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Pioglitazone liver enzyme profile is similar to placebo in US controlled clinical trials
Track 2. Clinical Research & Care lipid profile in patients with type 2 diabetes was evaluated in a multicenter, open-label, dose titration, monotherapy study. Patients (n=270) entering this study from a randomized, double-blind, dose-ranging study (rollover patients) were to start open-label PIO 7.5 mg once daily for < 4 weeks. Patients (n=299) entering the study directly (newly enrolled) were to complete an 8-week lead-in period before starting open-label PIO 7.5 mg once daily for < 4 weeks. The dose of PIO could be up-titrated to a maximum of 60 mg/day. An interim analysis of the ongoing, open-ended study was performed for those patients (n--276) who had completed 48 weeks of open-label therapy. Baseline was defined as the last measurement of the lead-in period for newly enrolled patients and the last measurement in the previous study for rollover patients. Mean HbAlc and FBG at baseline and A from baseline are reported below. NewlyEnrolled
RolloverPlacebo
RolloverPIO
Total
165 9.71 -1.57
23 9.86 -0.99
86 9.59 -1.03
274 9.68 -1.35
166 250.1 -74.9
23 243.3 -52.7
87 246.8 -59.2
276 248.5 -68. I
HbAlc (%) N Baseline A from Baseline FBG (mg/dL) N Baseline A from Baseline
PIO (up to 60 mg) once daily for up to 48 weeks was associated with reductions in mean HbAlc and FBG. Mean fasting plasma triglyceride levels were decreased while mean HDL-C levels were increased. Mean total cholesterol and LDL-C levels were not adversely affected. No increased incidence of adverse events was noted during the long-term treatment period. PIO monotherapy administered once daily improves long-term glycemic control and lipid profile in patients with type 2 diabetes. [Efficacy data from the continuation of the study will be presented.]
I'293 The Long-Term Effect of Pioglitazone as Monotherapy or Combination-Therapy on Glucose Control in Patients with Type 2 Diabetes JOHN W. EGAN 1, Renee Librizzi 2, James S. Geerlof 3. The Pioglitazone
031 Study Group ACTOS TM (pioglitazone hydrochloride) is a thiazolidinedione compound marketed for the treatment of patients with type 2 diabetes mellitus and is indicated for use as monotherapy and in combination with a sulfonylurea (SU), metformin (MET), or insulin (INS). The long-term effect of pioglitazone (PIO) on glucose control was evaluated in a multicenter, open-label, open-ended, dose titration study. Patients (n=757) entered this study from five (two monotherapy and three combination-therapy) randomized, double-blind, paraUel-group studies. Patients were to start open-label PIO 15 mg once dally as monotherapy (n=56) or in combination with their current regimen of SU, MET, or INS (n=701). The dose of pioglitazone could be titrated based on fasting blood glucose (FBG) levels to a maximum dosage of 30 mg/day. The dose of companion medication was not to be adjusted. An interim analysis of the ongoing, open-ended study, was performed for those patients (n=536) who had completed 24 weeks of open-label therapy. Baseline was defined as the last measurement in the previous study. Mean HbAic and FBG at baseline and A from baseline for those patients who had completed 24 weeks of open-label therapy are reported below.
HbAic(%) FBG (mg/dL)
N
Baseline
A fromBaseline
533 536
9.77 236.7
-1.24 -45.3
PIO (up to 30 mg) administered once daily for up to 24 weeks as monotherapy and in combination with SU, MET, or INS was associated with reductions in mean HbAic and FBG. No increased incidence of
$59
adverse events was noted during the long-term treatment period. PIO administered once dally improves long-term glycemic control in patients with type 2 diabetes. [Additional long-term efficacy data from the continuation of the study will be presented].
P294 Echocardiographic Assessment in Patients with Type 2 Diabetes Mellitus Treated with Pioglitazone CINDY J. RUBIN 1, Susan J. Shaffer 1. The Pioglitazone 001 Study Group Echocardiographic evaluation of ACTOS TM (pioglitazone HCI), a thiazolidinedione compound, was included in a multicenter, double-blind, placebo-controlled study to determine if there was an effect of pioglitazone on cardiac mass or function in patients with type 2 diabetes. The benefits of pioglitazone on glycemic control and serum lipid profile were also examined. Patients were randomized to receive placebo or 7.5, 15, 30, or 45 mg of pioglitazone. Of the 334 patients who had echocardiographic data at baseline and endpoint (Week 26 or the last available measurement), the demographic and baseline characteristics were similar among the treatment groups. Mean left ventricular mass index (LVMI), cardiac index (CI), and fractional shortening (FS) at baseline and change from baseline at endpoint (last observation carried forward) are reported below: Placebo LVMI(g/m2) BaselineMean Mean Change CI (L/min/m2) BaselineMean Mean Change FS BaselineMean Mean Change
Pioglitazone 7.5 mg
15 mg
30 mg
45 mg
86.14 0.07
87.63 0.10
89.28 -0.25
85.47 -0.08
88.40 0.57
2.32 0.03
2.43 -0.08
2.32 -0.05
2.27 0.08
2.35 0.09
0.410 -0.004
0.406 -0.009
0.400 0.007
0.405 0.002
0.423 -0.009
Echocardiographic evaluation revealed only negligible mean changes from baseline in LVMI, CI, and FS for patients in all treatment groups. Patients treated with 15, 30, and 45 mg of pioglitazone had mean decreases from baseline in HbAm and FBG at Week 26 whereas mean increases were observed for placebo-treated patients. In addition, there were decreases from baseline in triglycerides and increases from baseline in HDL-cholesterol observed at Week 26 for the pioglitazone groups. In conclusion, pioglitazone (15 mg, 30 mg, and 45 mg/day for up to 26 weeks) had no adverse effect on cardiac structure and function as evaluated by echocardiography and was associated with significant improvement in glycemic control and serum lipid profile.
P295 Pioglitazone Liver Enzyme Profile Is Similar to Placebo in US Controlled Clinical Trials CINDY RUBIN J, Roberta Schneider i. The Pioglitazone Study Group Aims: Pioglitazone (PIO) is a new thiazolidinedione approved for oncedaily administration alone or in combination with a sulfonylurea, metformin, or insulin, for the treatment of type 2 diabetes mellitus. Investigations and clinical experience with other compounds in this class suggested that elevations in liver enzymes could be used as a marker for the risk of hepatic adverse events. The aim of this study was to investigate the incidence of elevations in liver enzymes during treatment with PIO. Methods: After the US PIO clinical program, a review of all patients who had elevations in ALT that were >3x the upper limit of normal (ULN) was undertaken. During placebo-controlled clinical trials in the U.S., a total of 4/1526 (0.26%) PIO-treated patients and 21793 (0.25%) placebo-treated patients had ALT values >3xULN.
$60
Poster Session 1
Results: During all clinical studies in the U.S., 11/2561 (0.43%) of PIOtreated patients had ALT values _>3xULN. All patients with follow-up values had reversible elevations in ALT. None of these elevations was considered serious. Conclusion: During evaluation as monotherapy or in combination with other antidiabetic agents, PIO was not different from placebo with respect to liver function tests.
P296 Pioglitazone Does Not Markedly Alter Oral Contraceptive or Hormone Replacement Therapy Pharmacokinetics ROBERTA L. SCHNEIDER l, Annette Mathisen i. The Pioglitazone 011 Study Group Hepatic enzyme-inducing agents have been shown to decrease the effectiveness of a number of drugs when administered concurrently. An important example of this type of interaction is the concomitant use of these agents with oral contraceptives (OC). Changes in OC pharmacokinetics (PK) may result in an increase in the likelihood of ovulation and risk of pregnancy. Post-menopausal subjects on hormone replacement therapy (HRT) may be affected if the PK of hormone therapy are altered. Pioglitazone (PIO) undergoes hepatic metabolism but, at the present time, there is no clear evidence that it induces or inhibits hepatic enzyme systems. The effect of PIO, a potent thiazolidinedione, on the PK of OC and HRT was evaluated. In the OC study, ethinyl estradiol (EE) and norethindrone (NE), the constituents of the OC, were measured while EE and estrone (ES), the predominant estrogen constituents of the HRT, were measured in the HRT study. Patients received OC (EE 0.035 mg and NE ® ® 0.5 to 1.0 mg) or HRT (Premarin 0.625 mg and Provera 5.0 mg) for 28 days followed by PIO 45 mg once daily plus the OC or HRT for 14 days. PK sampling was performed on Days 12-14 and 40-42. The mean serum PK parameters are summarized below. EthinylEstradiol Cmax(pg/mL) tmax(h) AUC0_24(pg.h/mL) tit2 (h)
Baseline LS A from A from Baseline LS A from Baseline LS A from HbAlc baseline placebo Tg baseline HDL-C baseline (% pts) (% pts) (mg/dL) (mg/dL) (mg/dL) (mg/dL) Mono 10.2% Pio+SU 10.0% Pio+lns 9.8%
-0.27 -0.8* -1.0"
- 1.0" 284 4- 34.4 -53.84-13.8* 40.4 4- 1.2 5.0 4- 0.8* -0.9* 2724-20.3 -38.74-13.4" 41.44-0.9 1.44-0.6" -0.73* 231 4- 17.8 -11.6:i: 14.9 43.4:t: 1.0 2.2 4-0.7"
*p<0.05
Conclusions: Pioglitazone 15 mg once dally, when used as monotherapy or in combination with either suphonylurea or insulin, is effective in improving HbA~c and lipid profile in patients with type 2 diabetes.
P298 Effect of Pioglitazone on Blood Glucose Following an Oral Glucose Tolerance Test SIDNEY ROSENBLATT I. The Pioglitazone 001 Study Group
Norethindrone
OC
OC+PIO
OC
OC+PIO
115.58 2.2 34.0 20.2
107.55 1.8 30.7 19.6
18.69 1.5 181.8 10.8
15.74 1.4 180.5 9.6
EthinylEstradiol Cmax(pg/mL) tmax(h) AUC0-24(pg.h/mL) tl/2 (h)
included the 15 mg once daily dose as well as other doses. A monotherapy study compared placebo (n=79) with pioglitazone 15 mg (n-- 79) for 26 weeks. One combination therapy study compared sulphonylurea [SU] + placebo (n=180) with SU + pioglitazone 15 mg (n=177) for 16 weeks. Another combination therapy study compared insulin + placebo (n=176) with insulin + pioglitazone 15 mg (n= 176) for 16 weeks. The primary efficacy end-point was HbAic. Secondary efficacy end-points included fasting serum triglycerides (Tg), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) for all studies. Only data on the 15-rag dose of pioglitazone are presented below. Results: In both monotherapy and combination therapy studies, pioglitazone 15 mg once daily lowered H b A l c at study endpoint. In both monotherapy and combination therapy studies, pioglitazone 15 mg once daily lowered serum Tg and raised HDL-C significantly from baseline at study endpoint:
Estrone
OC
OC+PIO
OC
OC+P10
26.87 12.0 530.6 24.4
27.22 10.1 484.9 22.6
165.34 9.2 3124.4 22.9
157.75 9.3 2942.5 30.5
Aims: Pioglitazone (PIO) is a new thiazolidinedione, which has previously been shown to improve fasting blood glucose levels (FBG) and overall glycemic control (HbAlc) in patients with type 2 diabetes. There is growing scientific evidence that a reduction in postprandial hyperglycemia may lead to a reduction in the complications of diabetes. The purpose of this study was to investigate the effect of pioglitazone on blood glucose following an oral glucose tolerance test (OGTT). Materials and Methods: Patients with type 2 diabetes entering a 26-week PIO monotherapy study underwent a 3-hour OGTT at baseline, and again at the end of the study (week 26). Patients with elevated FBG at baseline (> 240 mg/dL) were enrolled into the study but excluded from the OGTT. Results: The results of the OGTT are presented as least square (LS) mean changes (+SEM) in glucose AUCs as follows:
In conclusion, co-administration of PIO did not alter the PK of OC or HRT and dose adjustment should not be necessary.
Placebo(n=21)
Pioglitazone 7.5 mg (n=26) 15 mg (n=22) 30 mg (n=22) 45 mg (n=23)
I'297 Pioglitazone (15 mg Once Daily) Improves Glycemic Control and Lipid Profile in Patients with ~l~pe 2 Diabetes STEPHEN L. ARONOFF 1. The Pioglitazone Study Group
® Pioglitazone ( A C T O S ) , a thiazolidinedione, enhances insulin sensitivity in type 2 diabetes patients. In so doing, it improves glycemic control and lipid profiles of these patients. In pre-approval clinical trials conducted in the US (monotherapy and combination therapy), various doses of pioglitazone were used. Aim: To determine the effect of a low dose (15 mg once daily) of pioglitazone on the glycemic control and lipid profile of patients with type 2 diabetes. Methods: Three double blind, randomized, multicenter clinical trials
Baseline LS meanAUCa Endpoint ALS meanAUCa
995.36 4-50.94 21.6 4-44.47
1000.89 4-46.96 -90.78 4-40.98
973.54 4-48.88 -151.86 4-42.85+*
993.99 4-49.35 -247.80 4-43.1+*
l 114.33 4-49.86 -281.00 4-44.12+*
a AUC0-3h(hr.mg/dL)calculatedusingthe trapezoidalrule (+SEM); LS = least square; A = change;+ p < 0.05 vs. baseline(pairedt-test); * p < 0.05 vs. baseline;(Dunnett'stest) Pioglitazone significantly reduced, in a dose-related fashion, the glucose AUC following a 3h OGTT. Significant decreases in maximal observed effects compared to placebo in FBG (-3.62 mmol/L; p<0.05) and HbAic (-1.6%; p<0.05) mirrored the improvements noted post-glucose challenge. Conclusion: These data suggest that pioglitazone improves overall glycemic control via beneficial effects on both the fasting and postprandial glucose levels.
RolloverPlacebo
RolloverPIO
Total
165 9.71 -1.57
23 9.86 -0.99
86 9.59 -1.03
274 9.68 -1.35
166 250.1 -74.9
23 243.3 -52.7
87 246.8 -59.2
276 248.5 -68. I
HbAlc (%) N Baseline A from Baseline FBG (mg/dL) N Baseline A from Baseline
PIO (up to 60 mg) once daily for up to 48 weeks was associated with reductions in mean HbAlc and FBG. Mean fasting plasma triglyceride levels were decreased while mean HDL-C levels were increased. Mean total cholesterol and LDL-C levels were not adversely affected. No increased incidence of adverse events was noted during the long-term treatment period. PIO monotherapy administered once daily improves long-term glycemic control and lipid profile in patients with type 2 diabetes. [Efficacy data from the continuation of the study will be presented.]
I'293 The Long-Term Effect of Pioglitazone as Monotherapy or Combination-Therapy on Glucose Control in Patients with Type 2 Diabetes JOHN W. EGAN 1, Renee Librizzi 2, James S. Geerlof 3. The Pioglitazone
031 Study Group ACTOS TM (pioglitazone hydrochloride) is a thiazolidinedione compound marketed for the treatment of patients with type 2 diabetes mellitus and is indicated for use as monotherapy and in combination with a sulfonylurea (SU), metformin (MET), or insulin (INS). The long-term effect of pioglitazone (PIO) on glucose control was evaluated in a multicenter, open-label, open-ended, dose titration study. Patients (n=757) entered this study from five (two monotherapy and three combination-therapy) randomized, double-blind, paraUel-group studies. Patients were to start open-label PIO 15 mg once dally as monotherapy (n=56) or in combination with their current regimen of SU, MET, or INS (n=701). The dose of pioglitazone could be titrated based on fasting blood glucose (FBG) levels to a maximum dosage of 30 mg/day. The dose of companion medication was not to be adjusted. An interim analysis of the ongoing, open-ended study, was performed for those patients (n=536) who had completed 24 weeks of open-label therapy. Baseline was defined as the last measurement in the previous study. Mean HbAic and FBG at baseline and A from baseline for those patients who had completed 24 weeks of open-label therapy are reported below.
HbAic(%) FBG (mg/dL)
N
Baseline
A fromBaseline
533 536
9.77 236.7
-1.24 -45.3
PIO (up to 30 mg) administered once daily for up to 24 weeks as monotherapy and in combination with SU, MET, or INS was associated with reductions in mean HbAic and FBG. No increased incidence of
$59
adverse events was noted during the long-term treatment period. PIO administered once dally improves long-term glycemic control in patients with type 2 diabetes. [Additional long-term efficacy data from the continuation of the study will be presented].
P294 Echocardiographic Assessment in Patients with Type 2 Diabetes Mellitus Treated with Pioglitazone CINDY J. RUBIN 1, Susan J. Shaffer 1. The Pioglitazone 001 Study Group Echocardiographic evaluation of ACTOS TM (pioglitazone HCI), a thiazolidinedione compound, was included in a multicenter, double-blind, placebo-controlled study to determine if there was an effect of pioglitazone on cardiac mass or function in patients with type 2 diabetes. The benefits of pioglitazone on glycemic control and serum lipid profile were also examined. Patients were randomized to receive placebo or 7.5, 15, 30, or 45 mg of pioglitazone. Of the 334 patients who had echocardiographic data at baseline and endpoint (Week 26 or the last available measurement), the demographic and baseline characteristics were similar among the treatment groups. Mean left ventricular mass index (LVMI), cardiac index (CI), and fractional shortening (FS) at baseline and change from baseline at endpoint (last observation carried forward) are reported below: Placebo LVMI(g/m2) BaselineMean Mean Change CI (L/min/m2) BaselineMean Mean Change FS BaselineMean Mean Change
Pioglitazone 7.5 mg
15 mg
30 mg
45 mg
86.14 0.07
87.63 0.10
89.28 -0.25
85.47 -0.08
88.40 0.57
2.32 0.03
2.43 -0.08
2.32 -0.05
2.27 0.08
2.35 0.09
0.410 -0.004
0.406 -0.009
0.400 0.007
0.405 0.002
0.423 -0.009
Echocardiographic evaluation revealed only negligible mean changes from baseline in LVMI, CI, and FS for patients in all treatment groups. Patients treated with 15, 30, and 45 mg of pioglitazone had mean decreases from baseline in HbAm and FBG at Week 26 whereas mean increases were observed for placebo-treated patients. In addition, there were decreases from baseline in triglycerides and increases from baseline in HDL-cholesterol observed at Week 26 for the pioglitazone groups. In conclusion, pioglitazone (15 mg, 30 mg, and 45 mg/day for up to 26 weeks) had no adverse effect on cardiac structure and function as evaluated by echocardiography and was associated with significant improvement in glycemic control and serum lipid profile.
P295 Pioglitazone Liver Enzyme Profile Is Similar to Placebo in US Controlled Clinical Trials CINDY RUBIN J, Roberta Schneider i. The Pioglitazone Study Group Aims: Pioglitazone (PIO) is a new thiazolidinedione approved for oncedaily administration alone or in combination with a sulfonylurea, metformin, or insulin, for the treatment of type 2 diabetes mellitus. Investigations and clinical experience with other compounds in this class suggested that elevations in liver enzymes could be used as a marker for the risk of hepatic adverse events. The aim of this study was to investigate the incidence of elevations in liver enzymes during treatment with PIO. Methods: After the US PIO clinical program, a review of all patients who had elevations in ALT that were >3x the upper limit of normal (ULN) was undertaken. During placebo-controlled clinical trials in the U.S., a total of 4/1526 (0.26%) PIO-treated patients and 21793 (0.25%) placebo-treated patients had ALT values >3xULN.
$60
Poster Session 1
Results: During all clinical studies in the U.S., 11/2561 (0.43%) of PIOtreated patients had ALT values _>3xULN. All patients with follow-up values had reversible elevations in ALT. None of these elevations was considered serious. Conclusion: During evaluation as monotherapy or in combination with other antidiabetic agents, PIO was not different from placebo with respect to liver function tests.
P296 Pioglitazone Does Not Markedly Alter Oral Contraceptive or Hormone Replacement Therapy Pharmacokinetics ROBERTA L. SCHNEIDER l, Annette Mathisen i. The Pioglitazone 011 Study Group Hepatic enzyme-inducing agents have been shown to decrease the effectiveness of a number of drugs when administered concurrently. An important example of this type of interaction is the concomitant use of these agents with oral contraceptives (OC). Changes in OC pharmacokinetics (PK) may result in an increase in the likelihood of ovulation and risk of pregnancy. Post-menopausal subjects on hormone replacement therapy (HRT) may be affected if the PK of hormone therapy are altered. Pioglitazone (PIO) undergoes hepatic metabolism but, at the present time, there is no clear evidence that it induces or inhibits hepatic enzyme systems. The effect of PIO, a potent thiazolidinedione, on the PK of OC and HRT was evaluated. In the OC study, ethinyl estradiol (EE) and norethindrone (NE), the constituents of the OC, were measured while EE and estrone (ES), the predominant estrogen constituents of the HRT, were measured in the HRT study. Patients received OC (EE 0.035 mg and NE ® ® 0.5 to 1.0 mg) or HRT (Premarin 0.625 mg and Provera 5.0 mg) for 28 days followed by PIO 45 mg once daily plus the OC or HRT for 14 days. PK sampling was performed on Days 12-14 and 40-42. The mean serum PK parameters are summarized below. EthinylEstradiol Cmax(pg/mL) tmax(h) AUC0_24(pg.h/mL) tit2 (h)
Baseline LS A from A from Baseline LS A from Baseline LS A from HbAlc baseline placebo Tg baseline HDL-C baseline (% pts) (% pts) (mg/dL) (mg/dL) (mg/dL) (mg/dL) Mono 10.2% Pio+SU 10.0% Pio+lns 9.8%
-0.27 -0.8* -1.0"
- 1.0" 284 4- 34.4 -53.84-13.8* 40.4 4- 1.2 5.0 4- 0.8* -0.9* 2724-20.3 -38.74-13.4" 41.44-0.9 1.44-0.6" -0.73* 231 4- 17.8 -11.6:i: 14.9 43.4:t: 1.0 2.2 4-0.7"
*p<0.05
Conclusions: Pioglitazone 15 mg once dally, when used as monotherapy or in combination with either suphonylurea or insulin, is effective in improving HbA~c and lipid profile in patients with type 2 diabetes.
P298 Effect of Pioglitazone on Blood Glucose Following an Oral Glucose Tolerance Test SIDNEY ROSENBLATT I. The Pioglitazone 001 Study Group
Norethindrone
OC
OC+PIO
OC
OC+PIO
115.58 2.2 34.0 20.2
107.55 1.8 30.7 19.6
18.69 1.5 181.8 10.8
15.74 1.4 180.5 9.6
EthinylEstradiol Cmax(pg/mL) tmax(h) AUC0-24(pg.h/mL) tl/2 (h)
included the 15 mg once daily dose as well as other doses. A monotherapy study compared placebo (n=79) with pioglitazone 15 mg (n-- 79) for 26 weeks. One combination therapy study compared sulphonylurea [SU] + placebo (n=180) with SU + pioglitazone 15 mg (n=177) for 16 weeks. Another combination therapy study compared insulin + placebo (n=176) with insulin + pioglitazone 15 mg (n= 176) for 16 weeks. The primary efficacy end-point was HbAic. Secondary efficacy end-points included fasting serum triglycerides (Tg), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) for all studies. Only data on the 15-rag dose of pioglitazone are presented below. Results: In both monotherapy and combination therapy studies, pioglitazone 15 mg once daily lowered H b A l c at study endpoint. In both monotherapy and combination therapy studies, pioglitazone 15 mg once daily lowered serum Tg and raised HDL-C significantly from baseline at study endpoint:
Estrone
OC
OC+PIO
OC
OC+P10
26.87 12.0 530.6 24.4
27.22 10.1 484.9 22.6
165.34 9.2 3124.4 22.9
157.75 9.3 2942.5 30.5
Aims: Pioglitazone (PIO) is a new thiazolidinedione, which has previously been shown to improve fasting blood glucose levels (FBG) and overall glycemic control (HbAlc) in patients with type 2 diabetes. There is growing scientific evidence that a reduction in postprandial hyperglycemia may lead to a reduction in the complications of diabetes. The purpose of this study was to investigate the effect of pioglitazone on blood glucose following an oral glucose tolerance test (OGTT). Materials and Methods: Patients with type 2 diabetes entering a 26-week PIO monotherapy study underwent a 3-hour OGTT at baseline, and again at the end of the study (week 26). Patients with elevated FBG at baseline (> 240 mg/dL) were enrolled into the study but excluded from the OGTT. Results: The results of the OGTT are presented as least square (LS) mean changes (+SEM) in glucose AUCs as follows:
In conclusion, co-administration of PIO did not alter the PK of OC or HRT and dose adjustment should not be necessary.
Placebo(n=21)
Pioglitazone 7.5 mg (n=26) 15 mg (n=22) 30 mg (n=22) 45 mg (n=23)
I'297 Pioglitazone (15 mg Once Daily) Improves Glycemic Control and Lipid Profile in Patients with ~l~pe 2 Diabetes STEPHEN L. ARONOFF 1. The Pioglitazone Study Group
® Pioglitazone ( A C T O S ) , a thiazolidinedione, enhances insulin sensitivity in type 2 diabetes patients. In so doing, it improves glycemic control and lipid profiles of these patients. In pre-approval clinical trials conducted in the US (monotherapy and combination therapy), various doses of pioglitazone were used. Aim: To determine the effect of a low dose (15 mg once daily) of pioglitazone on the glycemic control and lipid profile of patients with type 2 diabetes. Methods: Three double blind, randomized, multicenter clinical trials
Baseline LS meanAUCa Endpoint ALS meanAUCa
995.36 4-50.94 21.6 4-44.47
1000.89 4-46.96 -90.78 4-40.98
973.54 4-48.88 -151.86 4-42.85+*
993.99 4-49.35 -247.80 4-43.1+*
l 114.33 4-49.86 -281.00 4-44.12+*
a AUC0-3h(hr.mg/dL)calculatedusingthe trapezoidalrule (+SEM); LS = least square; A = change;+ p < 0.05 vs. baseline(pairedt-test); * p < 0.05 vs. baseline;(Dunnett'stest) Pioglitazone significantly reduced, in a dose-related fashion, the glucose AUC following a 3h OGTT. Significant decreases in maximal observed effects compared to placebo in FBG (-3.62 mmol/L; p<0.05) and HbAic (-1.6%; p<0.05) mirrored the improvements noted post-glucose challenge. Conclusion: These data suggest that pioglitazone improves overall glycemic control via beneficial effects on both the fasting and postprandial glucose levels.