Mechanism of Action

Tradjenta (linagliptin) is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. DPP-4 degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation.

Clinical Trial Results

FDA approval of Tradjenta was based on eight studies involving approximately 3,800 studies. Tradjenta was evaluated as a monotherapy and in combination with metformin, glimepiride and pioglitazone therapy.

Monotherapy
Two double-blind, placebo-controlled studies, one of 18-week and another of 24-week duration, enrolled a total of 730 subjects. In both monotherapy studies subjects with inadequate glycemic control after a six weeks washout period were randomized. In the 18-week study, 76 subjects were randomized to placebo and 151 to linagliptin 5 mg; in the 24-week study 167 subjects were randomized to placebo and 336 to linagliptin 5 mg. Treatment with Tradjenta 5 mg daily provided statistically significant improvements in A1C, FPG and two-hour PPG compared with placebo. In these 18- and 24-week studies, the changes from baseline in A1C were -0.4 percent and -0.4 percent, respectively, for those given Tradjenta and 0.1 percent and 0.3 percent, respectively, for those given placebo.

Add-on Combination Therapy with Metformin
A 24-week, randomized, double-blind, placebo-controlled study enrolled 701 subjects who received either linagliptin 5 mg or placebo, administered once daily in combination with metformin. The combination showed statistically significant improvements in A1C, FPG, and 2-hour PPG compared with placebo. The mean change from baseline in A1C of Tradjenta/metformin versus placebo/metformin over the 24-week treatment period was -0.5 and 0.15, respectively.

Active-Controlled Study vs. Glimepiride in Combination with Metformin
Linagliptin was evaluated in a 104-week double-blind, glimepiride-controlled non-inferiority study. After 52 weeks, linagliptin and glimepiride both had reductions from baseline in A1C (-0.4 percent for linagliptin, -0.6 percent for glimepiride) from a baseline mean of 7.7 percent. The subjects treated with linagliptin exhibited a significant mean decrease from baseline body weight compared to a significant weight gain in patients administered glimepiride (-1.1 kg vs +1.4 kg, p< 0.0001).

Add-On Combination Therapy with Pioglitazone
A 24-week, randomized, double-blind, placebo-controlled study enrolled 389 subjects who received linagliptin 5 mg or placebo, both in addition to pioglitazone 30 mg daily. In initial combination with pioglitazone 30 mg, linagliptin 5 mg provided statistically significant improvements in A1C and FPG compared to placebo with pioglitazone. The mean change from baseline in A1C of linagliptin/pioglitazon versus placebo/pioglitazon over the 24-week treatment period was -1.1 and -0.6, respectively.

Add-On Combination with Sulfonylureas
An 18-week, randomized, double-blind, placebo-controlled study enrolled 245 subjects who received the addition of linagliptin 5 mg or to placebo, each administered once daily in combination with sulfonylurea. When combined with a sulfonylurea, linagliptin provided statistically significant improvements in A1C compared with placebo following 18 weeks treatment; the improvements in FPG observed with linagliptin were not statistically significant compared with placebo.

Add-On Combination Therapy with Metformin and a Sulfonylurea
A 24-week, randomized, double-blind, placebo-controlled study enrolled 1,058 subjects on a sulfonylurea and metformin who were randomized to receive linagliptin 5 mg or placebo, each administered once daily. The combination provided statistically significant improvements in A1C and FPG compared with placebo. Data showed a mean reduction from baseline relative to placebo in A1C of - 0.6 percent and in FPG of -12.7 mg/dL.