Initial Combination Therapy with Linagliptin + Metformin

STATISTICALLY SIGNIFICANT A1C REDUCTIONS IN A FIXED-DOSE COMBINATION

PLACEBO-ADJUSTED MEAN DIFFERENCE IN A1C AT 24 WEEKS IN PATIENTS RECEIVING LINAGLIPTIN AND METFORMIN, ALONE OR IN COMBINATION (%)^1†‡§

^†Superiority of both free combination therapies, consisting of the twice-daily administration of linagliptin 2.5 mg and metformin (500 mg or 1000 mg), was shown over the individual metformin components (500 mg and 1000 mg, both twice daily) and over linagliptin 5 mg once daily for the change in A1C from baseline at week 24. Linagliptin
2.5 mg twice daily + metformin 1000 mg twice daily was superior to metformin 1000 mg twice daily (P<0.0001); linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily was superior to linagliptin 5 mg once daily (P<0.0001); linagliptin 2.5 mg twice daily + metformin 500 mg twice daily was superior to metformin 500 mg twice daily (P<0.0001); linagliptin 2.5 mg twice daily + metformin 500 mg twice daily was superior to linagliptin 5 mg once daily (P<0.0001).

^‡Results are adjusted for a 0.1% mean A1C increase for placebo (n=65).

^§Full analysis population using last observation on study. ANCOVA model included treatment and number of prior oral antihyperglycemic drugs (OADs) as class effects, as well as baseline A1C as continuous covariates.

^||Linagliptin and metformin were studied as coadministered tablets; total daily dose of linagliptin was equal to 5 mg.

^¶1.6% mean A1C reduction from baseline in patients treated with twice-daily linagliptin 2.5 mg and metformin 1000 mg (mean baseline A1C 8.7%) compared with 0.1% increase from baseline with placebo.

Initial Combination Therapy with Linagliptin + Metformin

A randomized, double-blind, placebo-controlled, parallel-group study of drug-naïve or previously treated (4 weeks washout and 2 weeks placebo run-in) patients with type 2 diabetes with insufficient glycemic control (aged 18 to 80 years) who were randomized to placebo (n=72), linagliptin 5 mg once daily (n=142), metformin 500 mg twice daily (n=144), linagliptin 2.5 mg twice daily + metformin 500 mg twice daily (n=143), metformin 1000 mg twice daily (n=147), or linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily (n=143). Primary endpoint was change from baseline A1C after 24 weeks of treatment. Secondary endpoints included change from baseline in fasting plasma glucose (FPG) 2 hour postprandial glucose (2hPPG) after 24 weeks of treatment. 29.2% of patients in the placebo group required use of rescue therapy vs 11.1% of patients receiving linagliptin 5 mg once daily, 13.5% of patients receiving metformin 500 mg twice daily, 8.0% of patients receiving metformin 1000 mg twice daily, 7.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 500 mg twice daily, and 4.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily. Full analysis population using last observation on study.¹

Reference: 1. Haak T, Meinicke T, Jones R, Weber S, von Eynatten M, Woerle H-J. Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2012;14(6):565-574.

IN PATIENTS RECEIVING CO-ADMINISTERED LINAGLIPTIN 2.5
MG/ METFORMIN 1000 MG TWICE DAILY AS INITIAL THERAPY^1†

SECONDARY ENDPOINT: PERCENT OF PATIENTS WHO ACHIEVED A1C <7%^‡

^†Superiority of both free combination therapies, consisting of the twice-daily administration of linagliptin 2.5 mg and metformin (500 mg or 1000 mg), was shown over the individual metformin components (500 mg and 1000 mg, both twice daily) and over linagliptin 5 mg once daily for the change in A1C from baseline at week 24. Linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily was superior to metformin 1000 mg twice daily (P<0.0001); linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily was superior to linagliptin 5 mg once daily (P<0.0001); linagliptin 2.5 mg twice daily + metformin 500 mg twice daily was superior to metformin 500 mg twice daily (P<0.0001); linagliptin 2.5 mg twice daily + metformin 500 mg twice daily was superior to linagliptin 5 mg once daily (P<0.0001).

^‡Among patients with a baseline A1C of ≥7%.

Initial Combination Therapy with Linagliptin + Metformin

A randomized, double-blind, placebo-controlled, parallel-group study of drug-naïve or previously treated (4 weeks washout and 2 weeks placebo run-in) patients with type 2 diabetes with insufficient glycemic control (aged 18 to 80 years) who were randomized to placebo (n=72), linagliptin 5 mg once daily (n=142), metformin 500 mg twice daily (n=144), linagliptin 2.5 mg twice daily + metformin 500 mg twice daily (n=143), metformin 1000 mg twice daily (n=147), or linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily (n=143). Primary endpoint was change from baseline A1C after 24 weeks of treatment. Secondary endpoints included change from baseline in FPG 2hPPG after 24 weeks of treatment. 29.2% of patients in the placebo group required use of rescue therapy vs 11.1% of patients receiving linagliptin 5 mg once daily, 13.5% of patients receiving metformin 500 mg twice daily, 8.0% of patients receiving metformin 1000 mg twice daily, 7.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 500 mg twice daily, and 4.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily. Full analysis population using last observation on study.¹

Study in Patients with High Baseline A1C

A1C REDUCTION WITH LINGLIPTION + METFORMIN VS LINAGLIPTIN ALONE

PRIMARY ENDPOINT: ADJUSTED MEAN DIFFERENCE IN A1C FROM BASELINE AT 24 WEEKS IN TREATMENT-NAÏVE PATIENTS WITH HIGH BASELINE A1C (≥8.5% TO ≤12.0%)

*MMRM model included treatment, continuous baseline A1C, baseline A1C by visit interaction, visit by treatment interaction, baseline renal impairment by treatment interaction, and baseline renal impairment by treatment by visit interaction.

^†Full analysis set (FAS) population.

Study in Patients with High Baseline A1C

A 24-week, randomized, double-blind, parallel-group trial to assess the efficacy of linagliptin and metformin compared with linagliptin monotherapy in adult patients with type 2 diabetes diagnosed within the previous 12 months who were treatment naïve (no antidiabetic therapy for 12 weeks prior to randomization) and had inadequate glycemic control (A1C ≥8.5% to ≤12%). Patients were randomized (1:1) after a 2-week run-in period to either linagliptin 5 mg/day + placebo (n=157) or linagliptin 5 mg/day + metformin 500 mg BID (n=159). Metformin was initiated at 1000 mg/day (500 mg BID) for 7 days. Patients were up-titrated to
1500 mg/day (500 mg qAM and 1000 mg qPM) for a subsequent 7 days based upon tolerability to the increased dose. Thereafter, metformin could be further up-titrated to a maximum daily dose of 2000 mg (1000 mg BID) up to a period of 6 weeks if the FPG was >110 mg/dL and the patient was able to tolerate the maximum dose. Titration of metformin was performed under double-blind conditions. Patients who failed to meet glycemic goals were treated with sulfonylurea, insulin, or glitazone rescue.¹

Reference: 1. Ross SA, Caballero AE, Del Prato S, et al. Initial combination of linagliptin and metformin compared with linagliptin monotherapy in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia: a randomized, double-blind, active-controlled, parallel group, multinational clinical trial. Diabetes Obes Metab. 2015;17(2):136-144.

A1C Reductions Over Time in Treatment-Naïve Patients With a High Baseline A1C

SECONDARY ENDPOINT: ADJUSTED MEAN CHANGE IN A1C FROM BASELINE (≥8.5% TO ≤12.0%) OVER 24 WEEKS IN AN FAS COMPLETERS ANALYSIS^1*

Adjusted Mean Change in A1C from Baseline Over 24 Weeks

*FAS, Completers (Observed Cases). Mixed Model Measurement Analysis includes treatment, continuous baseline A1C in addition to week repeated within patient, week by baseline A1C interaction, and week by treatment interaction.²

The adjusted mean changes for A1C (%) from baseline over time for linagliptin and metformin as compared with linagliptin alone were maintained throughout the 24-week treatment period. Using the completers analysis, the respective adjusted means for A1C (%) changes from baseline for linagliptin and metformin as compared with linagliptin alone were −1.9 and −1.3 at week 6, −2.7 and −1.8 at week 12, −2.8 and −1.9 at week 18, and −2.8 and −2.0 at week 24.¹

Study in Patients with High Baseline A1C

Reference: 2. Data on file. Boehringer Ingelheim Pharmaceuticals, Inc.