Cardiovascular Safety of Degarelix Versus Leuprolide for Advanced Prostate Cancer: The PRONOUNCE Trial Study Design.

OBJECTIVES: This study will compare the incidence of major adverse cardiovascular events (MACEs) with androgen deprivation therapy (ADT) among men with advanced prostate cancer who are being treated with a gonadotropin-releasing hormone (GnRH) antagonist versus a GnRH agonist. BACKGROUND: Treatment of advanced prostate cancer with ADT might increase the risk of subsequent cardiovascular events among men with known atherosclerotic cardiovascular disease (ASCVD), but a recent meta-analysis suggested that this risk might be lower with ADT using a GnRH antagonist versus a GnRH agonist. METHODS: PRONOUNCE is a multicenter, prospective, randomized, open, blinded endpoint trial that will enroll approximately 900 patients with advanced prostate cancer and pre-existing ASCVD who will be treated with ADT. Participants will be randomized to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide as ADT for 12 months. The primary endpoint is time from randomization to first confirmed, adjudicated occurrence of a MACE, which is defined as a composite of all-cause death, nonfatal myocardial infarction, or nonfatal stroke through 12 months of ADT treatment. Baseline cardiovascular biomarkers (high-sensitivity C-reactive protein, high-sensitivity troponin T, and N-terminal pro-brain natriuretic peptide), as well as serial inflammatory and immune biomarkers, will be evaluated in exploratory analyses. RESULTS: As of October 1, 2019, a total of 364 patients have been enrolled. The mean age is 74 years, 90% are white, 80% have hypertension or dyslipidemia, 30% diabetes mellitus, 40% have had a previous myocardial infarction, and 65% have had previous revascularization. Regarding prostate cancer features at randomization, 48% of the patients had localized disease, 23% had locally advanced disease, and 18% had metastatic disease. CONCLUSIONS: PRONOUNCE is the first prospective cardiovascular outcomes trial in advanced prostate cancer that will delineate whether the risk of subsequent cardiovascular events associated with ADT is lower with a GnRH antagonist versus a GnRH agonist for men with pre-existing ASCVD. (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease [PRONOUNCE]; NCT02663908).

Oral N-acetylcysteine reduces plasma homocysteine concentrations regardless of lipid or smoking status.

BACKGROUND: Elevated total plasma homocysteine (tHcy) is considered to be an independent cardiovascular disease risk factor, although tHcy lowering by B-vitamins improves only certain clinical endpoints. N-acetylcysteine (NAC), a thiol-containing antioxidant, acutely lowers tHcy and possibly also blood pressure. However, to our knowledge, at present no conclusive long-term evaluation exists that controls for factors such as hyperlipidemia, smoking, medication, and disease stage, all of which affect the thiol redox state, including tHcy. OBJECTIVE: We reanalyzed 2 double-blind, placebo-controlled trials in unmedicated middle-aged men, one in a hyperlipidemic group (HYL group; n = 40) and one in a normolipidemic group (NOL group; n = 42), each stratified for smokers and nonsmokers. DESIGN: We evaluated the effect of 4 wk of oral NAC (1.8 g/d) on tHcy (primary endpoint), plasma thiol (cysteine), and intracellular glutathione concentrations as well as on blood pressure. The HYL group had total cholesterol >220 mg/dL or triglycerides >150 mg/dL. RESULTS: NAC treatment significantly (P = 0.001, multivariate analysis of variance for repeated measures) lowered postabsorptive plasma concentrations of tHcy by -11.7% ± 3.0% (placebo: 4.1% ± 3.6%) while increasing those of cysteine by 28.1% ± 5.7% (placebo: 4.0% ± 3.4%) with no significant impact of hyperlipidemia or smoking. Moreover, NAC significantly decreased systolic (P = 0.003) and diastolic (P = 0.017) blood pressure within all subjects with a significant reduction in diastolic pressure in the HYL group (P = 0.008) but not in the NOL group. An explorative stepwise multiple regression analysis identified 1) post-treatment cysteine as well as 2) pretreatment tHcy and 3) albumin plasma concentrations as being significant contributors to tHcy reduction. CONCLUSIONS: Four weeks of oral NAC treatment significantly decreased plasma tHcy concentrations, irrespective of lipid or smoking status, and lowered systolic blood pressure in both normolipidemic and hyperlipidemic men, with significant diastolic blood pressure reductions in the HYL group only. Increased oral intake of cysteine may therefore be considered for primary or secondary prevention of vascular events with regard to the 2 independent risk factors of hyperhomocysteinemia and arterial hypertension.

Influence of TCF7L2 gene variants on the therapeutic response to the dipeptidylpeptidase-4 inhibitor linagliptin.

AIMS/HYPOTHESIS: Individuals carrying variants of the transcription factor 7-like 2 gene (TCF7L2) are at increased risk for type 2 diabetes. These metabolic genetic risk factors have been linked to diminished pancreatic islet-cell responsiveness to incretins, thus pharmacological interventions aimed at amplifying endogenous incretin biology may be affected. However, clinical evidence from randomised controlled trials so far is lacking. We investigated the influence of TCF7L2 risk alleles on the response to treatment with the dipeptidylpeptidase-4 (DPP-4) inhibitor linagliptin from four 24 week, phase III, placebo-controlled trials. METHODS: Pharmacogenomic samples and clinical data were available from 961 patients with type 2 diabetes. Whole-blood DNA samples were genotyped for TCF7L2 single-nucleotide polymorphisms in conjunction with assessments of 24 week changes in HbA1c. RESULTS: Linagliptin lowered HbA1c meaningfully in all three genotypes of rs7903146 (non-risk variant carriers CC [n = 356]: -0.82% [-9.0 mmol/mol], p < 0.0001; heterozygous CT [n = 264]: -0.77% [-8.4 mmol/mol], p < 0.0001; homozygous risk variant carriers TT [n = 73]: -0.57% [-6.2 mmol/mol], p < 0.0006). No significant treatment differences were seen between CC and CT patients, although HbA1c response was reduced in TT compared with CC patients (~0.26% [~2.8 mmol/mol], p = 0.0182). CONCLUSIONS/INTERPRETATION: Linagliptin significantly improved hyperglycaemia in patients with type 2 diabetes both with and without the TCF7L2 gene diabetes risk alleles. However, differences in treatment response were observed, indicating that diabetes susceptibility genes may be an important contributor to the inter-individual variability of treatment response.

Association between a gene variant near ataxia telangiectasia mutated and coronary artery disease in men.

OBJECTIVE: Type 2 diabetes is accompanied by increased mortality from coronary artery disease (CAD), but the mechanisms linking these conditions remain elusive. Hence, treatment of hyperglycaemia alone is not sufficient to avoid CAD in diabetes. Alternative views suggest that metabolic and vascular diseases share unifying cellular defects that could serve as targets for novel therapeutic strategies. Recently, a variant [single-nucleotide polymorphism (SNP); rs11212617] near the gene for ataxia telangiectasia mutated (ATM) has been associated with glycaemic response to metformin. MATERIALS AND METHODS: We determined rs11212617 in 240 male patients who underwent elective coronary angiography. RESULTS: While the variant was not associated with glucose concentrations, the A allele was significantly associated with the presence of CAD (chi-square, p = 0.003), as well as with logarithmically transformed quantitative CAD indices [severe score (SS): 0.5 (0.4-0.6) vs 0.3 (0.2-0.5); extent score (ES): 2.63 (2.4-2.9) vs 1.94 (1.4-2.4), both p < 0.05, respectively]. Multivariate analysis revealed an independent association between the A allele with ES (ß = 0.17, p < 0.01). CONCLUSION: Our data suggest that ATM-dependent signalling might play a role in the development of atherosclerotic vascular disease, but larger studies are necessary to substantiate such a hypothesis.

The epidemiological Boehringer Ingelheim Employee study--part I: impact of overweight and obesity on cardiometabolic risk.

OBJECTIVE: Obesity-dependent diseases cause economic burden to companies. Large-scale data for working populations are lacking. Prevalence of overweight and obesity in the Boehringer Ingelheim (BI) Employee cohort and the relationship between body mass index (BMI) and cardiometabolic risk factors and diseases were estimated. DESIGN AND METHODS: Employees (≥38 years, employed in Ingelheim ≥2 years; n = 3151) of BI Pharma GmbH & Co. KG were invited by the medical corporate department to participate in intensive health checkups. Cross-sectional analysis of baseline data collected through 2006-2011 was performed. RESULTS: 90% of eligible subjects participated (n = 2849). Prevalences of overweight and obesity were 40% and 18% and significantly higher in men and participants ≥50 years. Cardiometabolic risk factor levels and prevalences of cardiometabolic diseases significantly increased with BMI and were higher in overweight and obese participants. Cut-points for increased risk estimated from ROC curves were ≈ 25 kg/m(2) for hypertension, hypercholesterolemia, arteriosclerosis, and hypertriglyceridemia and 26.7-28.0 kg/m(2) for the metabolic syndrome, insulin resistance, hyperinsulinemia, increased intima media thickness, and type 2 diabetes. CONCLUSION: This is the first large-scale occupational health care cohort from a single company. Cardiometabolic risk factors and diseases accumulate with increasing BMI. Occupational weight reduction programs seem to be reasonable strategies.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of empagliflozin in patients with type 2 diabetes mellitus.

INTRODUCTION: This study examined the safety, tolerability, pharmacokinetics, and pharmacodynamics of empagliflozin, a potent and highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 48 patients with T2DM were randomized to receive one of four doses of empagliflozin (2.5, 10, 25, or 100 mg qd) or placebo over 8 days. In every dose group, nine patients received active drug and three received placebo. The primary endpoint was safety and tolerability. Pharmacokinetic and pharmacodynamic parameters were measured as secondary endpoints. RESULTS: Empagliflozin was rapidly absorbed, reaching peak levels 1.5-3.0 h after dosing and showed a biphasic decline. The mean terminal elimination half-life ranged from 10 to 19 h. Increases in exposure (area under the plasma concentration-time curve [AUC] and maximum concentration of analyte in plasma [C max]) were approximately proportional with dose. Empagliflozin increased the rate and total amount of glucose excreted in urine compared to placebo. After administration of a single dose of empagliflozin, cumulative amounts of glucose excreted in urine over 24 h ranged from 46.3 to 89.8 g, compared with 5.84 g with placebo. Similar results were seen after multiple doses. Fasting plasma glucose levels decreased by 17.2-25.8% with empagliflozin and by 12.7% with placebo. The frequency of adverse events was 33.3-66.7% with empagliflozin and 41.7% with placebo. There were no changes in urine volume or micturition frequency under the controlled study conditions. CONCLUSION: Overall, pharmacokinetic assessments demonstrated a dose-proportional increase in drug exposure and support once-daily dosing. Elevated urinary glucose excretion was observed with all doses. Multiple once-daily oral doses of empagliflozin (2.5-100 mg) reduced plasma glucose and were well tolerated in patients with T2DM. EudraCT (2007-000654-32).

Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in healthy Japanese subjects.

This randomized, placebo-controlled within dose groups, double-blind, single rising dose study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of 1 mg to 100 mg doses of empagliflozin in 48 healthy Japanese male subjects. Empagliflozin was rapidly absorbed, reaching peak levels in 1.25 to 2.50 h; thereafter, plasma concentrations declined in a biphasic fashion, with mean terminal elimination half-life ranging from 7.76 to 11.7 h. Increase in empagliflozin exposure was proportional to dose. Oral clearance was dose independent and ranged from 140 to 172 mL/min. In the 24 h following 100 mg empagliflozin administration, the mean (%CV) amount of glucose excreted in urine was 74.3 (17.1) g. The amount and the maximum rate of glucose excreted via urine increased with dose of empagliflozin. Nine adverse events, all of mild intensity, were reported by 8 subjects (7 with empagliflozin and 1 with the placebo). No hypoglycemia was reported. In conclusion, 1 mg to 100 mg doses of empagliflozin had a good safety and tolerability profile in healthy Japanese male subjects. Exposure to empagliflozin was dose proportional. The amount and rate of urinary glucose excretion were higher with empagliflozin than with the placebo, and increased with empagliflozin dose.

Empagliflozin (BI 10773), a Potent and Selective SGLT2 Inhibitor, Induces Dose-Dependent Glucosuria in Healthy Subjects.

Empagliflozin is an orally available, selective inhibitor of sodium glucose cotransporter 2. In this study, single oral doses of empagliflozin from 0.5 to 800 mg were not associated with any clinically significant safety concerns in healthy male volunteers. The incidence of adverse events (AEs) was similar in subjects receiving placebo (22.2%) or empagliflozin (25.0%) in the single rising dose part of the study and after 50 mg empagliflozin under fed (28.6%) or fasted (28.6%) conditions. The most frequent AE was headache. No clinically relevant changes in laboratory or electrocardiogram (ECG) measurements were observed. Single oral doses of empagliflozin were rapidly absorbed, reaching peak levels after 1.0-2.1 hours. Increases in empagliflozin exposure were roughly dose-proportional and a dose-dependent increase in urinary glucose excretion was observed for empagliflozin doses up to 100 mg. After ingestion of 50 mg empagliflozin in conjunction with a high-fat, high-calorie meal, no clinically relevant changes in exposure were found, indicating that empagliflozin can be administered independent of food. Empagliflozin up to 800 mg did not generate clinically significant safety concerns in healthy male subjects. The pharmacokinetic properties of empagliflozin support once daily administration independent of food.

Linagliptin increases incretin levels, lowers glucagon, and improves glycemic control in type 2 diabetes mellitus.

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. METHODS: Patients in this phase 2a, multicenter, randomized, double-blind, placebo-controlled study received placebo (n = 40) or linagliptin 5 mg (n = 40). Sitagliptin 100 mg (n = 41) once daily for 4 weeks was included for exploratory purposes. Primary endpoints for linagliptin versus placebo: change from baseline to day 28 in 24-h weighted mean glucose (WMG) and intact glucagon-like peptide (GLP)-1 area under the time-effect curve between 0 and 2 h (AUEC(0-2h)) following meal tolerance test on day 28. RESULTS: Linagliptin increased intact GLP-1 AUEC(0-2h) (+18.1 pmol/h/L) and lowered 24-h WMG (-1.1 mmol/L) versus placebo (both P < 0.0001) after 28 days. Intact glucose-dependent insulinotropic polypeptide increased in line with GLP-1 (+91.4 pmol/h/L increase vs. placebo; P < 0.0001). Glycated hemoglobin (-0.22%; P = 0.0021), fasting plasma glucose (-0.6 mmol/L; P = 0.0283), and glucose (AUEC(0-3h)) (-5.9 mmol/h/L; P < 0.0001) improved significantly with linagliptin versus placebo. Most adverse events were mild; hypoglycemia or serious adverse events were not reported. Sustained DPP-4 inhibition (≥80%) throughout the treatment period was accompanied by significant reductions in glucagon starting at day 1 of linagliptin administration. CONCLUSION: Linagliptin was well tolerated and effectively inhibited plasma DPP-4 activity in patients with T2DM, producing immediate improvements in incretin levels, glucagon suppression, and glycemic control that were maintained throughout the study period.

2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial.

BACKGROUND: Addition of a sulphonylurea to metformin improves glycaemic control in type 2 diabetes, but is associated with hypoglycaemia and weight gain. We aimed to compare a dipeptidyl peptidase-4 inhibitor (linagliptin) against a commonly used sulphonylurea (glimepiride). METHODS: In this 2-year, parallel-group, non-inferiority double-blind trial, outpatients with type 2 diabetes and glycated haemoglobin A(1c) (HbA(1c)) 6·5-10·0% on stable metformin alone or with one additional oral antidiabetic drug (washed out during screening) were randomly assigned (1:1) by computer-generated random sequence via a voice or web response system to linagliptin (5 mg) or glimepiride (1-4 mg) orally once daily. Study investigators and participants were masked to treatment assignment. The primary endpoint was change in HbA(1c) from baseline to week 104. Analyses included all patients randomly assigned to treatment groups who received at least one dose of treatment, had a baseline HbA(1c) measurement, and had at least one on-treatment HbA(1c) measurement. This trial is registered at ClinicalTrials.gov, number NCT00622284. FINDINGS: 777 patients were randomly assigned to linagliptin and 775 to glimepiride; 764 and 755 were included in analysis of the primary endpoint. Reductions in adjusted mean HbA(1c) (baseline 7·69% [SE 0·03] in both groups) were similar in the linagliptin (-0·16% [SE 0·03]) and glimepiride groups (-0·36% [0·03]; difference 0·20%, 97·5% CI 0·09-0·30), meeting the predefined non-inferiority criterion of 0·35%. Fewer participants had hypoglycaemia (58 [7%] of 776 vs 280 [36%] of 775 patients, p<0·0001) or severe hypoglycaemia (1 [<1%] vs 12 [2%]) with linagliptin compared with glimepiride. Linagliptin was associated with significantly fewer cardiovascular events (12 vs 26 patients; relative risk 0·46, 95% CI 0·23-0·91, p=0·0213). INTERPRETATION: The results of this long-term randomised active-controlled trial advance the clinical evidence and comparative effectiveness bases for treatment options available to patients with type 2 diabetes mellitus. The findings could improve decision making for clinical treatment when metformin alone is insufficient. FUNDING: Boehringer Ingelheim.

Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor linagliptin: a 4-week multicenter, randomized, double-blind, placebo-controlled phase IIa study in Japanese type 2 diabetes patients.

BACKGROUND: The dipeptidyl-peptidase-4 (DPP-4) inhibitor linagliptin is under clinical development for treatment of type 2 diabetes mellitus (T2DM). In previous studies in white populations it showed potential as a once-daily oral antidiabetic drug. OBJECTIVES: In compliance with regulatory requirements for new drugs intended for use in the Japanese population, this study investigated the pharmacokinetics, pharmacodynamics, and tolerability of multiple oral doses of linagliptin in Japanese patients with T2DM. METHODS: In this randomized, double-blind, placebo-controlled multiple dose study, 72 Japanese patients with T2DM were assigned to receive oral doses of linagliptin 0.5, 2.5, or 10 mg or placebo (1:1:1:1 ratio) once daily for 28 days. For analysis of pharmacokinetic properties, linagliptin concentrations were determined from plasma and urinary samples obtained throughout the treatment phase, with more intensive samplings on days 1 and 28. DPP-4 inhibition, glycosylated hemoglobin A1c (HbA(1c)) levels, and plasma glucose and glucagon-like peptide-1 (GLP-1) levels were compared by mixed effect model. Tolerability was assessed throughout the study by physical examination, including blood pressure and pulse rate measurements, 12-lead ECG, and laboratory analysis. RESULTS: Baseline demographic characteristics were well balanced across the 4 treatment groups (mean [SD] age, 59.7 [6.4] years in the placebo group, 60.8 [9.2] years in the 0.5 mg group, 60.2 [6.4] years in the 2.5 mg group, and 59.1 [8.6] years in the 10 mg group; mean [SD] weight, 67.2 [10.0] kg in the placebo group, 64.5 [9.0] kg in the 0.5 mg group, 69.6 [9.4] kg in the 2.5 mg group, and 63.5 [12.2] kg in the 10 mg group; mean [SD] duration of T2DM diagnosis, 5.1 [4.2] years in the placebo group, 5.2 [4.7] years in the 0.5 mg group, 5.9 [4.8] years in the 2.5 mg group, and 2.6 [2.3] years in the 10 mg group). The majority of the patients treated were male (76.4%). Use of previous antidiabetic medication was more common in the 2.5 mg linagliptin group (44%) than in the 0.5 or 10 mg linagliptin (15.8% and 22.2%, respectively) or placebo groups (35.3%). Total systemic exposure in terms of linagliptin AUC and C(max) (which occurred at 1.25-1.5 hours) increased in a less than dose-proportional manner. The terminal half-life was long (223-260 hours) but did not reflect the accumulation half-life (10.0-38.5 hours), resulting in a moderate accumulation ratio of <2.9 that decreased with increasing dose. Urinary excretion increased with linagliptin doses but was <7% at steady state for all dose groups. Inhibition of plasma DPP-4 at 24 hours after the last dose on day 28 was approximately 45.8%, 77.8%, and 89.7% after linagliptin 0.5, 2.5, and 10 mg, respectively. At steady state, linagliptin was associated with dose-dependent increases in plasma GLP-1 levels, and the postprandial GLP-1 response was enhanced. Statistically significant dose-dependent reductions were observed in fasting plasma glucose levels at day 29 for all linagliptin groups (-11.5, -13.6, and -25.0 mg/dL for the 0.5, 2.5, and 10 mg groups, respectively; P < 0.05 for all linagliptin groups). Linagliptin also produced statistically significant dose-dependent reductions from baseline for glucose area under the effect curve over 3 hours after meal tolerance tests (-29.0 to -68.1 mg × h/dL; P < 0.05 for all 3 linagliptin groups). For the 0.5 and 10 mg linagliptin-treated groups, there were statistically significant reductions in HbA(1c) from baseline compared with placebo, despite the relatively low baseline HbA(1c) (7.2%) and small sample size (P < 0.01 for both groups). The greatest reduction in HbA(1c) (-0.44%) was seen in the highest linagliptin dose group (10 mg). On dosing for up to 28 days, linagliptin was well tolerated with no reported serious adverse events or symptoms suggestive of hypoglycemia. Overall, fewer adverse events were reported by patients after linagliptin than after placebo (11 of 55 [20%] vs 6 of 17 [35%]). CONCLUSIONS: Linagliptin demonstrated a nonlinear pharmacokinetic profile in these Japanese patients with T2DM consistent with the findings of previous studies in healthy Japanese and white patients. Linagliptin treatment resulted in statistically significant and clinically relevant reductions in HbA(1c) as soon as 4 weeks after starting therapy in these Japanese patients with T2DM, suggesting that clinical studies of longer duration in Japanese T2DM patients are warranted.

MRP8/14 is associated with systemic inflammation in stable coronary atherosclerosis in men.

BACKGROUND: MRP8/14, a secreted heterodimeric protein complex secreted upon phagocyte activation, plays an important role in atherogenesis and vascular injury. Phagocyte activation is crucially involved in the development of atherosclerotic processes, and MRP8/14 levels have also been linked to acute cardiovascular events. We investigated whether circulating MRP8/14 correlates to chronic coronary artery disease (CAD) stages in this observational, cross-sectional study. METHODS AND RESULTS: A total of 240 male subjects undergoing elective coronary angiography were included in the study. CAD was present in 166 individuals, whereas 74 subjects were classified without prevalent CAD (control subjects). The atherosclerotic burden was obtained by three independent angiographic scores: the Severity, Gensini and Extent Score. Serum MRP8/14 levels were measured by ELISA. They were associated with hs-CRP, IL-6 and fibrinogen levels (r = 0·43, r = 0·40 and r = 0·44, respectively; all P < 0·001). However, MRP8/14 was neither associated with any other cardiovascular disease risk factor nor did serum levels differ between patients with stable CAD [0·82 (0·55-1·14) µg mL(-1) ] and control subjects [0·91 (0·63-1·30) µg mL(-1) ; P = 0·69]. Moreover, atherosclerotic wall irregularities did not demonstrate any association with circulating MRP8/14. CONCLUSIONS: The phagocyte activation marker MRP8/14 is significantly associated with markers of systemic inflammation in male patients with CAD. However, we were unable to find a correlation between circulating MRP8/14 complex and stable CAD.

The DPP-4 inhibitor linagliptin does not prolong the QT interval at therapeutic and supratherapeutic doses.

AIM: To evaluate the potential effects of therapeutic and supratherapeutic doses of linagliptin (BI 1356) on the QT/QT(c) 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 (QT(c) I) 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 QT(c) I, at any time point. The placebo-corrected MCfB of QT(c) I 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 QT(c) I 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.

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.

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). SUBJECTS AND METHODS: This was a single rising-dose, randomized, four-group, placebo-controlled, single-blind (within dose groups) study. Thirty-six healthy men aged 18-50 years were enrolled and randomized into four sequential treatment groups. Group 1 received linagliptin 0.5 mg intravenously, group 2 received 2.5 mg intravenously and group 4 received 10 mg intravenously. In group 3, subjects underwent a two-way randomized crossover, receiving 5 mg intravenously and a 10 mg oral tablet. Linagliptin concentrations in plasma and urine, as well as plasma DPP-4 activity, were determined by validated assays. Noncompartmental analysis and population pharmacokinetic modelling were performed. RESULTS: Linagliptin showed nonlinear pharmacokinetics after intravenous infusion of 0.5-10 mg, with a less than dose-proportional increase in exposure. Noncompartmental parameters were calculated on the basis of total (i.e. bound and unbound) plasma concentrations. The total clearance value was low and increased with dose from 2.51 to 14.3 L/h. The apparent steady-state volume of distribution (V(ss)) increased with dose from 380 to 1540 L. Renal excretion of the unchanged parent compound increased with increasing plasma concentrations from 2.72% in the 0.5 mg dose group to 23.0% in the 10 mg dose group. The terminal elimination half-life was comparable across dose groups (126-139 hours). Because of the nonlinear pharmacokinetics, the standard approach of comparing the area under the plasma concentration-time curve (AUC) after oral administration with the AUC after intravenous administration led to dose-dependent estimates of the absolute bioavailability. Therefore, a population pharmacokinetic model was developed, accounting for the concentration-dependent protein binding of linagliptin to its target enzyme, DPP-4. The model-derived estimates of the V(ss) and clearance of linagliptin not bound to DPP-4 were 402.2 L and 26.9 L/h, respectively. The absolute bioavailability was estimated to be about 30% for the linagliptin 10 mg tablet. CONCLUSION: The nonlinear pharmacokinetic characteristics and the pharmacokinetic/pharmacodynamic relationship of linagliptin were independent of the mode of administration (intravenous or oral). Because of the nonlinear pharmacokinetics, the standard approach of comparing the AUC after oral administration with the AUC after intravenous administration was inappropriate to determine the absolute bioavailability of linagliptin. By a modelling approach, the absolute bioavailability of the 10 mg linagliptin tablet was estimated to be about 30%.

Linagliptin, a dipeptidyl peptidase-4 inhibitor in development for the treatment of type 2 diabetes mellitus: a Phase I, randomized, double-blind, placebo-controlled trial of single and multiple escalating doses in healthy adult male Japanese subjects.

BACKGROUND: The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin is in clinical development for the treatment of type 2 diabetes mellitus (T2DM). In previous studies in non-Japanese populations, linagliptin showed potential as a once-daily oral antidiabetic drug. OBJECTIVE: This study investigated the tolerability, pharmacokinetics, and pharmacodynamics of linagliptin in healthy adult male Japanese volunteers, in compliance with Japanese regulatory requirements for new drugs intended for use in humans. METHODS: This was a Phase I, randomized, doubleblind, placebo-controlled study in healthy volunteers. Linagliptin or placebo was administered as single escalating doses of 1, 2.5, 5, and 10 mg, or as multiple escalating doses of 2.5, 5, and 10 mg once daily for 12 days. Three quarters of subjects in each dose group were randomized to active drug and one quarter to placebo. Blood and urine samples for determination of pharmacokinetic parameters were obtained before administration of the first dose of study drug and at regular time points after administration, with more frequent blood sampling on days 1 and 12 in subjects receiving multiple doses. Inhibition of DPP-4 activity and plasma concentrations of glucagon-like peptide-1 (GLP-1) and glucose were also determined. Tolerability was assessed throughout the study based on physical examinations, 12-lead ECGs, and standard laboratory tests. RESULTS: Eight subjects were enrolled in each dose group, 6 receiving active drug and 2 receiving placebo. Baseline demographic characteristics were comparable in the single-dose groups (mean [SD] age, 24.5 [3.6] years; mean weight, 61.2 [6.2] kg; mean height, 171.5 [5.3] cm) and multiple-dose groups (mean age, 25.4 [3.7] years; mean weight, 61.6 [5.2] kg; mean height, 170.9 [4.9] cm). Linagliptin displayed nonlinear pharmacokinetics. Total systemic exposure (AUC and C(max)) increased in a manner that was less than dose proportional. T(max) ranged from 1.50 to 6.00 hours, and elimination t((1/2)) ranged from 96.9 to 175.0 hours. Total CL increased with increasing dose (from 140 mL/min in the 1-mg group to 314 mL/min in the 10-mg group), as did apparent V(d) (from 1260 to 3060 L with doses up to 10 mg). Steady state was attained within 2 to 3 days. The accumulation t((1/2)) ranged from approximately 10 to 15 hours. The accumulation ratio with multiple dosing was <1.5 and decreased with increasing dose (approximately 1.2 in the 10-mg dose). Urinary excretion increased with increasing dose and over time in all dose groups, although it did not exceed 7% in any dose group on day 12. Linagliptin inhibited plasma DPP-4 activity in a dose-dependent manner. Mean DPP-4 inhibition was >or=80% over 24 hours after a single dose of 10 mg and after multiple doses of 5 and 10 mg for 12 days. Postprandial plasma GLP-1 concentrations increased from preprandial concentrations by 2- to 4-fold after administration of single doses and by 2- to 2.5-fold on day 12 after administration of multiple doses. Baseline (premeal) plasma GLP-1 concentrations were higher on day 12 than on day 1 in all linagliptin groups. A total of 3 adverse events were reported in 1 subject each: an increase in histamine concentration in a subject receiving a single dose of linagliptin 5 mg, vasovagal syncope in a subject receiving a single dose of linagliptin 10 mg, and pharyngitis in a subject receiving multiple doses of linagliptin 10 mg. None of these events was considered drug related. No episodes of hypoglycemia occurred during the study. CONCLUSIONS: In this short-term study in healthy adult male Japanese volunteers, multiple oral doses of linagliptin inhibited plasma DPP-4 activity and elevated active GLP-1 concentrations in a dose-dependent manner, with no episodes of hypoglycemia. Multiple dosing of linagliptin for 12 days was well tolerated and exhibited a pharmacokinetic/pharmacodynamic profile consistent with a once-daily regimen. Clinical studies in Japanese patients with T2DM appear to be warranted.

Design, statistical analysis and sample size calculation of a phase IIb/III study of linagliptin versus voglibose and placebo.

BACKGROUND: Many patients with diabetes mellitus (DM) require a combination of antidiabetic drugs with complementary mechanisms of action to lower their hemoglobin A1c levels to achieve therapeutic targets and reduce the risk of cardiovascular complications. Linagliptin is a novel member of the dipeptidyl peptidase-4 (DPP-4) inhibitor class of antidiabetic drugs. DPP-4 inhibitors increase incretin (glucagon-like peptide-1 and gastric inhibitory polypeptide) levels, inhibit glucagon release and, more importantly, increase insulin secretion and inhibit gastric emptying. Currently, phase III clinical studies with linagliptin are underway to evaluate its clinical efficacy and safety. Linagliptin is expected to be one of the most appropriate therapies for Japanese patients with DM, as deficient insulin secretion is a greater concern than insulin resistance in this population. The number of patients with DM in Japan is increasing and this trend is predicted to continue. Several antidiabetic drugs are currently marketed in Japan; however there is no information describing the effective dose of linagliptin for Japanese patients with DM. METHODS: This prospective, randomized, double-blind study will compare linagliptin with placebo over a 12-week period. The study has also been designed to evaluate the safety and efficacy of linagliptin by comparing it with another antidiabetic, voglibose, over a 26-week treatment period. Four treatment groups have been established for these comparisons. A phase IIb/III combined study design has been utilized for this purpose and the approach for calculating sample size is described. DISCUSSION: This is the first phase IIb/III study to examine the long-term safety and efficacy of linagliptin in diabetes patients in the Japanese population.

High-molecular weight adiponectin is independently associated with the extent of coronary artery disease in men.

OBJECTIVE: Adiponectin has anti-atherogenic properties and low circulating adiponectin has been linked to coronary atherosclerosis. Yet, there is considerable evidence that the high-molecular weight (HMW) complex of adiponectin is the major active form of this adipokine. We therefore investigated whether HMW adiponectin is associated with the extent of coronary artery disease (CAD) in men. RESEARCH DESIGN AND METHODS: Associations among CAD, HMW adiponectin and the HMW/total-adiponectin ratio were assessed in 240 male patients undergoing elective coronary angiography. Total adiponectin and HMW adiponectin was measured by enzyme-linked immunosorbent assay and serum levels were correlated with defined coronary scores and established cardiovascular risk factors. RESULTS: We found significant inverse correlations between angiographic scores and HMW adiponectin [Extent Score (ES): r=-0.39; Gensini Score (GS): r=-0.35; and Severity Score (SS): r=-0.40, all P<0.001], and the HMW/total-adiponectin ratio (ES: r=-0.49; GS: r=-0.46; SS: r=-0.46; all P<0.001). Multivariable regression analyses revealed that HMW adiponectin and the HMW/total-adiponectin ratio were significantly associated with the extent of CAD (both P<0.001). ROC analyses demonstrated that the predictive value of HMW adiponectin and the HMW/total-adiponectin ratio for the extent of coronary atherosclerosis significantly exceeded that of total adiponectin (P<0.001, P=0.010, respectively). CONCLUSIONS: HMW adiponectin and the HMW/total-adiponectin ratio inversely correlate with the extent of CAD. HMW adiponectin in particular seems to be a better marker for CAD extent than total adiponectin.

Increased gene expression of scavenger receptors and proinflammatory markers in peripheral blood mononuclear cells of hyperlipidemic males.

Interactions between peripheral blood mononuclear cells (PBMCs) and those within plaques are suggested to be pathophysiologically relevant to lipid-induced arteriosclerosis. In this study, gene expressions of scavenger receptors (CD36, CD68), LPS receptor (CD14), proinflammatory (tumor necrosis factor alpha [TNFalpha], CD40, interleukin-1 beta [IL-1beta]) and oxidative stress-related (manganese superoxide dismutase [MnSOD]) markers were analyzed in PBMCs of clinically asymptomatic males with classical proatherogenic risk factors such as smoking and/or hyperlipidemia. PBMCs were isolated from venous blood of normolipidemic non-smokers (n = 10) and smokers (n = 8), and hyperlipidemic non-smokers (n = 9) and smokers (n = 8). RNA from PBMCs was used for PCR analyses. Plasma concentrations of oxidized low-density lipoproteins (oxLDL) were measured by ELISA. The gene expressions of CD36, CD68, CD40, TNFalpha, and MnSOD were significantly higher in PBMCs of hyperlipidemics than in normolipidemics, irrespective of whether they were smoking or not. The individual expression of these genes showed significant positive correlations with each other but also with serum cholesterol or plasma oxLDL concentrations. The higher expressions of scavenger receptors, proinflammatory and oxidative stress-related genes of PBMCs are suggested to result mainly from hyperlipidemia and the accompanied increase of oxLDL concentrations.