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.

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.

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.

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%.

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.

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.

Increased cyclooxygenase-2 expression in peripheral blood mononuclear cells of smokers and hyperlipidemic subjects.

Cyclooxygenase (COX)-2 is expressed in macrophages of arteriosclerotic lesions and promotes inflammation. We investigated whether COX-2 is already expressed in peripheral blood mononuclear cells (PBMCs) of subjects possessing risk-related factors, such as in smokers and hyperlipidemics. PBMCs were isolated from the venous blood of normolipidemic nonsmokers (NL-NSM; n = 15), normolipidemic smokers (NL-SM; n = 12), hyperlipidemic nonsmokers (HL-NSM; n = 10), and hyperlipidemic smokers (HL-SM; n = 10). RNA from PBMCs was used for RT-PCR. Plasma concentrations of oxidized low-density lipoproteins (oxLDL) were measured by ELISA, those of glutamate and cystine by HPLC. The results show that COX-2 expression in PBMCs was significantly increased in the groups with cardiovascular risk factors (NL-SM, HL-SM, HL-NSM) compared with NL-NSM. COX-2 expression in PBMCs was positively correlated with concentrations of total serum cholesterol, oxLDL, glutamate, or cystine. We suggest that the elevated COX-2 expression indicates a priming of PBMCs as a response to a systemic pro-oxidative and proinflammatory shift in subjects with cardiovascular risk factors, which might also contribute to growth and instability of arteriosclerotic lesions.

Effect of thiol antioxidant on body fat and insulin reactivity.

Insulin signaling is enhanced by moderate concentrations of reactive oxygen species (ROS) and suppressed by persistent exposure to ROS. Diabetic patients show abnormally high ROS levels and a decrease in insulin reactivity which is ameliorated by antioxidants, such as N-acetylcysteine (NAC). A similar effect of NAC has not been reported for non-diabetic subjects. We now show that the insulin receptor (IR) kinase is inhibited in cell culture by physiologic concentrations of cysteine. In two double-blind trials involving a total of 140 non-diabetic subjects we found furthermore that NAC increased the HOMA-R index (derived from the fasting insulin and glucose concentrations) in smokers and obese patients, but not in nonobese non-smokers. In obese patients NAC also caused a decrease in glucose tolerance and body fat mass. Simultaneous treatment with creatine, a metabolite utilized by skeletal muscle and brain for the interconversion of ADP and ATP, reversed the NAC-mediated increase in HOMA-R index and the decrease in glucose tolerance without preventing the decrease in body fat. As the obese and hyperlipidemic patients had lower plasma thiol concentrations than the normolipidemic subjects, our results suggest that low thiol levels facilitate the development of obesity. Supplementation of thiols plus creatine may reduce body fat without compromising glucose tolerance.