Pharmacodynamics, safety, tolerability and pharmacokinetics of a single oral dose of an engineered phenylalanine ammonia-lyase in patients with phenylketonuria.

The cornerstone treatment of hyperphenylalaninemia (HPA) and phenylketonuria (PKU) is a lifelong low-protein diet with phenylalanine (Phe) free L-amino acid supplements. However, the PKU diet has significant shortcomings, and there is a clinically unmet need for new therapeutics to improve patient outcomes. CDX-6114 is a modified phenylalanine ammonia-lyase (PAL) enzyme obtained by a mutation in the PAL sequence.

Heart Failure Epidemiology in Patients With Diabetes Mellitus Without Coronary Heart Disease.

Background: Epidemiology of patients with comorbid heart failure (HF) and diabetes mellitus (DM) without coronary heart disease (CHD) is not well described.

Methods And Results: We assessed HF incidence and outcomes in 2896 participants of the Health ABC Study (age 74.0 ± 3.

Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial.

Importance: Type 2 diabetes is associated with increased cardiovascular (CV) risk. Prior trials have demonstrated CV safety of 3 dipeptidyl peptidase 4 (DPP-4) inhibitors but have included limited numbers of patients with high CV risk and chronic kidney disease.

Objective: To evaluate the effect of linagliptin, a selective DPP-4 inhibitor, on CV outcomes and kidney outcomes in patients with type 2 diabetes at high risk of CV and kidney events.

Empagliflozin and Kidney Function Decline in Patients with Type 2 Diabetes: A Slope Analysis from the EMPA-REG OUTCOME Trial.

Background: Empagliflozin slowed the progression of CKD in patients with type 2 diabetes and cardiovascular disease in the EMPA-REG OUTCOME Trial. In a prespecified statistical approach, we assessed treatment differences in kidney function by analyzing slopes of eGFR changes.

Methods: Participants (=7020) were randomized (1:1:1) to empagliflozin 10 mg/d, empagliflozin 25 mg/d, or placebo added to standard of care.

Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk.

Background: Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINA trial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk.

Methods: CARMELINA is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events.

Composite Primary End Points in Cardiovascular Outcomes Trials Involving Type 2 Diabetes Patients: Should Unstable Angina Be Included in the Primary End Point?

Reductions in cardiovascular (CV) outcomes in recently reported trials, along with the recent approval by the U.S. Food and Drug Administration of an additional indication for empagliflozin to reduce the risk of CV death in type 2 diabetes patients with evidence of CV disease, have renewed interest in CV outcome trials (CVOTs) of glucose-lowering drugs.

Empagliflozin and Cardiovascular Outcomes in Asian Patients With Type 2 Diabetes and Established Cardiovascular Disease - Results From EMPA-REG OUTCOME.

Background: In the EMPA-REG OUTCOMEtrial, empagliflozin added to standard of care reduced the risk of 3-point major adverse cardiovascular (CV) events (3-point MACE: composite of CV death, non-fatal myocardial infarction, or non-fatal stroke) by 14%, CV death by 38%, hospitalization for heart failure by 35%, and all-cause mortality by 32% in patients with type 2 diabetes (T2DM) and established CV disease. We investigated the effects of empagliflozin in patients of Asian race.Methods and Results:Patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo.

Linagliptin plus metformin in patients with newly diagnosed type 2 diabetes and marked hyperglycemia.

Objectives: Few studies of oral glucose-lowering drugs exist in newly diagnosed type 2 diabetes (T2D) patients with marked hyperglycemia, and insulin is often proposed as initial treatment. We evaluated the oral initial combination of metformin and linagliptin, a dipeptidyl peptidase-4 inhibitor, in this population.

Methods: We performed a pre-specified subgroup analysis of a randomized study in which newly diagnosed T2D patients with glycated hemoglobin A1c (HbA1c) 8.

Linagliptin and pioglitazone combination therapy versus monotherapy with linagliptin or pioglitazone: A randomised, double-blind, parallel-group, multinational clinical trial.

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.

Metabolic consequences of acute and chronic empagliflozin administration in treatment-naive and metformin pretreated patients with type 2 diabetes.

Aims/hypothesis: Sodium glucose co-transporter 2 (SGLT2) inhibitors lower glycaemia by inducing glycosuria, but raise endogenous glucose production (EGP). Metformin lowers glycaemia mainly by suppressing EGP. We compared the effects of the SGLT2 inhibitor empagliflozin in treatment-naive (TN) and metformin pretreated (Met) patients with type 2 diabetes.

Diurnal Glycemic Patterns during an 8-Week Open-Label Proof-of-Concept Trial of Empagliflozin in Type 1 Diabetes.

Background: We recently reported improved glycemic control with reduced insulin dose in subjects with type 1 diabetes treated with the sodium glucose co-transporter-2 inhibitor empagliflozin. To further characterize the effects, we analyzed diurnal glycemic patterns by continuous glucose monitoring (CGM).

Methods: In an 8-week single-arm open-label pilot study of empagliflozin, we compared ambulatory glucose profiles produced from CGM data during 2-week intervals in a placebo run-in baseline period, end-of-treatment, and post-treatment.

Efficacy and safety of linagliptin monotherapy in Asian patients with inadequately controlled type 2 diabetes mellitus: A multinational, 24-week, randomized, clinical trial.

Aims/introduction: Asian patients represent a large portion of the global population with type 2 diabetes mellitus, but are underrepresented in trials of glucose-lowering therapies. The present randomized, phase III, placebo-controlled, double-blind, 24-week study evaluated the dipeptidyl peptidase-4 inhibitor, linagliptin, as monotherapy in Asian patients with inadequately controlled type 2 diabetes mellitus.

Materials And Methods: Patients who were treatment naïve or had been treated with one oral antidiabetes drug were randomized to either linagliptin 5 mg daily or a placebo after washout.

Efficacy and Cardiovascular Safety of Linagliptin as an Add-On to Insulin in Type 2 Diabetes: A Pooled Comprehensive Post Hoc Analysis.

Objective: With the expanding armamentarium of noninsulin therapies for type 2 diabetes mellitus, the use of insulin with various oral agents is becoming more common. In this study, we assessed the efficacy and cardiovascular (CV) safety of the dipeptidyl peptidase-4 inhibitor linagliptin as add-on to insulin in patients with type 2 diabetes.

Methods: In this post hoc analysis, data for patients receiving basal or basal-bolus insulin were pooled from 4 randomized, double-blind, phase 3 clinical trials of linagliptin 5 mg once daily or placebo given as add-on to background glucose-lowering treatment.

Dipeptidyl peptidase-4 inhibition with linagliptin and effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: Rationale and design of the MARLINA-T2D™ trial.

Efficacy, Safety & Modification of Albuminuria in Type 2 Diabetes Subjects with Renal Disease with LINAgliptin (MARLINA-T2D™), a multicentre, multinational, randomized, double-blind, placebo-controlled, parallel-group, phase 3b clinical trial, aims to further define the potential renal effects of dipeptidyl peptidase-4 inhibition beyond glycaemic control. A total of 350 eligible individuals with inadequately controlled type 2 diabetes and evidence of renal disease are planned to be randomized in a 1:1 ratio to receive either linagliptin 5 mg or placebo in addition to their stable glucose-lowering background therapy for 24 weeks. Two predefined main endpoints will be tested in a hierarchical manner: (1) change from baseline in glycated haemoglobin and (2) time-weighted average of percentage change from baseline in urinary albumin-to-creatinine ratio.

Empagliflozin as Add-on Therapy to Pioglitazone With or Without Metformin in Patients With Type 2 Diabetes Mellitus.

Purpose: To investigate the long-term efficacy and safety of empagliflozin as add-on therapy to pioglitazone with or without metformin in patients with type 2 diabetes mellitus.

Methods: Of 498 patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily for 24 weeks in the EMPA-REG PIO™ study, 305 (61.2%) were treated in a double-blind extension trial for ≥52 weeks (total duration ≥76 weeks).

Cardiovascular safety of linagliptin in type 2 diabetes: a comprehensive patient-level pooled analysis of prospectively adjudicated cardiovascular events.

Background: The cardiovascular (CV) safety of linagliptin was evaluated in subjects with type 2 diabetes (T2DM).

Methods: Pre-specified patient-level pooled analysis of all available double-blind, randomized, controlled trials, ≥ 12 weeks' duration (19 trials, 9459 subjects) of linagliptin versus placebo/active treatment. Primary end point: composite of prospectively adjudicated CV death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina (4P-MACE).

Kidney Disease End Points in a Pooled Analysis of Individual Patient-Level Data From a Large Clinical Trials Program of the Dipeptidyl Peptidase 4 Inhibitor Linagliptin in Type 2 Diabetes.

Background: Although assessment of cardiovascular safety is mandated by regulatory agencies for the development of new drugs to treat type 2 diabetes, evaluation of their renal safety has been relatively neglected.

Study Design: Individual patient-level data pooled analysis of 13 phase 2 or 3 randomized, double-blind, placebo-controlled, clinical trials of the dipeptidyl peptidase 4 inhibitor linagliptin.

Setting & Participants: Participants who participated in any of 13 randomized clinical trials and fulfilled predefined inclusion/exclusion criteria, such as being drug-naive (hemoglobin A1c, 7.

Combination of the dipeptidyl peptidase-4 inhibitor linagliptin with insulin-based regimens in type 2 diabetes and chronic kidney disease.

Glucose-lowering treatment options for type 2 diabetes mellitus patients with chronic kidney disease are limited. We evaluated the potential for linagliptin in combination with insulin in type 2 diabetes mellitus patients with mild-to-severe renal impairment. Data for participants in two phase 3 trials with linagliptin who were receiving insulin were analysed separately (n = 811).

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in black/African American patients with type 2 diabetes: Pooled analysis from eight Phase III trials.

Background: The prevalence of type 2 diabetes in black/African Americans from North and South America is high; yet data evaluating antidiabetic agents in this population is scarce. To address this gap, we pooled data from the clinical development program for linagliptin.

Methods: A retrospective pooled analysis of eight completed randomized, placebo-controlled Phase III trials of linagliptin identified 336 patients with type 2 diabetes who self-identified their ethnicity as black or African American.

Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA®).

CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (NCT01243424) is an ongoing, randomized trial in subjects with early type 2 diabetes and increased cardiovascular risk or established complications that will determine the long-term cardiovascular impact of linagliptin versus the sulphonylurea glimepiride. Eligible patients were sulphonylurea-naïve with HbA1c 6.5%-8.

Linagliptin improves glycemic control after 1 year as add-on therapy to basal insulin in Asian patients with type 2 diabetes mellitus.

Objective: To evaluate the efficacy and long-term safety of linagliptin added to basal insulin in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled by basal insulin with/without oral agents.

Research Design And Methods: This was a post hoc analysis of Asian patients from a global ≥52 week study in which patients on basal insulin were randomized (1:1) to double-blind treatment with linagliptin 5 mg once daily or placebo (NCT00954447). Basal insulin dose remained stable for 24 weeks, after which adjustments could be made according to the investigator's discretion to improve glycemic control.

Efficacy and safety of linagliptin in Hispanic/Latino patients with type 2 diabetes mellitus: a pooled analysis from six randomized placebo-controlled phase 3 trials.

Objective: The number of individuals diagnosed with type 2 diabetes mellitus is expected to rise disproportionately in Hispanic/Latino populations. We therefore aimed to assess the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin specifically in Hispanic/Latino patients with type 2 diabetes mellitus.

Research Design And Methods: Data from 745 patients who self-identified their ethnicity as Hispanic or Latino were pooled from six randomized, placebo-controlled phase 3 trials.