No abstract

Introduction Phosphodiesterase type-5 (PDE-5) inhibitors have previously been evaluated for their efficacy and safety in various clinical trials in men with erectile dysfunction (ED) with or without associated comorbidities. Aim This is the first prospective, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of a PDE-5 inhibitor (i.e., vardenafil) in an exclusive population of men with ED and dyslipidemia. Main Outcome Measures Three coprimary efficacy measurements (Sexual Encounter Performance [SEP]2, SEP3, International Index of Erectile Function-Erectile Function [IIEF-EF] domain scores) were used to assess the differential effect of vardenafil vs. placebo in this patient population. Adverse events (AEs) safety data were obtained to compare safety outcomes. Methods This 12-week of randomized, double-blind, placebo-controlled study was conducted in 59 U.S. centers. Patients received either on-demand, flexible-dose vardenafil 10 mg (titrated to 5 mg or 20 mg based upon efficacy and safety) or placebo. Results Of the 712 patients screened and entered into the study, 395 were randomized. Baseline demographics for the intent-to-treat population included: mean age, 54.4 years (±7.5 standard deviation [SD]); 76% Caucasian; mean body mass index (BMI), 31.7 kg/m2 (±12.7 SD); 47% past/present smoker; and 42% severe ED. Aside from dyslipidemia, other comorbidities included hypertension, 61%; obesity (i.e., BMI ≥ 30), 51%; and type 1 or 2 diabetes, 40%. During the 12-week treatment period, the least squares (LS) adjusted mean success rates in patients on vardenafil vs. placebo were: SEP2, 79.09% vs. 51.92%; and SEP3, 66.69% vs. 33.83% (P <0.001). The LS adjusted mean IIEF-EF domain score for week 12 using LOCF was 21.99 in patients on vardenafil therapy vs. 14.83 in those on placebo (P <0.001). The most commonly encountered AEs were headache and nasal congestion. Conclusions Vardenafil was demonstrated to be safe and effective for managing ED in men with ED and associated dyslipidemia. The results of this study support the role of expanded research on outcomes related to effective ED treatment and aggressive lipid control.

Darapladib, a lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, failed to demonstrate efficacy for the primary endpoints in two large phase III cardiovascular outcomes trials, one in stable coronary heart disease patients (STABILITY) and one in acute coronary syndrome (SOLID-TIMI 52). No major safety signals were observed but tolerability issues of diarrhea and odor were common (up to 13%). We hypothesized that genetic variants associated with Lp-PLA2 activity may influence efficacy and tolerability and therefore performed a comprehensive pharmacogenetic analysis of both trials. We genotyped patients within the STABILITY and SOLID-TIMI 52 trials who provided a DNA sample and consent (n = 13,577 and 10,404 respectively, representing 86% and 82% of the trial participants) using genome-wide arrays with exome content and performed imputation using a 1000 Genomes reference panel. We investigated baseline and change from baseline in Lp-PLA2 activity, two efficacy endpoints (major coronary events and myocardial infarction) as well as tolerability parameters at genome-wide and candidate gene level using a meta-analytic approach. We replicated associations of published loci on baseline Lp-PLA2 activity (APOE, CELSR2, LPA, PLA2G7, LDLR and SCARB1) and identified three novel loci (TOMM5, FRMD5 and LPL) using the GWAS-significance threshold P≤5E-08. Review of the PLA2G7 gene (encoding Lp-PLA2) within these datasets identified V279F null allele carriers as well as three other rare exonic null alleles within various ethnic groups, however none of these variants nor any other loci associated with Lp-PLA2 activity at baseline were associated with any of the drug response endpoints. The analysis of darapladib efficacy endpoints, despite low power, identified six low frequency loci with main genotype effect (though with borderline imputation scores) and one common locus (minor allele frequency 0.24) with genotype by treatment interaction effect passing the GWAS-significance threshold. This locus conferred risk in placebo subjects, hazard ratio (HR) 1.22 with 95% confidence interval (CI) 1.11–1.33, but was protective in darapladib subjects, HR 0.79 (95% CI 0.71–0.88). No major loci for tolerability were found. Thus, genetic analysis confirmed and extended the influence of lipoprotein loci on Lp-PLA2 levels, identified some novel null alleles in the PLA2G7 gene, and only identified one potentially efficacious subgroup within these two large clinical trials.