14.2  Combination Therapy

Add-on Combination Therapy with Metformin
A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of linagliptin in combination with metformin. Patients already on metformin (n = 491) at a dose of at least 1500 mg per day were randomized after completing a 2-week open-label placebo run-in period. Patients on metformin and another antihyperglycemic agent (n = 207) were randomized after a run-in period of approximately 6 weeks on metformin (at a dose of at least 1500 mg per day) in monotherapy. Patients were randomized to the addition of either linagliptin 5 mg or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with glimepiride rescue.

In combination with metformin, linagliptin provided statistically significant improvements in A1C, FPG, and 2-hour PPG compared with placebo (Table 5). Rescue glycemic therapy was used in 7.8% of patients treated with linagliptin 5 mg and in 18.9% of patients treated with placebo. The mean change from baseline in A1C of TRADJENTA/metformin versus placebo/metformin over the 24-week treatment period is shown in Figure 2. A similar decrease in body weight was observed for both treatment groups.

Table 5 Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in Combination with Metformin*   TRADJENTA 5 mg + Metformin  Placebo + Metformin 
*Full analysis population using last observation on study
A1C (%)     
Number of patients n = 513  n = 175 
Baseline (mean) 8.1 8.0
Change from baseline (adjusted mean)  -0.5 0.15
Difference from placebo + metformin (adjusted mean) (95% CI)  -0.6 (-0.8, -0.5)  
Patients (%) achieving A1C <7%  145 (28.3) 20 (11.4)
FPG (mg/dL)    
Number of patients n = 495  n = 159 
Baseline (mean)  169.0 163.8
Change from baseline (adjusted mean)  -10.7 10.5
Difference from placebo + metformin (adjusted mean) (95% CI)  -21.1 (-27.3, -15.0)  
2-hour PPG (mg/dL)    
Number of patients n = 78  n = 21 
Baseline (mean)  270 274
Change from baseline (adjusted mean)  -48.9 18.3
Difference from placebo + metformin (adjusted mean) (95% CI)  -67.1 (-94.7, -39.6)  

Active-Controlled Study vs Glimepiride in Combination with Metformin
The efficacy of linagliptin is being eva luated in a 104-week double-blind, glimepiride-controlled non-inferiority study in type 2 diabetic patients with insufficient glycemic control despite metformin therapy. Patients being treated with metformin only entered a run-in period of 2 weeks duration, whereas patients pretreated with metformin and one additional antihyperglycemic agent entered a run-in treatment period of 6 weeks duration with metformin monotherapy (dose of ≥1500 mg per day) and washout of the other agent. After an additional 2-week placebo run-in period, those with inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of linagliptin 5 mg once daily or glimepiride. Patients receiving glimepiride were given an i