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The addition of AVANDIA to either metformin, a sulfonylurea, or insulin resulted in significant reductions in hyperglycemia compared to any of these agents alone. These results are consistent with an additive effect on glycemic control when AVANDIA is used as combination therapy.
Patients with lipid abnormalities were not excluded from clinical trials of AVANDIA. In all 26-week controlled trials, across the recommended dose range, AVANDIA as monotherapy was associated with increases in total cholesterol, LDL, and HDL and decreases in free fatty acids.
These changes were statistically significantly different from placebo or glyburide controls (see Table 2). Increases in LDL occurred primarily during the first 1 to 2 months of therapy with AVANDIA and LDL levels remained elevated above baseline throughout the trials. In contrast, HDL continued to rise over time. As a result, the LDL/ HDL ratio peaked after 2 months of therapy and then appeared to decrease over time. Because of the temporal nature of lipid changes, the 52-week glyburide-controlled study is most pertinent to assess long-term effects on lipids. At baseline, week 26, and week 52, mean LDL/ HDL ratios were 3.1, 3.2, and 3.0, respectively, for AVANDIA 4 mg twice daily. The corresponding values for glyburide were 3.2, 3.1, and 2.9. The differences in change from baseline between AVANDIA and glyburide at week 52 were statistically significant. The pattern of LDL and HDL changes following therapy with AVANDIA in combination with other hypoglycemic agents were generally similar to those seen with AVANDIA in monotherapy. Text Continues Below
The changes in triglycerides during therapy with AVANDIA were variable and were generally not statistically different from placebo or glyburide controls.
Table 2. Summary of Mean Lipid Changes in 26-Week Placebo-Controlled and 52-Week Glyburide-Controlled Monotherapy Studies
Placebo-controlled Studies
Week 26
Glyburide-controlled Study
Week 26 and Week 52
Placebo AVANDIA Glyburide Titration AVANDIA 8 mg
4 mg
daily *
8 mg
daily *
Wk 26 Wk 52 Wk 26 Wk 52 Free Fatty Acids
N
Baseline (mean)
% Change from
baseline (mean) 207
18.1 +0.2% 428
17.5 -7.8% 436
17.9 -14.7% 181
26.4 -2.4% 168
26.4 -4.7% 166
26.9 -20.8% 145
26.6 -21.5%
LDL
N
Baseline (mean)
% Change from
baseline (mean) 190
123.7 +4.8% 400
126.8 +14.1% 374
125.3 +18.6% 175
142.7 -0.9% 160
141.9 -0.5% 161
142.1 +11.9% 133
142.1 +12.1%
HDL
N
Baseline (mean)
% Change from
baseline (mean) 208
44.1 +8.0% 429
44.4 +11.4% 436
43.0 +14.2% 184
47.2 +4.3% 170
47.7 +8.7% 170
48.4 +14.0% 145
48.3 +18.5% *
Once daily and twice daily dosing groups were combined. Monotherapy A total of 2,315 patients with type 2 diabetes, previously treated with diet alone or antidiabetic medication( s), were treated with AVANDIA as monotherapy in 6 double-blind studies, which included two 26-week placebo-controlled studies, one 52-week glyburide-controlled study, and 3 placebo-controlled dose-ranging studies of 8 to 12 weeks duration. Previous antidiabetic medication( s) were withdrawn and patients entered a 2 to 4 week placebo run-in period prior to randomization. Two 26-week, double-blind, placebo-controlled trials, in patients with type 2 diabetes with inadequate glycemic control (mean baseline FPG approximately 228 mg/ dL and mean baseline HbA1c 8.9%), were conducted. Treatment with AVANDIA produced statistically significant improvements in FPG and HbA1c compared to baseline and relative to placebo (see Table 3).
Table 3. Glycemic Parameters in Two 26-Week Placebo-Controlled Trials
Study A Placebo AVANDIA
2 mg twice daily
AVANDIA
4 mg twice daily
N 158 166 169
FPG (mg/ dL)
Baseline (mean) 229 227 220
Change from baseline (mean) 19 -38 -54
Difference from placebo
(adjusted mean) -58 * -76 *
Responders ( 30 mg/ dL decrease from baseline) 16% 54% 64%
HbAlc (%)
Baseline (mean) 9.0 9.0 8.8
Change from baseline (mean) 0.9 -0.3 -0.6
Difference from placebo
(adjusted mean) -1.2 * -1.5 *
Responders ( 0.7% decrease from baseline) 6% 40% 42% Study B Placebo AVANDIA AVANDIA
4 mg once
daily
2 mg twice
daily
8 mg once
daily
4 mg twice
daily
N 173 180 186 181 187
FPG (mg/ dL)
Baseline (mean) 225 229 225 228 228
Change from baseline (mean) 8 -25 -35 -42 -55
Difference from placebo
(adjusted mean) – -31* -43* -49* -62*
Responders ( 30 mg/ dL
decrease from baseline) 19% 45% 54% 58% 70%
HbA1c (%)
Baseline (mean) 8.9 8.9 8.9 8.9 9.0
Change from baseline (mean) 0.8 0.0 -0.1 -0.3 -0.7
Difference from placebo
(adjusted mean) – -0.8 * -0.9 * -1.1 * -1.5 *
Responders ( 0.7% decrease from baseline) 9% 28% 29% 39% 54% * <0.0001 compared to placebo. When administered at the same total daily dose, AVANDIA was generally more effective in reducing FPG and HbA1c when administered in divided doses twice daily compared to once daily doses. However, for HbA1c, the difference between the 4 mg once daily and 2 mg twice daily doses was not statistically significant. Long-term maintenance of effect was evaluated in a 52-week, double-blind, glyburide-controlled trial in patients with type 2 diabetes. Patients were randomized to treatment with AVANDIA 2 mg twice daily (N = 195) or AVANDIA 4 mg twice daily (N = 189) or glyburide (N = 202) for 52 weeks. Patients receiving glyburide were given an initial dosage of either 2.5 mg/ day or 5.0 mg/ day. The dosage was then titrated in 2.5 mg/ day increments over the next 12 weeks, to a maximum dosage of 15.0 mg/ day in order to optimize glycemic control. Thereafter the glyburide dose was kept constant. The median titrated dose of glyburide was 7.5 mg. All treatments resulted in a statistically significant improvement in glycemic control from baseline (see Figure 1 and Figure 2). At the end of week 52, the reduction from baseline in FPG and HbA1c was -40.8 mg/ dL and -0.53% with AVANDIA 4 mg twice daily; -25.4 mg/ dL and -0.27% with AVANDIA 2 mg twice daily; and -30.0 mg/ dL and -0.72% with glyburide. For HbA1c, the difference between AVANDIA 4 mg twice daily and glyburide was not statistically significant at week 52. The initial fall in FPG with glyburide was greater than with AVANDIA; however, this effect was less durable over time. The improvement in glycemic control seen with AVANDIA 4 mg twice daily at week 26 was maintained through week 52 of the study.
Figure 1. Mean FPG Over Time in a 52-Week Glyburide-Controlled Study Figure 2. Mean HbA1c Over Time in a 52-Week Glyburide-Controlled Study Hypoglycemia was reported in 12.1% of glyburide-treated patients versus 0.5% (2 mg twice daily) and 1.6% (4 mg twice daily) of patients treated with AVANDIA. The improvements in glycemic control were associated with a mean weight gain of 1.75 kg and 2.95 kg for patients treated with 2 mg and 4 mg twice daily of AVANDIA, respectively, versus 1.9 kg in glyburide-treated patients. In patients treated with AVANDIA, C-peptide, insulin, pro-insulin, and pro-insulin split products were significantly reduced in a dose-ordered fashion, compared to an increase in the glyburide-treated patients. Combination With Metformin A total of 670 patients with type 2 diabetes participated in two 26-week, randomized, double-blind, placebo/ active-controlled studies designed to assess the efficacy of AVANDIA in combination with metformin. AVANDIA, administered in either once daily or twice daily dosing regimens, was added to the therapy of patients who were inadequately controlled on a maximum dose (2.5 grams/ day) of metformin. In one study, patients inadequately controlled on 2.5 grams/ day of metformin (mean baseline FPG 216 mg/ dL and mean baseline HbA1c 8.8%) were randomized to receive 4 mg of AVANDIA once daily, 8 mg of AVANDIA once daily, or placebo in addition to metformin. A statistically significant improvement in FPG and HbA1c was observed in patients treated with the combinations of metformin and 4 mg of AVANDIA once daily and 8 mg of AVANDIA once daily, versus patients continued on metformin alone (see Table 4). Table 4. Glycemic Parameters in a 26-Week Combination Study
Metformin AVANDIA
4 mg once daily
+ metformin AVANDIA
8 mg once daily
+ metformin
N 113 116 110
FPG (mg/ dL)
Baseline (mean) 214 215 220
Change from baseline (mean) 6 –33 –48
Difference from metformin alone
(adjusted mean) –40* –53*
Responders ( 30 mg/ dL decrease from baseline) 20% 45% 61% HbA1c (%)
Baseline (mean) 8.6 8.9 8.9
Change from baseline (mean) 0.5 –0.6 –0.8
Difference from metformin alone
(adjusted mean) –1.0* –1.2 *
Responders ( 0.7% decrease from baseline) 11% 45% 52% * <0.0001 compared to metformin. In a second 26-week study, patients with type 2 diabetes inadequately controlled on 2.5 grams/ day of metformin who were randomized to receive the combination of AVANDIA 4 mg twice daily and metformin (N = 105) showed a statistically significant improvement in glycemic control with a mean treatment effect for FPG of -56 mg/ dL and a mean treatment effect for HbA1c of -0.8% over metformin alone. The combination of metformin and AVANDIA resulted in lower levels of FPG and HbA1c than either agent alone. Patients who were inadequately controlled on a maximum dose (2.5 grams/ day) of metformin and who were switched to monotherapy with AVANDIA demonstrated loss of glycemic control, as evidenced by increases in FPG and HbA1c. In this group, increases in LDL and VLDL were also seen. Combination With a Sulfonylurea: A total of 1,216 patients with type 2 diabetes participated in three 26-week randomized, double-blind, placebo/ active-controlled studies designed to assess the efficacy and safety of AVANDIA in combination with a sulfonylurea. AVANDIA 2 mg or 4 mg daily, was administered either once daily or in divided doses twice daily, to patients inadequately controlled on a sulfonylurea. In the two placebo-controlled studies, patients inadequately controlled on sulfonylureas that were randomized to single dose or divided doses of AVANDIA 4 mg daily plus a sulfonylurea showed significantly reduced FPG and HbA1c compared to sulfonylurea plus placebo (see Table 5). Table 5. Glycemic Parameters in Two 26-Week Combination Studies
Study C (patients on prior
sulfonylurea monotherapy)
Sulfonylurea
AVANDIA 2 mg
twice daily +
sulfonylurea
N 192 183
FPG (mg/ dL)
Baseline (mean) 207 205
Change from baseline (mean) +6 –38
Difference from sulfonylurea alone
(adjusted mean) – –44*
Responders ( 30 mg/ dL decrease
from baseline) 21% 56%
HbA1c (%)
Baseline (mean) 9.2 9.2
Change from baseline (mean) +0.2 –0.9
Difference from sulfonylurea alone
(adjusted mean) – –1.0* Study D (patients on prior single or
multiple therapies)
Sulfonylurea
AVANDIA 4 mg
once daily +
sulfonylurea
N 115 116
FPG (mg/ dL)
Baseline (mean) 209 214
Change from baseline (mean) +23 –25
Difference from sulfonylurea alone
(adjusted mean)
– –47 * Responders ( 30 mg/ dL decrease
from baseline)
13% 46% HbA1c (%)
Baseline (mean) 8.9 9.1
Change from baseline (mean) +0.6 –0.3
Difference from sulfonylurea alone
(adjusted mean)
– –0.9 * * 0.0001 compared to sulfonylurea plus placebo. In the third study, including patients on prior single or multiple therapies, in patients inadequately controlled on the maximal dose of glyburide (20 mg daily), 2 mg of AVANDIA twice daily plus sulfonylurea significantly reduced FPG (n = 98, mean change from baseline of -31 mg/ dL) and HbA1c (mean change from baseline of -0.5%) compared to sulfonylurea plus placebo (n = 99, mean change from baseline of FPG of +24 mg/ dL and of HbA1c of +0.9%). The combination of sulfonylurea and AVANDIA resulted in lower levels of FPG and HbA1c than either agent alone. Patients who were switched from maximal dose of glyburide to 2 mg of AVANDIA twice daily as monotherapy demonstrated loss of glycemic control, as evidenced by increases in FPG and HbA1c. Combination With Insulin In two 26-week randomized, double-blind, fixed-dose studies designed to assess the efficacy and safety of AVANDIA in combination with insulin, patients inadequately controlled on insulin (65 to 67 units/ day, mean range at baseline) were randomized to receive AVANDIA 4 mg plus insulin (n = 206) or placebo plus insulin (n = 203). The mean duration of disease in these patients was 12 to 13 years. Compared to insulin plus placebo, single or divided doses of AVANDIA 4 mg daily plus insulin significantly reduced FPG (mean reduction of 32 to 40 mg/ dL) and HbA1c (mean reduction of 0.6% to 0.7%). Approximately 40% of all patients treated with AVANDIA reduced their insulin dose. Page: << Prev | 1 | 2 | 3 | 4 | 5
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