Effect of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on glycemia, body weight, and new-onset diabetes mellitus

Statin therapy modestly increases new-onset diabetes risk. The effect of proprotein convertase subtilisin/kexin type 9 inhibition on new-onset diabetes, glycemia, and weight remains unclear. We studied the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on fasting plasma glucose, glycated hemoglobin, weight, and new-onset diabetes mellitus. We pooled 1-year (48-week) data for participants who had completed an evolocumab parent study before entering an open-label extension (OLE) trial. Data were available for 4,802 participants (1,602 on standard of care [SOC]; 3,200 on evolocumab plus SOC) in 2 OLE trials. Evolocumab lowered low-density lipoprotein cholesterol by approximately 60% compared with SOC alone. Over the first year of the OLE trials, there was no difference in median (Q1, Q3) change in glycated hemoglobin (0.1% [-0.1, 0.2] for both SOC and evolocumab plus SOC) and fasting plasma glucose (0.06 mmol/L [-0.28, 0.38 mmol/L] for SOC and 0.06 mmol/L [-0.28, 0.44 mmol/L] for evolocumab plus SOC). Mean weight change (standard error) at 1 year was -0.1 kg (0.2) on SOC compared with 0.3 kg (0.1) on evolocumab plus SOC. The exposure-adjusted incidence rate (95% confidence intervals) for new-onset diabetes per 100 patient years was 3.7 (2.9 to 4.7) on control/SOC alone and 3.9 (3.2 to 4.6) on evolocumab/evolocumab plus SOC treatment. Glycemic changes observed in 6,430 participants at week 12 in the parent studies were comparable with OLE trial findings. In conclusion, evolocumab therapy has no effect on glucose homeostasis over 1 year of open-label treatment

Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events

BACKGROUND: Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in short-term studies. We conducted two extension studies to obtain longer-term data. METHODS: In two open-label, randomized trials, we enrolled 4465 patients who had completed 1 of 12 phase 2 or 3 studies ("parent trials") of evolocumab. Regardless of study-group assignments in the parent trials, eligible patients were randomly assigned in a 2:1 ratio to receive either evolocumab (140 mg every 2 weeks or 420 mg monthly) plus standard therapy or standard therapy alone. Patients were followed for a median of 11.1 months with assessment of lipid levels, safety, and (as a prespecified exploratory analysis) adjudicated cardiovascular events including death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, and heart failure. Data from the two trials were combined. RESULTS: As compared with standard therapy alone, evolocumab reduced the level of LDL cholesterol by 61%, from a median of 120 mg per deciliter to 48 mg per deciliter (P<0.001). Most adverse events occurred with similar frequency in the two groups, although neurocognitive events were reported more frequently in the evolocumab group. The risk of adverse events, including neurocognitive events, did not vary significantly according to the achieved level of LDL cholesterol. The rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (hazard ratio in the evolocumab group, 0.47; 95% confidence interval, 0.28 to 0.78; P=0.003). CONCLUSIONS: During approximately 1 year of therapy, the use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDL cholesterol levels and reduced the incidence of cardiovascular events in a prespecified but exploratory analysis. (Funded by Amgen; OSLER-1 and OSLER-2 ClinicalTrials.gov numbers, NCT01439880 and NCT01854918.)

Efficacy and tolerability of evolocumab vs. ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial

Importance: Muscle-related statin intolerance is reported by 5% to 20% of patients. Objective: To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. Design, Setting, and Participants: Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. Interventions: Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). Main Outcome and Measures: Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels. Results: Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, −16.7% (95% CI, −20.5% to −12.9%), absolute change, −31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, −54.5% (95% CI, −57.2% to −51.8%); absolute change, −106.8 mg/dL (P &lt; .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, −16.7% (95% CI, −20.8% to −12.5%); absolute change, −31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, −52.8% (95% CI, −55.8% to −49.8%); absolute change, −102.9 mg/dL (P &lt; .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was −37.8%; absolute difference, −75.8 mg/dL. For week 24, between-group difference in LDL-C was −36.1%; absolute difference, –71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). Conclusions and Relevance: Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety

Cost-Effectiveness of LDL-C Lowering With Evolocumab in Patients With High Cardiovascular Risk in the United States.

Randomized trials have shown marked reductions in low-density lipoprotein cholesterol (LDL-C), a risk factor for cardiovascular disease (CVD), when evolocumab is administered. We hypothesized that evolocumab added to standard of care (SOC) vs SOC alone is cost-effective in the treatment of patients with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic CVD (ASCVD) with or without statin intolerance and LDL-C &gt;100 mg/dL. Using a Markov cohort state transition model, primary and recurrent CVD event rates were predicted considering population-specific trial-based mean risk factors and calibrated against observed rates in the real world. The LDL-C-lowering effect from population-specific phase 3 randomized studies for evolocumab was used together with estimated LDL-C-lowering effect on CVD event rates per 38.67-mg/dL LDL-C lowering from a statin-trial meta-analysis. Costs and utilities were included from published sources. Evolocumab treatment was associated with both increased cost and improved quality-adjusted life-years (QALY): HeFH (incremental cost: US$153 289, incremental QALY: 2.02, incremental cost-effectiveness ratio: US$75 863/QALY); ASCVD (US$158 307, 1.12, US$141 699/QALY); and ASCVD with statin intolerance (US$136 903, 1.36, US$100 309/QALY). Evolocumab met both the American College of Cardiology/American Heart Association (ACC/AHA) and World Health Organization (WHO) thresholds in each population evaluated. Sensitivity and scenario analyses confirmed that model results were robust to changes in model parameters. Among patients with HeFH and ASCVD with or without statin intolerance, evolocumab added to SOC may provide a cost-effective treatment option for lowering LDL-C using ACC/AHA intermediate/high value and WHO cost-effectiveness thresholds. More definitive information on the clinical and economic value of evolocumab will be available from the forthcoming CVD outcomes study

Controlled study of the effect of proprotein convertase subtilisin-kexin type 9 inhibition with evolocumab on lipoprotein(a) particle kinetics

Aims Lipoprotein(a) [Lp(a)], a low-density lipoprotein (LDL) particle covalently bound to apolipoprotein(a) [apo(a)], is a potentially potent heritable risk factor for cardiovascular disease. We investigated the mechanism whereby evolocumab, a monoclonal antibody against proprotein convertase subtilisin-kexin type 9 (PCSK9), lowers Lp(a).Methods and results We studied the kinetics of Lp(a) particles in 63 healthy men, with plasma apo(a) concentration &gt;5 nmol/L, participating in an 8-week factorial trial of the effects of evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on lipoprotein metabolism. Lipoprotein(a)-apo(a) kinetics were studied using intravenous D3-leucine administration, mass spectrometry, and compartmental modelling; Lp(a)-apoB kinetics were also determined in 16 subjects randomly selected from the treatment groups. Evolocumab, but not atorvastatin, significantly decreased the plasma pool size of Lp(a)-apo(a) (−36%, 5 nmol/L, participating in an 8-week factorial trial of the effects of evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on lipoprotein metabolism. Lipoprotein(a)-apo(a) kinetics were studied using intravenous D3-leucine administration, mass spectrometry, and compartmental modelling; Lp(a)-apoB kinetics were also determined in 16 subjects randomly selected from the treatment groups. Evolocumab, but not atorvastatin, significantly decreased the plasma pool size of Lp(a)-apo(a) (−36%, P P Pr =0.966, ,P Conclusions Evolocumab monotherapy lowered the plasma Lp(a) pool size by decreasing the production of Lp(a) particles. In combination with atorvastatin, evolocumab lowered the plasma Lp(a) pool size by accelerating the catabolism of Lp(a) particles. This dual mechanism may relate to an effect of PCSK9 inhibition on Lp(a)-apo(a) production and to marked up-regulation of LDL receptor activity on Lp(a) holoparticle clearance

Comparative Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibition and Statins on Postprandial Triglyceride-Rich Lipoprotein Metabolism

Objective: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) and statins are known to lower plasma LDL (low-density lipoprotein)-cholesterol concentrations. However, the comparative effects of these treatments on the postprandial metabolism of TRLs (triglyceride-rich lipoproteins) remain to be investigated. Approach and Results: We performed a 2-by-2 factorial trial of the effects of 8 weeks of subcutaneous evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on postprandial TRL metabolism in 80 healthy, normolipidemic men after ingestion of an oral fat load. We evaluated plasma total and incremental area under the curves for triglycerides, apo (apolipoprotein)B-48, and VLDL (very-LDL)-apoB-100. We also examined the kinetics of apoB-48 using intravenous D3-leucine administration, mass spectrometry, and multicompartmental modeling. Atorvastatin and evolocumab independently lowered postprandial VLDL-apoB-100 total area under the curves (

Long-term safety, tolerability, and efficacy of evolocumab in patients with heterozygous familial hypercholesterolaemia

RUTHERFORD (phase 2) and RUTHERFORD-2 (phase 3) were randomised, double-blind, placebo-controlled trials evaluating evolocumab, a fully human monoclonal antibody against PCSK9, in patients with heterozygous familial hypercholesterolaemia (HeFH).1,2 Evolocumab was well tolerated and reduced LDL-C by 56%–61% when dosed 140 mg biweekly (Q2W) or 420 mg monthly (QM) vs placebo. • Patients completing RUTHERFORD and RUTHERFORD-2 were eligible to enter the evolocumab open-label extension (OLE) trial program (OSLER-1, phase 2 trials, and OSLER-2, phase 3 trials). • In the OLE, patients were re-randomised 2:1 to receive evolocumab + standard of care (SOC) or SOC alone for 52 weeks in OSLER-1 or 48 weeks in OSLER-2, after which all patients received evolocumab. This pooled analysis provides long-term data from 1 year of evolocumab treatment in open-label extension trials for 440 patients with HeFH. • This population had elevated LDL-C levels despite receiving high-intensity statins in addition to other lipid-lowering medications, and required additional LDL-C reduction. • Continued use of evolocumab added to standard of care in HeFH patients yielded persistent and marked LDL-C reductions, with a mean 53.6% reduction from parent study baseline after 48 weeks in the OLE. • Prolonged dosing of evolocumab in addition to standard of care was well tolerated in this population

Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab in patients with type 2 diabetes: a meta-analysis

Background: Patients with type 2 diabetes have increased cardiovascular risk. PCSK9 monoclonal antibodies have been shown to reduce LDL cholesterol and other lipids, but specific efficacy for patients with diabetes is unknown. We compared the effect of the PCSK9 inhibitor evolocumab on lipid parameters in patients with and without type 2 diabetes. Methods: We did a random-effects meta-analysis of randomised clinical trials comparing the efficacy of evolocumab, placebo, and ezetimibe to improve lipid parameters in adult patients (age 18–80 years) with or without type 2 diabetes. We searched MEDLINE and Embase to identify eligible 12-week, phase 3 trials published between Jan 1, 2012, and Feb 28, 2015. We excluded trials that included patients who had homozygous familial hypercholesterolaemia. All analyses were based on individual participant data. We used DerSimonian and Laird random-effects meta-analyses to compare the mean changes from baseline in concentrations of LDL cholesterol, non-HDL cholesterol, total cholesterol, triglycerides, lipoprotein(a), and HDL cholesterol at 12 weeks for evolocumab, placebo, and ezetimibe. We also assessed the effect of evolocumab therapy compared with placebo across subgroups of patients based on glycaemia, insulin use, renal function, and cardiovascular disease status at baseline. Results: Three trials met our inclusion criteria, and included 413 patients with type 2 diabetes and 2119 patients without type 2 diabetes. In patients with type 2 diabetes evolocumab caused mean reductions in LDL cholesterol concentration that were 60% (95% CI 51–69) versus placebo and 39% (32–47) versus ezetimibe. In patients without type 2 diabetes, evolocumab caused mean reductions in LDL cholesterol that were 66% (62–70) versus placebo and 40% (36–45) versus ezetimibe. In patients with type 2 diabetes, evolocumab was associated with reductions in non-HDL cholesterol (55% [47–63] vs placebo and 34% [26–41] vs ezetimibe), total cholesterol (38% [32–44] vs placebo and 24% [16–31] vs ezetimibe), and lipoprotein(a) (31% [25–37] vs placebo and 26% [16–35] vs ezetimibe), and an increase in HDL cholesterol (7% [4–11] vs placebo and 8% [4–13] vs ezetimibe). Findings were similar across diabetes subgroups based on glycaemia, insulin use, renal function, and cardiovascular disease status. Interpretation: Evolocumab markedly reduces atherogenic lipoproteins in patients with type 2 diabetes, an effect that is consistent across subgroups and similar to that seen in patients without type 2 diabetes. Results from ongoing cardiovascular outcome trials of PCSK9 inhibitors will provide additional data to inform the use of these drugs in patients with type 2 diabetes

Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism

Background: Monoclonal antibodies against proprotein convertase subtilisin kexin type 9 (PCSK9), such as evolocumab, lower plasma low-density lipoprotein (LDL)-cholesterol concentrations. Evolocumab is under investigation for its effects on cardiovascular outcomes in statin-treated, high-risk patients. The mechanism of action of PCSK9 monoclonal antibodies on lipoprotein metabolism remains to be fully evaluated. Stable isotope tracer kinetics can effectively elucidate the mode of action of new lipid-regulating pharmacotherapies. Methods: We conducted a 2-by-2 factorial trial of the effects of atorvastatin (80 mg daily) and subcutaneous evolocumab (420 mg every 2 weeks) for 8 weeks on the plasma kinetics of very-low-density lipoprotein (VLDL)–apolipoprotein B-100 (apoB), intermediate-density lipoprotein–apoB, and LDL-apoB in 81 healthy, normolipidemic, nonobese men. The kinetics of apoB in these lipoproteins was studied using a stable isotope infusion of D3-leucine, gas chromatography/mass spectrometry, and multicompartmental modeling. Results: Atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL-apoB (PP.032, respectively), intermediate-density lipoprotein–apoB (P=0.021 and P=.002, respectively), and LDL-apoB (PP=0.043) and LDL-apoB (PP Conclusions: In healthy, normolipidemic subjects, evolocumab decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism. Reductions in intermediate-density lipoprotein and LDL production also contributed to the decrease in LDL particle concentration with evolocumab by a mechanism distinct from that of atorvastatin. These kinetic findings provide a metabolic basis for understanding the potential benefits of PCSK9 monoclonal antibodies incremental to statins in on-going clinical end point trials