Alogliptin (Page 5 of 8)

14.2 Combination Therapy

Add-On Therapy to Metformin

A total of 2081 patients with type 2 diabetes participated in two 26 week, double-blind, placebo-controlled studies to evaluate the efficacy and safety of alogliptin tablets as add-on therapy to metformin. In both studies, patients were inadequately controlled on metformin at a dose of at least 1500 mg per day or at the maximum tolerated dose. All patients entered a four week, single-blind placebo run-in period prior to randomization. Patients who failed to meet prespecified hyperglycemic goals during the 26 week treatment periods received glycemic rescue therapy.

In the first 26 week, placebo-controlled study, a total of 527 patients already on metformin (mean baseline A1C = 8%) were randomized to receive alogliptin tablets 12.5 mg, alogliptin tablets 25 mg or placebo. Patients were maintained on a stable dose of metformin (median dose = 1700 mg) during the treatment period. Alogliptin tablets 25 mg in combination with metformin resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, when compared to placebo (Table 6). A total of 8% of patients receiving alogliptin tablets 25 mg and 24% of patients receiving placebo required glycemic rescue.

Improvements in A1C were not affected by gender, age, baseline BMI or baseline metformin dose.

The mean decrease in body weight was similar between alogliptin tablets and placebo when given in combination with metformin.

Table 6. Glycemic Parameters at Week 26 in a Placebo-Controlled Study of Alogliptin Tablets as Add-On Therapy to Metformin *
Alogliptin Tablets 25 mg + MetforminPlacebo + Metformin
*
Intent-to-treat population using last observation on study
Least squares means adjusted for treatment, baseline value, geographic region and baseline metformin dose
p<0.001 compared to placebo
A1C (%) N=203N=103
Baseline (mean)7.98.0
Change from baseline (adjusted mean )-0.6-0.1
Difference from placebo (adjusted mean with 95% confidence interval)-0.5 (-0.7, -0.3)˗
% of patients (n/N) achieving A1C ≤7%44% (92/207)18% (19/104)
FPG (mg/dL) N=204N=104
Baseline (mean)172180
Change from baseline (adjusted mean )-170
Difference from placebo (adjusted mean with 95% confidence interval)-17 (-26, -9)˗

In the second 26 week, double-blind, placebo-controlled study, a total of 1554 patients already on metformin (mean baseline A1C = 8.5%) were randomized to one of 12 double-blind treatment groups: placebo; 12.5 mg or 25 mg of alogliptin tablets alone; 15 mg, 30 mg or 45 mg of pioglitazone alone; or 12.5 mg or 25 mg of alogliptin tablets in combination with 15 mg, 30 mg or 45 mg of pioglitazone. Patients were maintained on a stable dose of metformin (median dose = 1700 mg) during the treatment period. Coadministration of alogliptin tablets and pioglitazone provided statistically significant improvements in A1C and FPG compared to placebo, to alogliptin tablets alone or to pioglitazone alone when added to background metformin therapy (Table 7, Figure 3). In addition, improvements from baseline A1C were comparable between alogliptin tablets alone and pioglitazone alone (15 mg, 30 mg and 45 mg) at Week 26. A total of 4%, 5% or 2% of patients receiving alogliptin tablets 25 mg with 15 mg, 30 mg or 45 mg pioglitazone, 33% of patients receiving placebo, 13% of patients receiving alogliptin tablets 25 mg and 10%, 15% or 9% of patients receiving pioglitazone 15 mg, 30 mg or 45 mg alone required glycemic rescue.

Improvements in A1C were not affected by gender, age or baseline BMI.

The mean increase in body weight was similar between pioglitazone alone and alogliptin tablets when coadministered with pioglitazone.

Table 7. Glycemic Parameters in a 26 Week Study of Alogliptin Tablets, Pioglitazone and Alogliptin Tablets in Combination with Pioglitazone when Added to Metformin *
PlaceboAlogliptin Tablets25 mgPioglitazone 15 mgPioglitazone 30 mgPioglitazone 45 mgAlogliptin Tablets 25 mg + Pioglitazone 15 mgAlogliptin Tablets 25 mg + Pioglitazone 30 mgAlogliptin Tablets 25 mg + Pioglitazone 45 mg
*
Intent-to-treat population using last observation on study
Least squares means adjusted for treatment, geographic region, metformin dose and baseline value
p≤0.01 when compared to corresponding doses of pioglitazone and alogliptin tablets alone
A1C (%) N=126N=123N=127N=123N=126N=127N=124N=126
Baseline(mean)8.58.68.58.58.58.58.58.6
Change from baseline (adjusted mean )-0.1-0.9-0.8-0.9-1.0-1.3-1.4-1.6
Difference from pioglitazone (adjusted mean with 95% confidence interval)-0.5(-0.7, -0.3)-0.5(-0.7, -0.3)-0.6(-0.8, -0.4)
Difference from Alogliptin Tablets (adjusted mean with 95% confidence interval)-0.4(-0.6, -0.1)-0.5(-0.7, -0.3)-0.7(-0.9, -0.5)
Patients (%) achieving A1C ≤7%6%(8/129)27%(35/129)26%(33/129)30%(38/129)36%(47/129)55%(71/130)53%(69/130)60%(78/130)
FPG (mg/dL) N=129N=126N=127N=125N=129N=130N=126N=127
Baseline(mean)177184177175181179179178
Change from baseline (adjusted mean )7-19-24-29-32-38-42-53
Difference from pioglitazone (adjusted mean with 95% confidence interval)-14 (-24, -5)-13 (-23, -3)-20 (-30, -11)
Difference from Alogliptin Tablets (adjusted mean with 95% confidence interval)-19 (-29, -10)-23 (-33, -13)-34 (-44, -24)

Figure 3. Change from Baseline in A1C at Week 26 with Alogliptin Tablets and Pioglitazone Alone and Alogliptin Tablets in Combination with Pioglitazone When Added to Metformin

Figure 3
(click image for full-size original)

Add-On Therapy to a Thiazolidinedione

In a 26 week, placebo-controlled study, a total of 493 patients inadequately controlled on a thiazolidinedione alone or in combination with metformin or a sulfonylurea (10 mg) (mean baseline A1C = 8%) were randomized to receive alogliptin tablets 12.5 mg, alogliptin tablets 25 mg or placebo. Patients were maintained on a stable dose of pioglitazone (median dose = 30 mg) during the treatment period; those who were also previously treated on metformin (median dose = 2000 mg) or sulfonylurea (median dose = 10 mg) prior to randomization were maintained on the combination therapy during the treatment period. All patients entered into a four week, single-blind placebo run-in period prior to randomization. Patients who failed to meet prespecified hyperglycemic goals during the 26 week treatment period received glycemic rescue therapy.

The addition of alogliptin tablets 25 mg once daily to pioglitazone therapy resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, compared to placebo (Table 8). A total of 9% of patients who were receiving alogliptin tablets 25 mg and 12% of patients receiving placebo required glycemic rescue.

Improvements in A1C were not affected by gender, age, baseline BMI or baseline pioglitazone dose.

Clinically meaningful reductions in A1C were observed with alogliptin tablets compared to placebo regardless of whether subjects were receiving concomitant metformin or sulfonylurea (-0.2% placebo versus -0.9% alogliptin tablets) therapy or pioglitazone alone (0% placebo versus -0.52% alogliptin tablets).

The mean increase in body weight was similar between alogliptin tablets and placebo when given in combination with pioglitazone.

Table 8. Glycemic Parameters in a 26 Week, Placebo-Controlled Study of Alogliptin Tablets as Add-On Therapy to Pioglitazone *
Alogliptin Tablets 25 mg + Pioglitazone ± Metformin ± Sulfonylurea Placebo + Pioglitazone ± Metformin ± Sulfonylurea
*
Intent-to-treat population using last observation on study
Least squares means adjusted for treatment, baseline value, geographic region, baseline treatment regimen (pioglitazone, pioglitazone + metformin or pioglitazone + sulfonylurea) and baseline pioglitazone dose
p<0.01 compared to placebo
A1C (%) N=195 N=95
Baseline (mean) 8 8
Change from baseline (adjusted mean ) -0.8 -0.2
Difference from placebo (adjusted mean with 95% confidence interval) -0.6 (-0.8, -0.4) ˗
% of patients (n/N) achieving A1C ≤7% 49% (98/199) 34% (33/97)
FPG (mg/dL) N=197 N=97
Baseline (mean) 170 172
Change from baseline (adjusted mean ) -20 -6
Difference from placebo (adjusted mean with 95% confidence interval) -14 (-23, -5) ˗

Add-on Combination Therapy with Pioglitazone and Metformin

In a 52 week, active-comparator study, a total of 803 patients inadequately controlled (mean baseline A1C = 8.2%) on a current regimen of pioglitazone 30 mg and metformin at least 1500 mg per day or at the maximum tolerated dose were randomized to either receive the addition of alogliptin tablets 25 mg or the titration of pioglitazone 30 mg to 45 mg following a four week, single-blind placebo run-in period. Patients were maintained on a stable dose of metformin (median dose = 1700 mg). Patients who failed to meet prespecified hyperglycemic goals during the 52 week treatment period received glycemic rescue therapy.

In combination with pioglitazone and metformin, alogliptin tablets 25 mg were shown to be statistically superior in lowering A1C and FPG compared with the titration of pioglitazone from 30 mg to 45 mg at Week 26 and at Week 52 (Table 9; results shown only for Week 52). A total of 11% of patients in the alogliptin tablets 25 mg treatment group and 22% of patients in the pioglitazone up-titration group required glycemic rescue.

Improvements in A1C were not affected by gender, age, race or baseline BMI.

The mean increase in body weight was similar in both treatment arms.

Table 9. Glycemic Parameters in a 52 Week, Active-Controlled Study of Alogliptin Tablets as Add-On Combination Therapy to Metformin and Pioglitazone *
Alogliptin Tablets 25 mg + Pioglitazone 30 mg + Metformin Pioglitazone 45 mg + Metformin
*
Intent-to-treat population using last observation on study
Least squares means adjusted for treatment, baseline value, geographic region and baseline metformin dose.
Noninferior and statistically superior to metformin + pioglitazone at the 0.025 one-sided significance level
§
p<0.001 compared to pioglitazone 45 mg + metformin
A1C (%) N=397 N=394
Baseline (mean) 8.2 8.1
Change from baseline(adjusted mean ) -0.7 -0.3
Difference from pioglitazone 45 mg + metformin(adjusted mean with 95% confidence interval) -0.4 (-0.5, -0.3) ˗
% of Patients (n/N) achieving A1C≤7% 33% (134/404)§ 21% (85/399)
Fasting Plasma Glucose (mg/dL) N=399 N=396
Baseline (mean) 162 162
Change from baseline (adjusted mean ) -15 -4
Difference from pioglitazone 45 mg + metformin(adjusted mean with 95% confidence interval) -11§ (-16, -6) ˗

Add-On Therapy to a Sulfonylurea

In a 26 week, placebo-controlled study, a total of 500 patients inadequately controlled on a sulfonylurea (mean baseline A1C = 8.1%) were randomized to receive alogliptin tablets 12.5 mg, alogliptin tablets 25 mg or placebo. Patients were maintained on a stable dose of glyburide (median dose = 10 mg) during the treatment period. All patients entered into a four week, single-blind, placebo run-in period prior to randomization. Patients who failed to meet prespecified hyperglycemic goals during the 26 week treatment period received glycemic rescue therapy.

The addition of alogliptin tablets 25 mg to glyburide therapy resulted in statistically significant improvements from baseline in A1C at Week 26 when compared to placebo (Table 10). Improvements in FPG observed with alogliptin tablets 25 mg were not statistically significant compared with placebo. A total of 16% of patients receiving alogliptin tablets 25 mg and 28% of those receiving placebo required glycemic rescue.

Improvements in A1C were not affected by gender, age, baseline BMI or baseline glyburide dose.

The mean change in body weight was similar between alogliptin tablets and placebo when given in combination with glyburide.

Table 10. Glycemic Parameters in a 26 Week, Placebo-Controlled Study of Alogliptin Tablets as Add-On Therapy to Glyburide *
Alogliptin Tablets 25 mg + Glyburide Placebo + Glyburide
*
Intent-to-treat population using last observation on study
Least squares means adjusted for treatment, baseline value, geographic region and baseline glyburide dose
p<0.01 compared to placebo
A1C (%) N=197 N=97
Baseline (mean) 8.1 8.2
Change from baseline(adjusted mean ) -0.5 0
Difference from placebo(adjusted mean with 95% confidence interval) -0.5 (-0.7, -0.3) ˗
% of Patients (n/N) achieving A1C ≤7% 35% (69/198) 18% (18/99)
FPG (mg/dL) N=198 N=99
Baseline (mean) 174 177
Change from baseline(adjusted mean ) -8 2
Difference from placebo(adjusted mean with 95% confidence interval) -11 (-22, 1) ˗

Add-On Therapy to Insulin

In a 26 week, placebo-controlled study, a total of 390 patients inadequately controlled on insulin alone (42%) or in combination with metformin (58%) (mean baseline A1C = 9.3%) were randomized to receive alogliptin tablets 12.5 mg, alogliptin tablets 25 mg or placebo. Patients were maintained on their insulin regimen (median dose = 55 IU) upon randomization and those previously treated with insulin in combination with metformin (median dose = 1700 mg) prior to randomization continued on the combination regimen during the treatment period. Patients entered the trial on short-, intermediate- or long-acting (basal) insulin or premixed insulin. Patients who failed to meet prespecified hyperglycemic goals during the 26 week treatment period received glycemic rescue therapy.

The addition of alogliptin tablets 25 mg once daily to insulin therapy resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, when compared to placebo (Table 11). A total of 20% of patients receiving alogliptin tablets 25 mg and 40% of those receiving placebo required glycemic rescue.

Improvements in A1C were not affected by gender, age, baseline BMI or baseline insulin dose. Clinically meaningful reductions in A1C were observed with alogliptin tablets compared to placebo regardless of whether subjects were receiving concomitant metformin and insulin (-0.2% placebo versus -0.8% alogliptin tablets) therapy or insulin alone (0.1% placebo versus -0.7% alogliptin tablets).

The mean increase in body weight was similar between alogliptin tablets and placebo when given in combination with insulin.

Table 11. Glycemic Parameters in a 26 Week, Placebo-Controlled Study of Alogliptin Tablets as Add-On Therapy to Insulin *
Alogliptin Tablets 25 mg + Insulin ± Metformin Placebo + Insulin ± Metformin
*
Intent-to-treat population using last observation on study
Least squares means adjusted for treatment, baseline value, geographic region, baseline treatment regimen (insulin or insulin + metformin) and baseline daily insulin dose
p<0.05 compared to placebo
A1C (%) N=126 N=126
Baseline (mean) 9.3 9.3
Change from baseline (adjusted mean ) -0.7 -0.1
Difference from placebo (adjusted mean with 95% confidence interval) -0.6 (-0.8, -0.4) ˗
% of patients (n/N) achieving A1C ≤7% 8% (10/129) 1% (1/129)
FPG (mg/dL) N=128 N=127
Baseline (mean) 186 196
Change from baseline (adjusted mean ) -12 6
Difference from placebo (adjusted mean with 95% confidence interval) -18 (-33, -2) ˗

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