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Hansjuergen Woerle - One of the best experts on this subject based on the ideXlab platform.

  • Linagliptin and pioglitazone combination therapy versus monotherapy with Linagliptin or pioglitazone: A randomised, double-blind, parallel-group, multinational clinical trial.
    Diabetes & vascular disease research, 2016
    Co-Authors: Michael A. Nauck, Sanjay Patel, Maximiliano Di Domenico, Maureen Kobe, Robert Toorawa, Hansjuergen Woerle
    Abstract:

    Linagliptin plus pioglitazone single-pill combinations were evaluated. Patients (n = 936) with insufficient glycaemic control, despite lifestyle interventions, were randomised for 30 weeks to either monotherapy with Linagliptin 5 mg; pioglitazone 15, 30 or 45 mg; or single-pill combination with Linagliptin 5 mg plus pioglitazone 15, 30 or 45 mg. An extension (⩽54 weeks) planned to evaluate Linagliptin plus pioglitazone 30 or 45 mg single-pill combinations was not completed due to a protocol amendment. Adjusted mean (95% confidence interval) differences in HbA1c change from baseline at week 30 for Linagliptin plus pioglitazone 15, 30 and 45 mg were −0.17% (−0.41, 0.07), −0.37% (−0.60, −0.14) and −0.41% (−0.64, −0.18) versus pioglitazone monotherapies, respectively, and −0.44% (−0.67, −0.20), −0.68% (−0.91, −0.44) and −0.89% (−1.12, −0.66) versus Linagliptin monotherapy, respectively. Single-pill combinations were generally well tolerated. Hypoglycaemia frequency was ⩽1.5% per group. Linagliptin plus piogli...

  • Efficacy and safety of Linagliptin as add‐on therapy to basal insulin and metformin in people with Type 2 diabetes
    Diabetic medicine : a journal of the British Diabetic Association, 2016
    Co-Authors: S Durán-garcia, Sanjay Patel, Sandra Thiemann, Jisoo Lee, Hannele Yki-järvinen, Julio Rosenstock, Uwe Hehnke, Hansjuergen Woerle
    Abstract:

    Aim To evaluate the efficacy and safety of Linagliptin in people with Type 2 diabetes inadequately controlled on basal insulin and metformin. Methods This was a post hoc subanalysis of participants who received basal insulin and metformin in a global phase III study that randomized participants (1:1) to receive Linagliptin 5 mg once daily or placebo for ≥52 weeks as add-on therapy to basal insulin alone or in combination with metformin and/or pioglitazone. During the first 24 weeks, the background dose of basal insulin remained stable; thereafter, adjustments based on glucose concentrations were recommended. The primary endpoint of the subanalysis was the change from baseline in HbA1c after 24 weeks. The safety analysis incorporated data up to a maximum of 110 weeks. Results A total of 950 participants receiving background insulin and metformin were included in this subanalysis (Linagliptin and placebo, both n = 475). At week 24, the placebo-corrected adjusted mean (±se) change from baseline in HbA1c with Linagliptin was –7 (±1) mmol/mol [–0.7 (±0.1) %; 95% CI –0.8, –0.6; P < 0.0001]. The overall frequency of drug-related adverse events (Linagliptin, 18.9%; placebo, 21.9%) and investigator-reported hypoglycaemia (Linagliptin, 30.7%; placebo, 31.6%) were similar in both groups at the end of treatment. The frequency of severe hypoglycaemia was low (Linagliptin, 1.7%; placebo, 0.8%). No meaningful changes in mean (±sd) body weight were noted in either group [week 52: Linagliptin, –0.5 (±3.2) kg; placebo, 0.0 (±3.1) kg]. Conclusions Linagliptin added to basal insulin and metformin improved glycaemic control, without increasing the risk of hypoglycaemia or body weight gain.

  • improved glucose control with reduced hypoglycaemic risk when Linagliptin is added to basal insulin in elderly patients with type 2 diabetes
    Diabetes Obesity and Metabolism, 2015
    Co-Authors: Silvio E Inzucchi, Hansjuergen Woerle, Michael A. Nauck, M Von Eynatten, Uwe Hehnke, Robert R Henry
    Abstract:

    Aim To assess the efficacy, hypoglycaemia risk and other safety markers of Linagliptin as an additional therapy in older patients (aged ≥70 years) inadequately controlled with basal insulin. Methods A prespecified safety analysis from the Linagliptin trials programme was carried out to explore the hypoglycaemia risk when Linagliptin was added to background basal insulin therapy in elderly patients (≥70 years). To do this, two eligible, randomized, placebo-controlled, clinical trials (NCT00954447 and NCT01084005) of 24 and ≥52 weeks, respectively, were analysed. Results A total of 247 elderly individuals [mean ± standard deviation (s.d.) age 74 ± 4 years, glycated haemoglobin (HbA1c) 8.2 ± 0.8%] on basal insulin (mean ± s.d. baseline dose 36 ± 25 IU/day) were identified. Alongside placebo-adjusted change in HbA1c with Linagliptin of −0.77% [95% confidence interval (CI) −0.95 to 0.59; p < 0.0001] after 24 weeks, the hazard ratios (HRs) of both overall and confirmed hypoglycaemia [blood glucose ≤3.9 mmol/l (70 mg/dl)], were significantly lower with Linagliptin than with placebo: HR 0.61 (95% CI 0.39–0.97) versus 0.59 (95% CI 0.37–0.94), respectively (both p < 0.05). Moreover, significantly less confirmed hypoglycaemia was present in Linagliptin-treated patients with renal impairment [HR 0.45 (95% CI 0.27–0.76)], moderate hyperglycaemia [HbA1c 7.5 to <9.0%; HR 0.51 (95% CI 0.27–0.99)], lower fasting plasma glucose levels [<152 mg/dl; HR 0.49 (95% CI 0.28–0.86)] and those treated with higher insulin doses [insulin ≥35.6 IU/day; HR 0.46 (95% CI 0.23–0.91); p < 0.05 for all]. Severe hypoglycaemia was rare and the incidence was lower with Linagliptin (0.8%) versus placebo (2.5%): HR 0.21 (95% CI 0.02–2.30). Conclusions Despite improvements in hyperglycaemia and no relevant on-trial insulin dose reductions, adding Linagliptin to basal insulin appears to decrease hypoglycaemia risk. The biological basis of this phenomenon warrants further research but may involve counter-regulatory effects of incretin hormones.

  • initial combination of empagliflozin and Linagliptin in subjects with type 2 diabetes
    Diabetes Care, 2015
    Co-Authors: Andrew Lewin, Ralph A Defronzo, Sanjay Patel, Dacheng Liu, Renee Kaste, Hansjuergen Woerle, Uli C Broedl
    Abstract:

    OBJECTIVE To evaluate the efficacy and safety of empagliflozin/Linagliptin in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS Subjects not receiving antidiabetes therapy for ≥12 weeks were randomized to empagliflozin 25 mg/Linagliptin 5 mg ( n = 137), empagliflozin 10 mg/Linagliptin 5 mg ( n = 136), empagliflozin 25 mg ( n = 135), empagliflozin 10 mg ( n = 134), or Linagliptin 5 mg ( n = 135) for 52 weeks. The primary end point was change from baseline in HbA1c at week 24. RESULTS Mean HbA1c at baseline was 7.99–8.05% (64 mmol/mol). At week 24, adjusted mean (SE) changes from baseline in HbA1c with empagliflozin 25 mg/Linagliptin 5 mg, empagliflozin 10 mg/Linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and Linagliptin 5 mg were −1.08 (0.06)% (−11.8 [0.7] mmol/mol), −1.24 (0.06)% (−13.6 [0.7] mmol/mol), −0.95 (0.06)% (−10.4 [0.7] mmol/mol), −0.83 (0.06)% (−9.1 [0.7] mmol/mol), and −0.67 (0.06)% (−7.3 [0.7] mmol/mol), respectively. Reductions in HbA1c were significantly greater for empagliflozin 25 mg/Linagliptin 5 mg compared with Linagliptin 5 mg ( P < 0.001) but not compared with empagliflozin 25 mg and were significantly greater for empagliflozin 10 mg/Linagliptin 5 mg compared with the individual components ( P < 0.001 for both). At week 24, 55.4%, 62.3%, 41.5%, 38.8%, and 32.3% of subjects with baseline HbA1c ≥7% (≥53 mmol/mol) reached HbA1c <7% with empagliflozin 25 mg/Linagliptin 5 mg, empagliflozin 10 mg/Linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and Linagliptin 5 mg, respectively. Efficacy was maintained at week 52. The proportion of subjects with adverse events (AEs) over 52 weeks was similar across groups (68.9–81.5%), with no confirmed hypoglycemic AEs. CONCLUSIONS Reductions from baseline in HbA1c with empagliflozin/Linagliptin were significantly different versus Linagliptin and empagliflozin 10 mg but not versus empagliflozin 25 mg. Empagliflozin/Linagliptin was well tolerated.

  • 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 Obesity and Metabolism, 2015
    Co-Authors: Stuart A Ross, Hansjuergen Woerle, Sandra Thiemann, S Del Prato, A E Caballero, Baptist Gallwitz, Diane J Lewisdagostino, Zelie Bailes, S Patel, M Von Eynatten
    Abstract:

    Aims To evaluate glucose-lowering treatment strategies with Linagliptin and metformin in people with newly diagnosed type 2 diabetes and marked hyperglycaemia, a prevalent population for which few dedicated studies of oral antidiabetes drugs have been conducted. Methods A total of 316 patients, with type 2 diabetes diagnosed for ≤12 months and with glycated haemoglobin (HbA1c) concentration in the range 8.5–12.0%, were randomized 1:1 to double-blind, free-combination treatment with Linagliptin 5 mg once daily and metformin twice daily (uptitrated to 2000 mg/day maximum) or to Linagliptin monotherapy. The primary endpoint was change in HbA1c concentration from baseline at week 24 (per-protocol completers' cohort: n = 245). Results The mean (standard deviation) age and HbA1c at baseline were 48.8 (11.0) years and 9.8 (1.1)%, respectively. At week 24, the mean ± standard error (s.e.) HbA1c decreased from baseline by –2.8 ± 0.1% with Linagliptin/metformin and –2.0 ± 0.1% with Linagliptin; a treatment difference of –0.8% (95% confidence interval –1.1 to –0.5; p <0.0001). Similar results were observed in a sensitivity analysis based on intent-to-treat principles: adjusted mean ± s.e. changes in HbA1c of –2.7 ± 0.1% and –1.8 ± 0.1%, respectively; treatment difference of –0.9% (95% CI –1.3 to –0.6; p <0.0001). A treatment response of HbA1c <7.0% was achieved by 61 and 40% of patients in the Linagliptin/metformin and Linagliptin groups, respectively. Few patients experienced drug-related adverse events (8.8 and 5.7% of patients in the Linagliptin/metformin and Linagliptin groups, respectively). Hypoglycaemia occurred in 1.9 and 3.2% of patients in the Linagliptin/metformin and Linagliptin groups, respectively (no severe episodes). Body weight decreased significantly with the combination therapy (–1.3 kg between-group difference; p =0.0033). Conclusions Linagliptin in initial combination with metformin in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia, an understudied group, elicited significant improvements in glycaemic control with a low incidence of hypoglycaemia, weight gain or other adverse effects. These results support early combination treatment strategies and suggest that newly diagnosed patients with marked hyperglycaemia may be effectively managed with oral, non-insulin therapy.

Klaus Dugi - One of the best experts on this subject based on the ideXlab platform.

  • Long-term safety of Linagliptin monotherapy in Japanese patients with type 2 diabetes.
    Diabetes obesity & metabolism, 2012
    Co-Authors: Eiichi Araki, Nobuya Inagaki, Ryuzo Kawamori, Hirotaka Watada, Naoyuki Hayashi, Yoshiharu Horie, Akiko Sarashina, M Von Eynatten, Sandra Thiemann, Klaus Dugi
    Abstract:

    Aims In a phase III study conducted among Japanese patients with type 2 diabetes mellitus (T2DM), Linagliptin 5 and 10 mg showed clinically meaningful improvements in glycaemic parameters after 12 and 26 weeks compared with placebo and voglibose, respectively. This extension study assessed long-term tolerability of Linagliptin over 52 weeks. Methods Japanese patients with T2DM who completed either phase of a 12-week/26-week study comparing Linagliptin monotherapy with placebo or voglibose were eligible to enrol. In the extension study, the comparator groups switched to Linagliptin 5 or 10 mg, while the Linagliptin groups maintained dosage. Results In all, 540 patients received at least one dose of Linagliptin 5 or 10 mg and 494 completed the extension. Long-term treatment with Linagliptin was well tolerated; adverse events (AEs) of special interest and serious AEs occurred in small percentages of patients. Drug-related AEs occurred in 10.2 and 10.6% of patients in the Linagliptin 5- and 10-mg groups, respectively, and discontinuations due to drug-related AEs occurred in 1.1 and 0.7%, respectively. Only one (0.4%) patient in each dose group experienced investigator-defined hypoglycaemia during the treatment period (both events were non-severe). Body weight was not clinically altered in either group. The glycated haemoglobin A1c profiles over time were similar with Linagliptin 5 and 10 mg. Conclusions These findings provide evidence for the safety and tolerability of oral Linagliptin at either 5 or 10 mg for up to 52 weeks for the treatment of Japanese patients with T2DM, without clinically relevant increase in the risk of hypoglycaemia or weight gain.

  • Linagliptin increases incretin levels, lowers glucagon, and improves glycemic control in type 2 diabetes mellitus.
    Diabetes therapy : research treatment and education of diabetes and related disorders, 2012
    Co-Authors: Thomas Rauch, Hansjuergen Woerle, Jens J Holst, Arne Ring, Klaus Dugi, Ulrike Graefe-mody, Carolyn F. Deacon, T Heise
    Abstract:

    Introduction Linagliptin is a xanthine-based dipeptidyl peptidase (DPP)-4 inhibitor that is now available in numerous countries worldwide for the treatment of type 2 diabetes mellitus (T2DM). The aim of this study was to evaluate further the mechanisms underlying the improvements in glycemic control observed with Linagliptin. The effects of Linagliptin on DPP-4, pharmacodynamic parameters, and glycemic control versus placebo were assessed in patients with inadequately controlled T2DM.

  • efficacy and safety of Linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea a 24 week randomized study1
    Diabetic Medicine, 2011
    Co-Authors: David R Owens, Klaus Dugi, R Swallow, Hansjuergen Woerle
    Abstract:

    Aims To examine the efficacy and safety of the dipeptidyl peptidase-4 inhibitor Linagliptin in persons with Type 2 diabetes mellitus inadequately controlled [HbA1c 53–86 mmol/mol (7.0–10.0%)] by metformin and sulphonylurea combination treatment. Methods A multi-centre, 24-week, randomized, double-blind, parallel-group study in 1058 patients comparing Linagliptin (5 mg once daily) and placebo when added to metformin plus sulphonylurea. The primary endpoint was the change in HbA1c after 24 weeks. Results At week 24, the Linagliptin placebo-corrected HbA1c adjusted mean change from baseline was −7 mmol/mol (−0.62%) [95% CI −8 to −6 mmol/mol (−0.73 to −0.50%); P < 0.0001]. More participants with baseline HbA1c≥ 53 mmol/mol (≥ 7.0%) achieved an HbA1c < 53 mmol/mol (< 7.0%) with Linagliptin compared with placebo (29.2% vs. 8.1%, P < 0.0001). Fasting plasma glucose was reduced with Linagliptin relative to placebo (−0.7 mmol/l, 95% CI −1.0 to −0.4; P < 0.0001). Improvements in homeostasis model assessment of β-cell function were seen with Linagliptin (P < 0.001). The proportion of patients who reported a severe adverse event was low in both groups (Linagliptin 2.4%; placebo 1.5%). Symptomatic hypoglycaemia occurred in 16.7 and 10.3% of the Linagliptin and placebo groups, respectively. Hypoglycaemia was generally mild or moderate; severe hypoglycaemia was reported in 2.7 and 4.8% of the participants experiencing hypoglycaemic episodes in the Linagliptin and placebo groups, respectively. No significant weight changes were noted. Conclusions In patients with Type 2 diabetes, adding Linagliptin to metformin given in combination with a sulphonylurea significantly improved glycaemic control and this was well tolerated. Linagliptin could provide a valuable treatment option for individuals with inadequate glycaemic control despite ongoing combination therapy with metformin and a sulphonylurea.

  • The DPP-4 inhibitor Linagliptin does not prolong the QT interval at therapeutic and supratherapeutic doses.
    British journal of clinical pharmacology, 2011
    Co-Authors: Arne Ring, Mario Iovino, A. Port, E. Ulrike Graefe‐mody, Ivette Revollo, Klaus Dugi
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Linagliptin (BI 1356) is an oral, highly selective dipeptidyl peptidase-4 inhibitor which is under development for the treatment of type 2 diabetes mellitus and for which the pivotal phase III programme has recently been completed. • There have been no observed electrocardiogram changes in a Linagliptin single rising dose study with up to 600 mg, and no preclinical signals for QT liability. WHAT THIS STUDY ADDS • This manuscript describes the findings of a thorough QT study for Linagliptin conducted according to the ICH E14 guideline, with a therapeutic dose (5 mg) and a 20-fold therapeutic dose (100 mg). • Linagliptin does not cause clinically relevant changes of the corrected QT interval with a therapeutic dose and a 20-fold therapeutic dose. • The 20-fold therapeutic dose of Linagliptin was safe and well tolerated. AIM To evaluate the potential effects of therapeutic and supratherapeutic doses of Linagliptin (BI 1356) on the QT/QTc interval in healthy subjects. METHODS The study was a randomized, double-blind, placebo-controlled, four-period crossover study using single oral doses of Linagliptin (5 mg and 100 mg), moxifloxacin (400 mg) and placebo. Electrocardiogram (ECG) profiles using triplicates of 12-lead 10-s ECGs were digitally recorded pre-dose and after drug administration. The mean change from baseline (MCfB) of the individually heart rate corrected QT interval (QTcI) between 1 and 4 h postdrug administration was the primary end point. Blood samples to measure plasma concentrations of Linagliptin and its main metabolite were also obtained. RESULTS Forty-four Caucasian subjects (26 male) entered the study and 43 subjects completed the study as planned in the protocol. Linagliptin was not associated with an increase in the baseline-adjusted mean QTcI, at any time point. The placebo-corrected MCfB of QTcI was −1.1 (90% CI −2.7, 0.5) ms and −2.5 (–4.1, –0.9) ms for Linagliptin 5 mg and 100 mg, respectively, thus within the non-inferiority margin of 10 ms according to ICH E14. Linagliptin was well tolerated; the assessment of ECGs and other safety parameters gave no clinically relevant findings at either dose tested. Maximum plasma concentrations after administration of 100-mg Linagliptin were ∼24-fold higher than those observed previously for chronic treatment with the therapeutic 5-mg dose. Assay sensitivity was confirmed by a placebo-corrected MCfB of QTcI with moxifloxacin of 6.9 (90% CI 5.4, 8.5) ms. CONCLUSIONS Therapeutic and significantly supratherapeutic exposure to Linagliptin is not associated with QT interval prolongation.

  • the oral dpp 4 inhibitor Linagliptin significantly lowers hba1c after 4 weeks of treatment in patients with type 2 diabetes mellitus
    Diabetes Obesity and Metabolism, 2011
    Co-Authors: T Forst, Arne Ring, Ulrike Graefemody, B Uhliglaske, A Ritzhaupt, Klaus Dugi
    Abstract:

    Aim: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of Linagliptin in patients with type 2 diabetes mellitus (T2DM). Methods: After screening and a 14-day washout, subjects received Linagliptin 2.5, 5 or 10 mg or placebo once-daily for 28 days in this randomized, double-blind, parallel, placebo-controlled within-dose groups study. Results: Seventy-seven patients entered the study (Linagliptin: 61; placebo: 16). Four patients withdrew prematurely. There was little evidence of Linagliptin accumulation. Exposure, maximum and trough plasma concentrations of Linagliptin increased less than dose-proportionally. Rapid and sustained inhibition of dipeptidyl peptidase-4 reached 91–93% across Linagliptin doses at steady state. At the end of the 24-h dosing interval, inhibition was still high (82–90%). There were marked increases in plasma glucagon-like peptide-1 after 28 days of dosing. Compared to placebo, all Linagliptin doses resulted in statistically significant decreases of the area under the glucose curve following a meal tolerance test on day 29, that is, 24 h after the last study drug intake. After 28 days of treatment with Linagliptin the placebo-corrected mean change in haemoglobin A1c (HbA1c) (median baseline 7.0%) was −0.31% (2.5-mg dose), −0.37% (5-mg dose) and −0.28% (10-mg dose). The frequency of adverse events was similar for Linagliptin (31%) and placebo (34%). There were no notable safety concerns. Conclusions: Linagliptin administration led to attenuation of postprandial glucose excursions and, despite a low HbA1c at baseline, statistically significant reductions in HbA1c after only 4 weeks of treatment. Linagliptin had a safety and tolerability profile similar to placebo in T2DM patients.

Sanjay Patel - One of the best experts on this subject based on the ideXlab platform.

  • Oral glucose lowering with Linagliptin and metformin compared with Linagliptin alone as initial treatment in Asian patients with newly diagnosed type 2 diabetes and marked hyperglycemia: Subgroup analysis of a randomized clinical trial.
    Journal of diabetes investigation, 2017
    Co-Authors: Stefano Del Prato, Sanjay Patel, Maximilian Von Eynatten, Baptist Gallwitz, Zelie Bailes, Jisoo Lee, Diane J. Lewis-d’agostino, Vyankatesh K Shivane, Maximiliano Di Domenico
    Abstract:

    AIMS/INTRODUCTION Type 2 diabetes mellitus is an epidemic in Asia, yet clinical trials of glucose-lowering therapies often enroll predominantly Western populations. We explored the initial combination of metformin and Linagliptin, a dipeptidyl peptidase-4 inhibitor, in newly diagnosed type 2 diabetes mellitus patients in Asia with marked hyperglycemia. MATERIALS AND METHODS This was a post-hoc subgroup analysis of a multinational, parallel-group clinical trial in which 316 newly diagnosed type 2 diabetes mellitus patients with glycated hemoglobin A1c (HbA1c) 8.5-12.0% were randomized to double-blind oral treatment with Linagliptin/metformin or Linagliptin monotherapy. The primary end-point was the change from baseline in HbA1c at week 24. We evaluated data for the 125 participants from Asian countries. RESULTS After 24 weeks, the mean ± standard error reduction from baseline in HbA1c (mean 10.0%) was -2.99 ± 0.18% with Linagliptin/metformin and -1.84 ± 0.18% with Linagliptin; a treatment difference of -1.15% (95% confidence interval -1.65 to -0.66, P < 0.0001). HbA1c

  • Linagliptin and pioglitazone combination therapy versus monotherapy with Linagliptin or pioglitazone: A randomised, double-blind, parallel-group, multinational clinical trial.
    Diabetes & vascular disease research, 2016
    Co-Authors: Michael A. Nauck, Sanjay Patel, Maximiliano Di Domenico, Maureen Kobe, Robert Toorawa, Hansjuergen Woerle
    Abstract:

    Linagliptin plus pioglitazone single-pill combinations were evaluated. Patients (n = 936) with insufficient glycaemic control, despite lifestyle interventions, were randomised for 30 weeks to either monotherapy with Linagliptin 5 mg; pioglitazone 15, 30 or 45 mg; or single-pill combination with Linagliptin 5 mg plus pioglitazone 15, 30 or 45 mg. An extension (⩽54 weeks) planned to evaluate Linagliptin plus pioglitazone 30 or 45 mg single-pill combinations was not completed due to a protocol amendment. Adjusted mean (95% confidence interval) differences in HbA1c change from baseline at week 30 for Linagliptin plus pioglitazone 15, 30 and 45 mg were −0.17% (−0.41, 0.07), −0.37% (−0.60, −0.14) and −0.41% (−0.64, −0.18) versus pioglitazone monotherapies, respectively, and −0.44% (−0.67, −0.20), −0.68% (−0.91, −0.44) and −0.89% (−1.12, −0.66) versus Linagliptin monotherapy, respectively. Single-pill combinations were generally well tolerated. Hypoglycaemia frequency was ⩽1.5% per group. Linagliptin plus piogli...

  • Efficacy and safety of Linagliptin as add‐on therapy to basal insulin and metformin in people with Type 2 diabetes
    Diabetic medicine : a journal of the British Diabetic Association, 2016
    Co-Authors: S Durán-garcia, Sanjay Patel, Sandra Thiemann, Jisoo Lee, Hannele Yki-järvinen, Julio Rosenstock, Uwe Hehnke, Hansjuergen Woerle
    Abstract:

    Aim To evaluate the efficacy and safety of Linagliptin in people with Type 2 diabetes inadequately controlled on basal insulin and metformin. Methods This was a post hoc subanalysis of participants who received basal insulin and metformin in a global phase III study that randomized participants (1:1) to receive Linagliptin 5 mg once daily or placebo for ≥52 weeks as add-on therapy to basal insulin alone or in combination with metformin and/or pioglitazone. During the first 24 weeks, the background dose of basal insulin remained stable; thereafter, adjustments based on glucose concentrations were recommended. The primary endpoint of the subanalysis was the change from baseline in HbA1c after 24 weeks. The safety analysis incorporated data up to a maximum of 110 weeks. Results A total of 950 participants receiving background insulin and metformin were included in this subanalysis (Linagliptin and placebo, both n = 475). At week 24, the placebo-corrected adjusted mean (±se) change from baseline in HbA1c with Linagliptin was –7 (±1) mmol/mol [–0.7 (±0.1) %; 95% CI –0.8, –0.6; P < 0.0001]. The overall frequency of drug-related adverse events (Linagliptin, 18.9%; placebo, 21.9%) and investigator-reported hypoglycaemia (Linagliptin, 30.7%; placebo, 31.6%) were similar in both groups at the end of treatment. The frequency of severe hypoglycaemia was low (Linagliptin, 1.7%; placebo, 0.8%). No meaningful changes in mean (±sd) body weight were noted in either group [week 52: Linagliptin, –0.5 (±3.2) kg; placebo, 0.0 (±3.1) kg]. Conclusions Linagliptin added to basal insulin and metformin improved glycaemic control, without increasing the risk of hypoglycaemia or body weight gain.

  • initial combination of empagliflozin and Linagliptin in subjects with type 2 diabetes
    Diabetes Care, 2015
    Co-Authors: Andrew Lewin, Ralph A Defronzo, Sanjay Patel, Dacheng Liu, Renee Kaste, Hansjuergen Woerle, Uli C Broedl
    Abstract:

    OBJECTIVE To evaluate the efficacy and safety of empagliflozin/Linagliptin in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS Subjects not receiving antidiabetes therapy for ≥12 weeks were randomized to empagliflozin 25 mg/Linagliptin 5 mg ( n = 137), empagliflozin 10 mg/Linagliptin 5 mg ( n = 136), empagliflozin 25 mg ( n = 135), empagliflozin 10 mg ( n = 134), or Linagliptin 5 mg ( n = 135) for 52 weeks. The primary end point was change from baseline in HbA1c at week 24. RESULTS Mean HbA1c at baseline was 7.99–8.05% (64 mmol/mol). At week 24, adjusted mean (SE) changes from baseline in HbA1c with empagliflozin 25 mg/Linagliptin 5 mg, empagliflozin 10 mg/Linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and Linagliptin 5 mg were −1.08 (0.06)% (−11.8 [0.7] mmol/mol), −1.24 (0.06)% (−13.6 [0.7] mmol/mol), −0.95 (0.06)% (−10.4 [0.7] mmol/mol), −0.83 (0.06)% (−9.1 [0.7] mmol/mol), and −0.67 (0.06)% (−7.3 [0.7] mmol/mol), respectively. Reductions in HbA1c were significantly greater for empagliflozin 25 mg/Linagliptin 5 mg compared with Linagliptin 5 mg ( P < 0.001) but not compared with empagliflozin 25 mg and were significantly greater for empagliflozin 10 mg/Linagliptin 5 mg compared with the individual components ( P < 0.001 for both). At week 24, 55.4%, 62.3%, 41.5%, 38.8%, and 32.3% of subjects with baseline HbA1c ≥7% (≥53 mmol/mol) reached HbA1c <7% with empagliflozin 25 mg/Linagliptin 5 mg, empagliflozin 10 mg/Linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and Linagliptin 5 mg, respectively. Efficacy was maintained at week 52. The proportion of subjects with adverse events (AEs) over 52 weeks was similar across groups (68.9–81.5%), with no confirmed hypoglycemic AEs. CONCLUSIONS Reductions from baseline in HbA1c with empagliflozin/Linagliptin were significantly different versus Linagliptin and empagliflozin 10 mg but not versus empagliflozin 25 mg. Empagliflozin/Linagliptin was well tolerated.

  • Initial Combination of Empagliflozin and Linagliptin in Subjects With Type 2 Diabetes
    Diabetes Care, 2015
    Co-Authors: Andrew Lewin, Ralph A Defronzo, Sanjay Patel, Dacheng Liu, Renee Kaste, Hansjuergen Woerle, Uli C Broedl
    Abstract:

    OBJECTIVE To evaluate the efficacy and safety of empagliflozin/Linagliptin in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS Subjects not receiving antidiabetes therapy for ≥12 weeks were randomized to empagliflozin 25 mg/Linagliptin 5 mg ( n = 137), empagliflozin 10 mg/Linagliptin 5 mg ( n = 136), empagliflozin 25 mg ( n = 135), empagliflozin 10 mg ( n = 134), or Linagliptin 5 mg ( n = 135) for 52 weeks. The primary end point was change from baseline in HbA1c at week 24. RESULTS Mean HbA1c at baseline was 7.99–8.05% (64 mmol/mol). At week 24, adjusted mean (SE) changes from baseline in HbA1c with empagliflozin 25 mg/Linagliptin 5 mg, empagliflozin 10 mg/Linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and Linagliptin 5 mg were −1.08 (0.06)% (−11.8 [0.7] mmol/mol), −1.24 (0.06)% (−13.6 [0.7] mmol/mol), −0.95 (0.06)% (−10.4 [0.7] mmol/mol), −0.83 (0.06)% (−9.1 [0.7] mmol/mol), and −0.67 (0.06)% (−7.3 [0.7] mmol/mol), respectively. Reductions in HbA1c were significantly greater for empagliflozin 25 mg/Linagliptin 5 mg compared with Linagliptin 5 mg ( P < 0.001) but not compared with empagliflozin 25 mg and were significantly greater for empagliflozin 10 mg/Linagliptin 5 mg compared with the individual components ( P < 0.001 for both). At week 24, 55.4%, 62.3%, 41.5%, 38.8%, and 32.3% of subjects with baseline HbA1c ≥7% (≥53 mmol/mol) reached HbA1c

Arne Ring - One of the best experts on this subject based on the ideXlab platform.

  • Linagliptin increases incretin levels, lowers glucagon, and improves glycemic control in type 2 diabetes mellitus.
    Diabetes therapy : research treatment and education of diabetes and related disorders, 2012
    Co-Authors: Thomas Rauch, Hansjuergen Woerle, Jens J Holst, Arne Ring, Klaus Dugi, Ulrike Graefe-mody, Carolyn F. Deacon, T Heise
    Abstract:

    Introduction Linagliptin is a xanthine-based dipeptidyl peptidase (DPP)-4 inhibitor that is now available in numerous countries worldwide for the treatment of type 2 diabetes mellitus (T2DM). The aim of this study was to evaluate further the mechanisms underlying the improvements in glycemic control observed with Linagliptin. The effects of Linagliptin on DPP-4, pharmacodynamic parameters, and glycemic control versus placebo were assessed in patients with inadequately controlled T2DM.

  • The DPP-4 inhibitor Linagliptin does not prolong the QT interval at therapeutic and supratherapeutic doses.
    British journal of clinical pharmacology, 2011
    Co-Authors: Arne Ring, Mario Iovino, A. Port, E. Ulrike Graefe‐mody, Ivette Revollo, Klaus Dugi
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Linagliptin (BI 1356) is an oral, highly selective dipeptidyl peptidase-4 inhibitor which is under development for the treatment of type 2 diabetes mellitus and for which the pivotal phase III programme has recently been completed. • There have been no observed electrocardiogram changes in a Linagliptin single rising dose study with up to 600 mg, and no preclinical signals for QT liability. WHAT THIS STUDY ADDS • This manuscript describes the findings of a thorough QT study for Linagliptin conducted according to the ICH E14 guideline, with a therapeutic dose (5 mg) and a 20-fold therapeutic dose (100 mg). • Linagliptin does not cause clinically relevant changes of the corrected QT interval with a therapeutic dose and a 20-fold therapeutic dose. • The 20-fold therapeutic dose of Linagliptin was safe and well tolerated. AIM To evaluate the potential effects of therapeutic and supratherapeutic doses of Linagliptin (BI 1356) on the QT/QTc interval in healthy subjects. METHODS The study was a randomized, double-blind, placebo-controlled, four-period crossover study using single oral doses of Linagliptin (5 mg and 100 mg), moxifloxacin (400 mg) and placebo. Electrocardiogram (ECG) profiles using triplicates of 12-lead 10-s ECGs were digitally recorded pre-dose and after drug administration. The mean change from baseline (MCfB) of the individually heart rate corrected QT interval (QTcI) between 1 and 4 h postdrug administration was the primary end point. Blood samples to measure plasma concentrations of Linagliptin and its main metabolite were also obtained. RESULTS Forty-four Caucasian subjects (26 male) entered the study and 43 subjects completed the study as planned in the protocol. Linagliptin was not associated with an increase in the baseline-adjusted mean QTcI, at any time point. The placebo-corrected MCfB of QTcI was −1.1 (90% CI −2.7, 0.5) ms and −2.5 (–4.1, –0.9) ms for Linagliptin 5 mg and 100 mg, respectively, thus within the non-inferiority margin of 10 ms according to ICH E14. Linagliptin was well tolerated; the assessment of ECGs and other safety parameters gave no clinically relevant findings at either dose tested. Maximum plasma concentrations after administration of 100-mg Linagliptin were ∼24-fold higher than those observed previously for chronic treatment with the therapeutic 5-mg dose. Assay sensitivity was confirmed by a placebo-corrected MCfB of QTcI with moxifloxacin of 6.9 (90% CI 5.4, 8.5) ms. CONCLUSIONS Therapeutic and significantly supratherapeutic exposure to Linagliptin is not associated with QT interval prolongation.

  • the oral dpp 4 inhibitor Linagliptin significantly lowers hba1c after 4 weeks of treatment in patients with type 2 diabetes mellitus
    Diabetes Obesity and Metabolism, 2011
    Co-Authors: T Forst, Arne Ring, Ulrike Graefemody, B Uhliglaske, A Ritzhaupt, Klaus Dugi
    Abstract:

    Aim: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of Linagliptin in patients with type 2 diabetes mellitus (T2DM). Methods: After screening and a 14-day washout, subjects received Linagliptin 2.5, 5 or 10 mg or placebo once-daily for 28 days in this randomized, double-blind, parallel, placebo-controlled within-dose groups study. Results: Seventy-seven patients entered the study (Linagliptin: 61; placebo: 16). Four patients withdrew prematurely. There was little evidence of Linagliptin accumulation. Exposure, maximum and trough plasma concentrations of Linagliptin increased less than dose-proportionally. Rapid and sustained inhibition of dipeptidyl peptidase-4 reached 91–93% across Linagliptin doses at steady state. At the end of the 24-h dosing interval, inhibition was still high (82–90%). There were marked increases in plasma glucagon-like peptide-1 after 28 days of dosing. Compared to placebo, all Linagliptin doses resulted in statistically significant decreases of the area under the glucose curve following a meal tolerance test on day 29, that is, 24 h after the last study drug intake. After 28 days of treatment with Linagliptin the placebo-corrected mean change in haemoglobin A1c (HbA1c) (median baseline 7.0%) was −0.31% (2.5-mg dose), −0.37% (5-mg dose) and −0.28% (10-mg dose). The frequency of adverse events was similar for Linagliptin (31%) and placebo (34%). There were no notable safety concerns. Conclusions: Linagliptin administration led to attenuation of postprandial glucose excursions and, despite a low HbA1c at baseline, statistically significant reductions in HbA1c after only 4 weeks of treatment. Linagliptin had a safety and tolerability profile similar to placebo in T2DM patients.

  • Effect of Linagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers.
    International journal of clinical pharmacology and therapeutics, 2011
    Co-Authors: Eva Ulrike Graefe-mody, Arne Ring, B Withopf, Mario Iovino, Tobias Brand, Joachim Stangier, Hansjuergen Woerle
    Abstract:

    OBJECTIVE To investigate the effect of the estimated highest therapeutic dose of Linagliptin (5 mg) on the pharmacokinetics and pharmacodynamics of warfarin, a CYP2C9 substrate. SUBJECTS AND METHODS This open-label, 2-period, fixed-sequence trial enrolled 18 healthy male volunteers, 17 of whom were homozygous for CYP2C9*1/*1. Subjects received a single oral dose of warfarin (10 mg) followed by a washout period of at least 14 days. Subjects then received oral Linagliptin 5 mg once daily for 12 days (i.e. steady state) with a single dose of warfarin (10 mg) on Day 6. R(+) warfarin, S(-) warfarin, prothrombin time (PT) and international normalized ratio (INR) were assayed pre-dose and up to 168 h post-dose. RESULTS The geometric mean ratios (GMRs) (90% confidence interval (CI)) of AUC0-∞ and Cmax for (Linagliptin + warfarin)/warfarin were 98.5 (95.7 - 101.5) and 99.7 (94.7 - 104.9), respectively, for R-warfarin; 103.0 (99.1 - 107.0) and 100.9 (93.7 - 108.6), respectively, for S-warfarin. Concomitant administration of Linagliptin and warfarin had o clinically relevant effect on the AUC0-168 for INR or PT. The GMRs (90% CI) of INR nd PT AUC0-168 for (Linagliptin + warfarin)/ warfarin were 93.4 (86.2 - 101.1) and 103.2 (95.4 - 111.6), respectively. The corresponding Eax values for both INR and PT were slightly increased after co-administration of Linagliptin and warfarin compared with warfarin alone, being 104.3 (85.2 - 127.6) and 15.1 (94.3 -140.6), respectively, reflecting the higher variability of these endpoints. Co-administration of Linagliptin and warfarin was well tolerated. CONCLUSIONS Coadministration of Linagliptin did not alter the pharmacokinetics or pharmacodynamics of R- or S-warfarin, indicating that no dosage adjustment for warfarin is necessary when co-administered with Linagliptin.

  • pharmacokinetics and pharmacodynamics of single rising intravenous doses 0 5 mg 10 mg and determination of absolute bioavailability of the dipeptidyl peptidase 4 inhibitor Linagliptin bi 1356 in healthy male subjects
    Clinical Pharmacokinectics, 2010
    Co-Authors: Silke Retlich, Arne Ring, Klaus Dugi, Vincent Duval, Ulrich Jaehde, Alexander Staab, Arvid Jungnik, Silke Huttner, Ulrike Graefemody
    Abstract:

    Background and Objectives Linagliptin (BI 1356) is a highly specific inhibitor of dipeptidyl peptidase (DPP)-4, which is currently in phase III clinical development for the treatment of type 2 diabetes mellitus. Linagliptin exhibits nonlinear pharmacokinetics after oral administration, which are mainly related to concentration-dependent binding of Linagliptin to its target, DPP-4. The objectives of the study were to investigate the pharmacokinetics and pharmacodynamics after intravenous administration of Linagliptin and to determine its absolute bioavailability (F).

Maximilian Von Eynatten - One of the best experts on this subject based on the ideXlab platform.

  • Oral glucose lowering with Linagliptin and metformin compared with Linagliptin alone as initial treatment in Asian patients with newly diagnosed type 2 diabetes and marked hyperglycemia: Subgroup analysis of a randomized clinical trial.
    Journal of diabetes investigation, 2017
    Co-Authors: Stefano Del Prato, Sanjay Patel, Maximilian Von Eynatten, Baptist Gallwitz, Zelie Bailes, Jisoo Lee, Diane J. Lewis-d’agostino, Vyankatesh K Shivane, Maximiliano Di Domenico
    Abstract:

    AIMS/INTRODUCTION Type 2 diabetes mellitus is an epidemic in Asia, yet clinical trials of glucose-lowering therapies often enroll predominantly Western populations. We explored the initial combination of metformin and Linagliptin, a dipeptidyl peptidase-4 inhibitor, in newly diagnosed type 2 diabetes mellitus patients in Asia with marked hyperglycemia. MATERIALS AND METHODS This was a post-hoc subgroup analysis of a multinational, parallel-group clinical trial in which 316 newly diagnosed type 2 diabetes mellitus patients with glycated hemoglobin A1c (HbA1c) 8.5-12.0% were randomized to double-blind oral treatment with Linagliptin/metformin or Linagliptin monotherapy. The primary end-point was the change from baseline in HbA1c at week 24. We evaluated data for the 125 participants from Asian countries. RESULTS After 24 weeks, the mean ± standard error reduction from baseline in HbA1c (mean 10.0%) was -2.99 ± 0.18% with Linagliptin/metformin and -1.84 ± 0.18% with Linagliptin; a treatment difference of -1.15% (95% confidence interval -1.65 to -0.66, P < 0.0001). HbA1c

  • safety and tolerability of Linagliptin in patients with type 2 diabetes a comprehensive pooled analysis of 22 placebo controlled studies
    Clinical Therapeutics, 2014
    Co-Authors: Michael Lehrke, Sanjay Patel, Nikolaus Marx, Thomas Seck, Susanne Crowe, Karen Cheng, Maximilian Von Eynatten, Odd Erik Johansen
    Abstract:

    Purpose: Dipeptidyl peptidase (DPP)-4 inhibitors are an increasingly used antihyperglycemic therapy for patients with type 2 diabetes mellitus (T2DM). Linagliptin, an orally administered DPP-4 inhibitor, has demonstrated favorable efficacy/safety in clinical trials. The aim of this post hoc pooled analysis was to expand current knowledge of the safety of Linagliptin. Methods: Safety data for once-daily Linagliptin 5 mg (1 study of Linagliptin 2.5 mg twice daily) were analyzed from 22 randomized, double-blind, Phase I– III, placebo-controlled clinical trials of r102 weeks’ duration. Assessments of pooled data included incidence of patient-reported adverse events (AEs). Findings: Data from 7400 patients (Linagliptin, 4810; placebo, 2590) were pooled. Most patients (58.4%) had T2DM diagnosis for 45 years; approximately 75% were receiving Z1 type of background therapy in addition to Linagliptin/placebo. Overall exposure to the study drug was 2412.8 years for Linagliptin and 1481.4 years for placebo (mean [SD], 183 [120] days and 209 [150] days, respectively). Overall frequencies of AEs were similar for Linagliptinand placebo-treated patients (57.3% and 61.8%, respectively). The incidence of neoplastic AEs was low (0.6% and 0.9%, respectively); there were no reports of pancreatic neoplasia. Pancreatitis was observed in 2 Linagliptin-treated patients (o0.1%) and 1 placebo-treated patient (o0.1%). The occurrence of cardiac disorder AEs was similar in Linagliptin- and placebo-treated patients (3.2% [n ¼ 153] and 3.3% [n ¼ 83], respectively); the incidence of heart failure AEs for Linagliptin- and placebo-treated patients was 0.2% (n ¼ 11) and 0.3% (n ¼ 7), respectively. Overall, Linagliptin was weight neutral. Occurrence of investigator-defined hypoglycemic AEs was low for both Linagliptin and placebo (11.5% vs 14.0%). In patients receiving concomitant sulfonylurea therapy, investigator-defined hypoglycemic AEs were more frequent with Linagliptin versus placebo (22.1% [238/ 1079] vs 14.5% [61/421], respectively). Subgroup analyses showed similar frequencies of AEs for Linagliptin- and placebo-treated patients across different

  • Linagliptin added to sulphonylurea in uncontrolled type 2 diabetes patients with moderate-to-severe renal impairment:
    Diabetes & vascular disease research, 2013
    Co-Authors: Janet B. Mcgill, Sanjay Patel, Maximilian Von Eynatten, Dietmar Neubacher, Anthony H. Barnett, Andrew J Lewin, Hansjuergen Woerle
    Abstract:

    Glucose-lowering treatment options are limited for uncontrolled type 2 diabetes mellitus (T2DM) patients with advanced stages of renal impairment (RI). This retrospective analysis evaluated glycaemic efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor Linagliptin added to sulphonylurea. Three randomized phase 3 studies (n = 619) including T2DM subjects with moderate or severe RI [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m²] were analysed; only sulphonylurea-treated subjects who received additional Linagliptin (n = 58) or placebo (n = 33) were evaluated. Linagliptin provided meaningful placebo-adjusted HbA1c reductions of -0.68% (95% confidence interval: -1.19, -0.17), -1.08% (-2.02, -0.14) and -0.62% (-1.25, 0.01) after 24, 18 and 12 weeks, respectively. There was a similar incidence of overall adverse events (Linagliptin: 79.3%, placebo: 75.8%) and hypoglycaemia (Linagliptin: 37.9%, placebo: 39.4%). Severe hypoglycaemia was more common with placebo (Linagliptin: 1.7%, placebo: 6.1%). These data suggest that Linagliptin is a safe and effective glucose-lowering treatment in T2DM patients with moderate-to-severe RI for whom sulphonylurea treatment is no longer sufficient.

  • Linagliptin lowers albuminuria on top of recommended standard treatment in patients with type 2 diabetes and renal dysfunction
    Diabetes Care, 2013
    Co-Authors: Hansjuergen Woerle, Angela Emser, Perhenrik Groop, Mark E Cooper, Vlado Perkovic, Maximilian Von Eynatten
    Abstract:

    OBJECTIVE Preclinical data suggest that Linagliptin, a dipeptidyl peptidase-4 inhibitor, may lower urinary albumin excretion. The ability of Linagliptin to lower albuminuria on top of renin-angiotensin-aldosterone system (RAAS) inhibition in humans was analyzed by pooling data from four similarly designed, 24-week, randomized, double-blind, placebo-controlled, phase III trials. RESEARCH DESIGN AND METHODS A pooled analysis of four completed studies identified 217 subjects with type 2 diabetes and prevalent albuminuria (defined as a urinary albumin-to-creatinine ratio [UACR] of 30−3,000 mg/g creatinine) while receiving stable doses of RAAS inhibitors. Participants were randomized to either Linagliptin 5 mg/day ( n = 162) or placebo ( n = 55). The primary end point was the percentage change in geometric mean UACR from baseline to week 24. RESULTS UACR at week 24 was reduced by 32% (95% CI −42 to −21; P < 0.05) with Linagliptin compared with 6% (95% CI −27 to +23) with placebo, with a between-group difference of 28% (95% CI −47 to −2; P = 0.0357). The between-group difference in the change in HbA1c from baseline to week 24 was −0.61% (−6.7 mmol/mol) in favor of Linagliptin (95% CI −0.88 to −0.34% [−9.6 to −3.7 mmol/mol]; P < 0.0001). The albuminuria-lowering effect of Linagliptin, however, was not influenced by race or HbA1c and systolic blood pressure (SBP) values at baseline or after treatment. CONCLUSIONS Linagliptin administered in addition to stable RAAS inhibitors led to a significant reduction in albuminuria in patients with type 2 diabetes and renal dysfunction. This observation was independent of changes in glucose level or SBP. Further research to prospectively investigate the renal effects of Linagliptin is underway.

  • efficacy and tolerability of Linagliptin added to a sulfonylurea regimen in patients with inadequately controlled type 2 diabetes mellitus an 18 week multicenter randomized double blind placebo controlled trial
    Clinical Therapeutics, 2012
    Co-Authors: Andrew Lewin, Sanjay Patel, Dacheng Liu, Maximilian Von Eynatten, Lisa Arvay, Hansjuergen Woerle
    Abstract:

    Abstract Background Some patients with type 2 diabetes mellitus (T2DM) receiving monotherapy with a sulfonylurea (SU) are unable to meet recommended glycemic targets over the long term and require additional pharmacologic agents to maintain glycemic control. This study was designed to assess the utility of adjunctive therapy with the dipeptidyl peptidase (DPP)-4 inhibitor Linagliptin in patients with T2DM inadequately controlled with SU monotherapy. Objective To assess the efficacy and tolerability of Linagliptin as add-on therapy in patients with inadequately controlled T2DM despite background therapy with an SU. Methods In this Phase III, multicenter, randomized, double-blind, placebo-controlled trial, patients with inadequately controlled T2DM on SU monotherapy were randomly assigned to receive treatment with Linagliptin 5 mg once daily (n = 161) or placebo (n = 84) for 18 weeks. The primary end point was the mean change in hemoglobin (Hb) A 1c from baseline to week 18, evaluated using ANCOVA. Tolerability was assessed using laboratory analysis, spontaneous reporting, and physical examination and interview. Results Mean baseline characteristics were similar in the Linagliptin and placebo groups. Linagliptin treatment was associated with a placebo-corrected mean (95% CI) change in HbA 1c from baseline (8.6%) to 18 weeks of −0.47% (−0.70 to −0.24; P 1c target level of P = 0.007). Similarly, patients in the Linagliptin group were more likely to achieve an HbA 1c reduction of ≥0.5% compared with those in the placebo group (57.6% vs 22.0%; OR=5.1, 95% CI 2.7–9.6; P P = 0.12). Conclusions The addition of Linagliptin to SU therapy for 18 weeks in these patients with T2DM was associated with statistically significant and clinically meaningful reductions in HbA 1c compared with placebo. The overall tolerability of Linagliptin was similar to that of placebo, with a low risk for hypoglycemia and no significant weight gain. These findings support the use of Linagliptin as adjunctive therapy in patients with T2DM inadequately controlled on SU monotherapy. ClinicalTrials.gov identifier: NCT00819091.