Efficacy and safety of the PCSK9 inhibitor evolocumab in patients with mixed hyperlipidemia

Purpose Evolocumab significantly reduces low-density lipoprotein-cholesterol (LDL-C); we investigated its effects on LDL-C lowering in patients with mixed hyperlipidemia. Methods We compared the efficacy and safety of evolocumab in hypercholesterolemic patients selected from the phase 2 and 3 trials who had fasting triglyceride levels ≥1.7 mmol/L (150 mg/dL elevated triglycerides) and <1.7 mmol/L (without elevated triglycerides). Fasting triglyceride level ≥ 4.5 mmol/L at screening was an exclusion criterion for these studies, but post-enrollment triglyceride levels may have exceeded 4.5 mmol/L (400 mg/dL). Efficacy was evaluated in four phase 3 randomized studies (n = 1148) and safety from the phase 2 and 3 studies (n = 2246) and their open-label extension studies (n = 1698). Efficacy analyses were based on 12-week studies, while safety analyses included data from all available studies. Treatment differences were calculated vs. placebo and ezetimibe after pooling dose frequencies. Results Mean treatment difference in percentage change from baseline in LDL-C for participants with elevated triglycerides and those without elevated triglycerides (mean of weeks 10 and 12) with evolocumab was approximately −67 % vs. placebo and −42 % vs. ezetimibe (all P < 0.001) compared to −6 % vs. placebo and −39 % vs. ezetimibe, respectively. Treatment differences for evolocumab vs. placebo and ezetimibe followed a similar pattern for non–high-density lipoprotein (HDL-C) and apolipoprotein B. Evolocumab was well tolerated, with balanced rates of adverse events leading to discontinuation of evolocumab vs. comparator (placebo and/or ezetimibe). Conclusion The significant reductions of atherogenic lipids including LDL-C, non–HDL-C, and apolipoprotein B seen with evolocumab are similar in patients with and without mixed hyperlipidemia

Efficacy and safety of the PCSK9 inhibitor evolocumab in patients with mixed hyperlipidemia

Purpose Evolocumab significantly reduces low-density lipoprotein-cholesterol (LDL-C); we investigated its effects on LDL-C lowering in patients with mixed hyperlipidemia. Methods We compared the efficacy and safety of evolocumab in hypercholesterolemic patients selected from the phase 2 and 3 trials who had fasting triglyceride levels ≥1.7 mmol/L (150 mg/dL elevated triglycerides) and <1.7 mmol/L (without elevated triglycerides). Fasting triglyceride level ≥ 4.5 mmol/L at screening was an exclusion criterion for these studies, but post-enrollment triglyceride levels may have exceeded 4.5 mmol/L (400 mg/dL). Efficacy was evaluated in four phase 3 randomized studies (n = 1148) and safety from the phase 2 and 3 studies (n = 2246) and their open-label extension studies (n = 1698). Efficacy analyses were based on 12-week studies, while safety analyses included data from all available studies. Treatment differences were calculated vs. placebo and ezetimibe after pooling dose frequencies. Results Mean treatment difference in percentage change from baseline in LDL-C for participants with elevated triglycerides and those without elevated triglycerides (mean of weeks 10 and 12) with evolocumab was approximately −67 % vs. placebo and −42 % vs. ezetimibe (all P < 0.001) compared to −6 % vs. placebo and −39 % vs. ezetimibe, respectively. Treatment differences for evolocumab vs. placebo and ezetimibe followed a similar pattern for non–high-density lipoprotein (HDL-C) and apolipoprotein B. Evolocumab was well tolerated, with balanced rates of adverse events leading to discontinuation of evolocumab vs. comparator (placebo and/or ezetimibe). Conclusion The significant reductions of atherogenic lipids including LDL-C, non–HDL-C, and apolipoprotein B seen with evolocumab are similar in patients with and without mixed hyperlipidemia

Evaluation of the efficacy, safety and glycaemic effects of evolocumab (AMG 145) in hypercholesterolaemic patients stratified by glycaemic status and metabolic syndrome.

Aim To examine the lipid and glycaemic effects of 52 weeks of evolocumab treatment. Materials and Methods DESCARTES was a 52-week placebo-controlled trial of evolocumab. DESCARTES randomised 905 patients from 88 study centres in nine countries with 901 receiving at least one dose of study drug. For this post-hoc analysis, DESCARTES patients were categorized by baseline glycaemic status – type 2 diabetes, impaired fasting glucose (IFG), metabolic syndrome (MetS), or none of these. Monthly subcutaneous evolocumab (420 mg) or placebo was administered. The main outcomes measured were percentage change in LDLcholesterol (LDL-C) at week 52 and safety. Results 413 patients had dysglycaemia (120 type 2 diabetes, 293 IFG), 289 MetS (194 also had IFG), and 393 none of these conditions. At week 52, evolocumab reduced LDL-C by &gt; 50% in all subgroups, with favourable effects on other lipids. No significant differences in fasting plasma glucose, HbA1c, insulin, C-peptide or HOMA indices were seen in any subgroup between evolocumab and placebo at week 52. The overall incidence of new-onset diabetes mellitus did not differ between placebo (6.6%) and evolocumab (5.6%); in those with baseline normoglycaemia, the incidences were 1.9% and 2.7%, respectively. Incidences of AEs were similar in evolocumab- and placebo-treated patients. Conclusions Evolocumab showed encouraging safety and efficacy at 52 weeks in patients with or without dysglycaemia or MetS. Changes in glycaemic parameters did not differ between evolocumab- and placebo-treated patients within the glycaemic subgroups examined.</p

Evaluation of the efficacy, safety and glycaemic effects of evolocumab (AMG 145) in hypercholesterolaemic patients stratified by glycaemic status and metabolic syndrome.

Aim To examine the lipid and glycaemic effects of 52 weeks of evolocumab treatment. Materials and Methods DESCARTES was a 52-week placebo-controlled trial of evolocumab. DESCARTES randomised 905 patients from 88 study centres in nine countries with 901 receiving at least one dose of study drug. For this post-hoc analysis, DESCARTES patients were categorized by baseline glycaemic status – type 2 diabetes, impaired fasting glucose (IFG), metabolic syndrome (MetS), or none of these. Monthly subcutaneous evolocumab (420 mg) or placebo was administered. The main outcomes measured were percentage change in LDLcholesterol (LDL-C) at week 52 and safety. Results 413 patients had dysglycaemia (120 type 2 diabetes, 293 IFG), 289 MetS (194 also had IFG), and 393 none of these conditions. At week 52, evolocumab reduced LDL-C by > 50% in all subgroups, with favourable effects on other lipids. No significant differences in fasting plasma glucose, HbA1c, insulin, C-peptide or HOMA indices were seen in any subgroup between evolocumab and placebo at week 52. The overall incidence of new-onset diabetes mellitus did not differ between placebo (6.6%) and evolocumab (5.6%); in those with baseline normoglycaemia, the incidences were 1.9% and 2.7%, respectively. Incidences of AEs were similar in evolocumab- and placebo-treated patients. Conclusions Evolocumab showed encouraging safety and efficacy at 52 weeks in patients with or without dysglycaemia or MetS. Changes in glycaemic parameters did not differ between evolocumab- and placebo-treated patients within the glycaemic subgroups examined.</p

Pooled safety analysis of evolocumab in over 6000 patients from double-blind and open-label extension studies

Background—Evolocumab, a fully human monoclonal antibody to PCSK9, markedly reduces LDL-C across diverse patient populations. The objective of this study was to assess the safety and tolerability of evolocumab in a pooled safety analysis from phase 2 or 3 randomized and placebo or comparator-controlled trials (integrated parent trials) and the first year of open-label extension (OLE) trials that included a standard-of-care control group. Methods—This analysis included adverse event (AE) data from 6026 patients in 12 phase 2 and 3 parent trials, with a median exposure of 2.8 months, and of those patients, from 4465 patients who continued with a median follow-up of 11.1 months in two OLE trials. Adverse events were analyzed separately for the parent and OLE trials. Overall AE rates, serious AEs (SAEs), laboratory assessments, and AEs of interest were evaluated. Results—Overall AE rates were similar between evolocumab and control in the parent trials (51.1% vs 49.6%) and in Year 1 of OLE trials (70.0% vs 66.0%), as were those for SAEs. Elevations of serum transaminases, bilirubin and creatine kinase were infrequent and similar between groups. Muscle-related AEs were similar between evolocumab and control. Neurocognitive adverse events were infrequent and balanced during the double-blind parent studies (5 events [0.1%], evolocumab groups vs 6 events [0.3%], control groups). In the OLE trials, 27 patients (0.9%) in the evolocumab groups and 5 patients (0.3%) in the control groups reported neurocognitive AEs. No neutralizing anti-evolocumab antibodies were detected. Conclusions—Overall, this integrated safety analysis of 6026 patients pooled across phase 2/3 trials and 4465 patients who continued in open-label extension trials for 1 year supports a favorable benefit-risk profile for evolocumab

Pooled Safety Analysis of Evolocumab in Over 6000 Patients From Double-Blind and Open-Label Extension Studies

Background: Evolocumab, a fully human monoclonal antibody to PCSK9 (proprotein convertase subtilisin/kexin type 9), markedly reduces low-density lipoprotein cholesterol across diverse patient populations. The objective of this study was to assess the safety and tolerability of evolocumab in a pooled safety analysis from phase 2 or 3 randomized and placebo or comparator-controlled trials (integrated parent trials) and the first year of open-label extension (OLE) trials that included a standard-of-care control group. Methods: This analysis included adverse event (AE) data from 6026 patients in 12 phase 2 and 3 parent trials, with a median exposure of 2.8 months, and, of those patients, from 4465 patients who continued with a median follow-up of 11.1 months in 2 OLE trials. AEs were analyzed separately for the parent and OLE trials. Overall AE rates, serious AEs, laboratory assessments, and AEs of interest were evaluated. Results: Overall AE rates were similar between evolocumab and control in the parent trials (51.1% versus 49.6%) and in year 1 of OLE trials (70.0% versus 66.0%), as were those for serious AEs. Elevations of serum transaminases, bilirubin, and creatine kinase were infrequent and similar between groups. Muscle-related AEs were similar between evolocumab and control. Neurocognitive AEs were infrequent and balanced during the double-blind parent studies (5 events [0.1%], evolocumab groups versus 6 events [0.3%], control groups). In the OLE trials, 27 patients (0.9%) in the evolocumab groups and 5 patients (0.3%) in the control groups reported neurocognitive AEs. No neutralizing antievolocumab antibodies were detected. Conclusions: Overall, this integrated safety analysis of 6026 patients pooled across phase 2/3 trials and 4465 patients who continued in OLE trials for 1 year supports a favorable benefit-risk profile for evolocumab. </jats:sec