RESEARCH AND DESIGN METHODS RESULTS CONCLUSIONS References

 
OBJECTIVE—The hypothesis that pioglitazone treatment is superior to gliclazide treatment in sustaining glycemic control for up to 2 years in patients with type 2 diabetes was tested.

RESEARCH DESIGN AND METHODS—This was a randomized, multicenter, double-blind, double-dummy, parallel-group, 2-year study. Approximately 600 patients from 98 centers participated. Eligible patients had completed a previous 12-month study and consented to continue treatment for a further year. To avoid selection bias, all patients from all centers were included in the primary analysis (a comparison of the time-to-failure distributions of the two groups by using a log-rank test) regardless of whether they continued treatment for a 2nd year. By using repeated-measures ANOVA, time course of least square means of HbA_1c and homeostasis model of assessment (HOMA) indexes (HOMA-%S and HOMA-%B) were analyzed.

RESULTS—A greater proportion of patients treated with pioglitazone maintained HbA_1c <8% over the 2-year period than those treated with gliclazide. A difference between the Kaplan-Meier curves was apparent as early as week 32 and widened at each time point thereafter, becoming statistically significant from week 52 onward. At week 104, 129 (47.8%) of 270 pioglitazone-treated patients and 110 (37.0%) of 297 gliclazide-treated patients maintained HbA_1c <8%. Compared with gliclazide treatment, pioglitazone treatment produced a larger decrease in HbA_1c, a larger increase in HOMA-%S, and a smaller increase in HOMA-%B during the 2nd year of treatment.

CONCLUSIONS—Pioglitazone is superior to gliclazide in sustaining glycemic control in patients with type 2 diabetes during the 2nd year of treatment.

Abbreviations: FPG, fasting plasma glucose • FSI, fasting serum insulin • HOMA, homeostasis model of assessment • IFG, impaired fasting glucose • IGT, impaired glucose tolerance • OAM, oral antihyperglycemic medication

	INTRODUCTION

TOP ABSTRACT INTRODUCTION RESEARCH AND DESIGN METHODS RESULTS CONCLUSIONS References

 
Type 2 diabetes, with its core defects of insulin resistance and relative insulin deficiency, is a progressive disease. Insulin resistance remains generally stable throughout the natural history of the disease, but there is a progressive loss of glycemic control due to the continuing loss of ß-cell function. The U.K. Prospective Diabetes Study (1) showed that at diagnosis, patients have already lost 50% of their ß-cell function, which was further reduced to 30% at 5 years.

The standard approach at initial diagnosis for many patients with type 2 diabetes is a prescription of diet and physical activity to correct their hyperglycemia. When glycemic targets cannot be attained or maintained with this approach, an oral antihyperglycemic medication (OAM) is added to the lifestyle regimen. When monotherapy fails, treatment is changed to combination OAM therapy, OAMs plus insulin, or insulin therapy (2). Most patients initially respond to OAM monotherapy when they use it. However, with continued therapy, some patients can no longer achieve their glycemic target. The inability to maintain the glycemic target may indicate progression of disease rather than lack of response to a drug (3,4).

Sulfonylureas, first introduced in the mid-1950s, are commonly used as monotherapy in patients with type 2 diabetes (5). More recently, two thiazolidinediones, pioglitazone and rosiglitazone, were approved for use as monotherapy for patients with type 2 diabetes who cannot achieve their glycemic targets with diet treatment (in Europe, patients who cannot tolerate metformin). Several groups have compared both thiazolidinediones with sulfonylureas with regard to their glycemic effects in 1-year studies (6–8). They have shown similar decreases in HbA_1c after 1 year of treatment. However, the pattern of glycemic control over time suggested that despite the quicker onset of action with sulfonylurea, the effects were less well maintained in the longer term. It is possible that the long-term glycemic effect of sulfonylureas and thiazolidinediones are not the same because of the differences in their mechanisms of action. Sulfonylureas stimulate the secretion of insulin by the patient’s pancreatic ß-cells and the resultant hyperinsulinemia corrects the hyperglycemia (5). Pioglitazone is a peroxisome proliferator–activated receptor agonist that reduces insulin resistance in peripheral organs (enhanced total body glucose disposal) and in the liver (decreased hepatic glucose production) (9).

We tested the hypothesis that pioglitazone, because it reduces insulin resistance, is superior to sulfonylurea in sustaining glycemic control beyond 1 year in patients with type 2 diabetes. This hypothesis was tested by comparing the time to failure for maintaining HbA_1c <8% in patients treated with pioglitazone or gliclazide for as long as 2 years. We also report the time course of HbA_1c, fasting plasma glucose (FPG), fasting serum insulin (FSI), and homeostasis model assessment (HOMA) for insulin sensitivity (HOMA-%S, an insulin sensitivity surrogate), and for ß-cell activity (HOMA-%B, a surrogate for ß-cell activity).

	RESEARCH AND DESIGN METHODS

TOP ABSTRACT INTRODUCTION RESEARCH AND DESIGN METHODS RESULTS CONCLUSIONS References

 
This was a randomized, multicenter, double-blind, double-dummy, parallel-group, 2-year study conducted in Australia, Canada, Finland, Poland, the Slovak Republic, South Africa, and the U.K. in accordance with good clinical practice guidelines and the principles of the Declaration of Helsinki. The institutional review board at each center approved the study protocol. Patients provided written informed consent before participation.

The primary analysis was the time to failure to maintain glycemic control (HbA_1c <8%). At the time this study was designed, the American Diabetes Association (10) recommended that additional action was suggested when the patient’s HbA_1c was >8%. For this study, we chose this as the failure threshold and not the treatment target. We determined that a sample size of 300 patients per group would provide at least 80% power to detect an 11% survival difference between treatments in the distributions of time to failure to maintain glycemic control with a log-rank test ( = 0.05, two sided), assuming a 60% success rate in maintaining glycemic control in the gliclazide group. Thus, of the original 206 centers from the parent study, a subset of 98 centers, with 600 patients to satisfy the sample size requirements, was involved in this study (Fig. 1). The 98 centers were selected solely on the basis of the numbers of patients recruited for the parent study. Outcomes of the parent study were not known at the time of the selection of these 98 centers because the parent study was still ongoing. All patients who completed the 1-year parent study at these 98 centers were invited to participate in the extension of the parent study. Those who consented continued treatment for a further year. In the gliclazide group, 34 patients did not consent, and in the pioglitazone group, 22 patients did not consent. To avoid selection bias, all patients from the 98 centers were included in the primary analysis, regardless of whether they continued treatment for a 2nd year. This included 297 patients randomized to gliclazide and 270 patients randomized to pioglitazone at the beginning of the parent study.

View larger version (21K): [in this window] [in a new window]   Figure 1— Patient recruitment and disposition.

We obtained fasting blood samples at each study visit for determination of HbA_1c, FPG, and FSI at a central laboratory as previously reported (11). By using HOMA, HOMA-%S and HOMA-%B were calculated (12). HOMA-%S is a surrogate for insulin sensitivity and HOMA-%B is a surrogate of ß-cell activity.

The primary efficacy analysis was a comparison of the time-to-failure distributions of the two treatment groups by using a log-rank test (13). Time to failure was measured as the time from randomization to a visit at which HbA_1c was 8%. Failure could not occur, however, until after completion of the titration period (week 16). Thus, the earliest time to failure was 24 weeks: the first visit after the titration period.

For patients who discontinued participation from the study for reasons other than reaching the failure threshold (e.g., adverse events, withdrawal of consent), if their HbA_1c level was 8% before or at the time of their withdrawal, they were classified in the category of treatment failure at the time of the above threshold value. If the discontinuing patient had HbA_1c less than the failure threshold, patient data were right censored for the analysis.

Secondary efficacy analyses were performed to compare treatments regarding prespecified end points: HbA_1c, FPG, FSI, HOMA-%S, and HOMA-%B. For each of the secondary efficacy measures, a likelihood-based repeated-measures ANCOVA was conducted using the Proc Mixed implementation of SAS (version 8.2; SAS Institute, Cary, NC). The statistical model included treatment, time, treatment by time interaction, and the baseline value of the dependent variable as independent variables and employed an unstructured covariance matrix to model the within-patient error. Least-squares means were estimated for each treatment at each time point. The difference between treatments was compared at each time point based on Student’s t test (14).

	RESULTS

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Patient demographic, baseline characteristics, and disposition
The pioglitazone and gliclazide groups were similar in age, duration of diabetes, height, weight, BMI, ethnicity, and sex distribution (Table 1). Participants were mainly middle-aged, obese, white patients who had diabetes for <3 years at entry into the study. Table 1 also shows the primary reasons for discontinuation from the study in both groups. For the adverse events category, 6 of 33 (18%) patients discontinued in the pioglitazone group, compared with 1 of 25 (4%) in the gliclazide group, because of weight increase. In the gliclazide group, 3 of 25 (12%) discontinued because of headaches compared with none in the pioglitazone group.

View larger version (14K): [in this window] [in a new window]   Figure 2— Kaplan-Meier curves showing the proportion of patients in pioglitazone and gliclazide treatment groups not failing (HbA1c <8%) at various time points during the 2 years.

Time course of HbA_1c and FPG
Figure 3A shows the time course of least square means for HbA_1c for both groups. Both groups had similar baseline HbA_1c. Between weeks 4 and 24, gliclazide treatment improved HbA_1c more than pioglitazone treatment did. At weeks 32 and 42, there was no difference in the HbA_1c between the two groups. From week 52 to 104, pioglitazone treatment improved HbA_1c more than gliclazide treatment did. At week 104, pioglitazone treatment lowered HbA_1c significantly more than did gliclazide treatment (pioglitazone-gliclazide HbA_1c –0.45 ± 0.11%; 95% confidence limit –0.66 to –0.23).

View larger version (25K): [in this window] [in a new window]   Figure 3— Time courses of HbA1c, FPG, and body weight during the 2-year treatment period. Time courses of HbA1c (A), FPG (B), and body weight (C) are shown. Data are presented as least square means ± SE.

Figure 3C shows the time course of least square means of body weight of patients for both groups. Both groups had similar body weight at baseline. At the end of the study, the pioglitazone group (n = 146) gained more weight than the gliclazide group (n = 127) (final weight of the two groups were 95.6 ± 0.42 vs. 93.4 ± 0.42 kg; P < 0.001).

Time course in FSI, HOMA-%S, and HOMA-%B
Figure 4A shows the time course of least square means for FSI for both groups. Both groups had similar baseline FSI. In contrast to gliclazide treatment, which increased FSI, pioglitazone treatment decreased FSI from week 4 to 104. At week 104, the pioglitazone treatment group had lower FSI than the gliclazide treatment group (pioglitazone-gliclazide FSI: –52.9 ± 9.9 pmol/l; 95% confidence limit –72.6 to –33.3).

View larger version (32K): [in this window] [in a new window]   Figure 4— Time courses of FSI, HOMA-%S, and HOMA-%B during the 2-year treatment period. Time courses of FSI (A), HOMA-%S (B), and HOMA-%B (C) are shown. Data are presented as least square means ± SE.

Figure 4C shows the time course of least square means for HOMA-%B for both groups. Both groups had similar baseline HOMA-%B. Overall, gliclazide treatment increased HOMA-%B more than pioglitazone treatment did from week 4 to 104. Between weeks 4 and 42, the difference in HOMA-%B between the two groups was substantial. After week 42, the increase in HOMA-%B in the gliclazide treatment group was much less. Hence, between weeks 52 and 104, the difference in HOMA-%B between the two groups was small. At week 104, the gliclazide treatment group had slightly higher HOMA-%B than the pioglitazone treatment group (pioglitazone-gliclazide HOMA-%B: –9.1 ± 3.7%; 95% confidence limit –16.3 to –1.82).

	CONCLUSIONS

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Several studies reported that sulfonylurea treatment, when compared with thiazolidinedione treatment, had a greater antihyperglycemic effect for as long as 4 months after therapy initiation. This effect was shown when glibenclamide (6) and glimepiride (7) were compared with pioglitazone. However, at week 52, both drugs (glibenclamide or glimepiride versus pioglitazone) showed comparable decreases in HbA_1c. This change was also observed when rosiglitazone was compared with glyburide in an open-label study (8). Glyburide resulted in an initially rapid reduction in HbA_1c, after which glycemic control deteriorated from week 16 to 52. There was no difference in HbA_1c between the rosiglitazone and glyburide groups at week 52. Similar findings were observed with gliclazide versus pioglitazone after 1 year (11). The present study extends these previous observations by analyzing time-to-treatment failure with pioglitazone and gliclazide over a 2-year treatment period and by describing the concomitant changes in HbA_1c, FPG, FSI, HOMA-%S, and HOMA-%B during this period.

These findings support the hypothesis that pioglitazone treatment is superior to gliclazide treatment in sustaining glycemic control in patients with type 2 diabetes by showing that the proportion of patients in the pioglitazone group who maintained HbA_1c <8% at any time during the 2nd year of treatment was higher than that in the gliclazide group (Fig. 2). The difference between the two treatment groups widened with each subsequent study visit. Furthermore, from week 52 onward, pioglitazone treatment improved HbA_1c and FPG more than gliclazide treatment (Fig. 3).

Kahn (15) proposed a model for the spectrum of glucose intolerance based on the relationship between insulin sensitivity and insulin secretion. As insulin sensitivity decreases, insulin secretion must proportionally increase to enable the subject to have normal glucose tolerance. If the insulin secretion is not proportionally increased, deterioration of glucose intolerance can occur. An extrapolation of this is that if insulin sensitivity is increased, insulin secretion can decrease proportionally.

HOMA is a widely used clinical tool and provides a method of assessing insulin sensitivity (or insulin resistance) and ß-cell activity from basal (fasting) glucose and insulin (16). Whereas pioglitazone treatment increased HOMA-%S, it was decreased by gliclazide treatment (Fig. 3B). The difference in insulin sensitivity between the pioglitazone and gliclazide groups is sustained throughout the 2 years. In contrast, the difference in ß-cell activity caused by the pioglitazone and gliclazide was not. In the gliclazide group, the initial rapid increase in HOMA-%B (which reflected the increase in ß-cell activity) during the first 16 weeks of treatment (titration period) declined substantially thereafter. In the pioglitazone group, the initial increase in HOMA-%B with pioglitazone treatment was smaller compared with that of gliclazide treatment, but the increase was maintained throughout the 2-year treatment period. These changes in HOMA-%B over time resulted in a large difference between the two groups at week 16 and a smaller difference during the 2nd year (Fig. 4C). The combination of a substantial difference in HOMA-%S and a small difference in HOMA-%B from week 52 to 104 may partially explain the difference between the two treatments in glycemic control during this period.

The relative contributions of insulin-stimulated glucose uptake and basal hepatic insulin sensitivity to surrogate measures of insulin sensitivity were recently described by Tripathy et al. (17). The M value of glucose clamp studies correlated with HOMA-IR in subjects with normal glucose tolerance and in patients with type 2 diabetes. However, there was no such correlation in subjects with either impaired fasting glucose (IFG) alone or IFG/impaired glucose tolerance (IGT). The HOMA-IR correlated with hepatic insulin sensitivity in patients with type 2 diabetes and in subjects with IFG/IGT. The authors concluded that these discrepancies develop as a result of a nonparallel deterioration of the variables included in the calculation with worsening glucose tolerance.

Groop et al. (4) reported that hepatic overproduction of glucose combined with impaired peripheral glucose metabolism accounted for 43.4% of their cases. Miyazaki et al. (9) reported that pioglitazone treatment in patients with type 2 diabetes, receiving monotherapy or combination pioglitazone and sulfonylurea therapy, decreased their hepatic glucose production and increased their total body glucose disposal. Recently, Bajaj et al. (18) showed that pioglitazone monotherapy decreased hepatic glucose production and increased whole-body glucose disposal. The decrease in hepatic glucose production was negatively correlated with the increase in plasma adiponectin concentration and positively with the reduction in hepatic fat content in these patients. The increase in whole-body glucose disposal was positively correlated with the increase in plasma adiponectin concentration. Whether the enhancement of insulin sensitivity in the pioglitazone group enabled it to have a more sustained glycemic effect than did gliclazide group that improved the hyperglycemia via hyperinsulinemia remains to be established.

Other causes may contribute to the differences in sustaining glycemic improvement in patients with type 2 diabetes treated with drugs (4). Among patient-related factors, BMI and age at diagnosis may play a role. Patients with type 2 diabetes with lower BMI at diagnosis have been considered to eventually require insulin, and this has been shown for sulfonylurea "secondary failure" (19). In the present study, the BMIs of the two groups were comparable and therefore not a factor. Others have reported that the age at diagnosis may influence the duration of successful sulfonylurea therapy (20). In the present study, the mean ages of the patients were similar in both groups. Because the duration of diabetes can affect secondary failure with OAM therapy (21) or progression of type 2 diabetes, the proportion of patients who fail to maintain HbA_1c <8% at different diabetes durations may vary. In this study, the mean duration of diabetes (3 years) for the participants was similar in both groups. Different sulfonylureas have different secondary failure rates: gliclazide 7%, glibenclamide 17.9%, and glipizide 25.6% (22). The difference be-tween pioglitazone and other sulfonylureas in maintaining a glycemic target is not established.

In closing, results of this study show that pioglitazone is superior to gliclazide in sustaining glycemic control in patients with type 2 diabetes during the 2nd year of treatment. The combination of a substantial difference in HOMA-%S and a small difference in HOMA-%B from week 52 to 104 may explain the difference between the two treatments in glycemic control over time. Whether enhanced insulin sensitivity in the pioglitazone group promoted a more sustained glycemic effect than did gliclazide (which decreased hyperglycemia via hyperinsulinemia) remains to be established.

	Acknowledgments

 
Takeda Europe Research and Development Centre, London, U.K., and Eli Lilly and Company, Indianapolis, Indiana, sponsored this study.

The authors thank Jane Pinaire, PhD, Neehar Gupta, MSc, Mario Widel, MS, and Todd Cravens, BA, for assistance in the preparation of this manuscript. In addition, the authors thank all of the investigators who participated in this study, without whose assistance this manuscript would not have been possible.

	Footnotes

 
A.B. has received grant/research support from Quintiles.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

Received for publication August 30, 2004. Accepted for publication December 12, 2004.

	References

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tan, M. H. Search for Related Content PubMed PubMed Citation Articles by Tan, M. H. Social Bookmarking                What's this?