A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia

Blom, Dirk; Hala, Tomas; Bolognese, Michael A.; Lillestol, Michael; Toth, Phillip D.; Burgess, Lesley; Češka, R.; Roth, Eli M.; Koren, Michael; Ballantyne, Christie M.; Monsalvo, Maria Laura; Tsirtsonis, Kate; Kim, Jae Bum; Scott, Rob; Wasserman, Scott M.; Stein, Evan A.

doi:10.1056/nejmoa1316222

Cited by 630 publications

(486 citation statements)

References 15 publications

Supporting

Mentioning

438

Contrasting

Unclassified

Order By: Relevance

“…Safety and tolerability profiles in the present study were consistent with previous studies of evolocumab6, 7, 8, 9, 10 and did not identify any risks. No anti‐evolocumab antibodies were detected in any participant.…”

Section: Discussionsupporting

confidence: 91%

“…The timing and magnitude of LDL‐C lowering after a dose of evolocumab were consistent with those seen in other studies in patients and healthy volunteers 5, 6, 8, 17, 31. For example, the randomized, double‐blind, placebo‐controlled, phase 2 MENDEL study showed that monotherapy with evolocumab 140 mg Q2W in 45 patients with hypercholesterolemia (baseline LDL‐C 3.6 mmol/L) reduced LDL‐C from baseline by 51% (95% CI –56% to –46%) after 12 weeks of treatment 31.…”

Section: Discussionsupporting

confidence: 87%

“…Through its PCSK9‐lowering effect, administration of evolocumab increases the density of LDL‐C receptors and significantly reduces LDL‐C levels in patients with hypercholesterolemia 4, 5. In several clinical trials up to 52 weeks in duration, the safety and tolerability profile of evolocumab was similar to that of placebo 6, 7, 8, 9, 10…”

mentioning

confidence: 93%

See 2 more Smart Citations

Evaluation of Evolocumab (AMG 145), a Fully Human Anti‐PCSK9 IgG2 Monoclonal Antibody, in Subjects With Hepatic Impairment

Gibbs

Slatter

Egbuna

et al. 2016

The Journal of Clinical Pharma

Self Cite

View full text Add to dashboard Cite

Evolocumab binds PCSK9, increasing low‐density lipoprotein cholesterol (LDL‐C) receptors and lowering LDL‐C. Target‐mediated evolocumab elimination is attributable to PCSK9 binding. As circulating PCSK9 and LDL‐C levels are primarily regulated by the liver, we compared evolocumab pharmacokinetics, pharmacodynamics, and safety in individuals with and without hepatic impairment. An open‐label, parallel‐group study evaluated the pharmacokinetics of evolocumab in hepatic‐impaired (Child‐Pugh Class A or B) or healthy adults. Participants were classified as having no, mild, or moderate hepatic impairment (n = 8/group) and received a single 140‐mg evolocumab dose. Assessments of unbound evolocumab and PCSK9 were made predose and postdose. Adverse events were monitored throughout the study. No significant association was observed between baseline PCSK9 and increasing level of hepatic impairment. No difference in extent and time course of PCSK9 or LDL‐C reduction was observed despite an apparent decrease in mean unbound evolocumab exposure with increasing hepatic impairment (Jonckheere‐Terpstra trend test; maximum serum concentration P = .18; area under the curve P = .09). Maximum reductions were observed in moderately impaired subjects vs healthy individuals: mean maximum serum concentration –34%; mean area under the concentration‐time curve (AUC) –47%. On average, unbound PCSK9 serum concentrations fell by >80% at 4 hours after a single evolocumab dose. Mean (95% confidence interval) maximum LDL‐C reductions in the healthy, mild, and moderate groups were –57% (–64% to –48%), –70% (–75% to –63%), and –53% (–61% to –43%), respectively. No safety risks were identified. These results support evolocumab use without dose adjustment in patients with active liver disease and mild or moderate hepatic impairment.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 87%

See 1 more Smart Citation

Evaluation of Evolocumab (AMG 145), a Fully Human Anti‐PCSK9 IgG2 Monoclonal Antibody, in Subjects With Hepatic Impairment

Gibbs

Slatter

Egbuna

et al. 2016

The Journal of Clinical Pharma

Self Cite

View full text Add to dashboard Cite

show abstract

“…A total of 138 study arms from 35 studies were analyzed, comprising 45 539 patients (Table S1). 5, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 Alirocumab was used in 18 studies (28 treatment arms), and evolocumab was used in 17 studies (39 treatment arms; Figure 1); placebo was the most common control used (52 control arms), with ezetimibe used in 17 arms, and standard therapy in 2 arms. Eight studies were of an exclusively FH population, and 5 studies included only patients intolerant to statins.…”

Section: Resultsmentioning

confidence: 99%

Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta‐Analysis of 35 Randomized Controlled Trials

Karatasakis

Danek

Karácsonyi

et al. 2017

JAHA

155

104

View full text Add to dashboard Cite

BackgroundWe sought to examine the efficacy and safety of 2 PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors: alirocumab and evolocumab.Methods and ResultsWe performed a systematic review and meta‐analysis of randomized controlled trials comparing treatment with and without PCSK9 inhibitors; 35 randomized controlled trials comprising 45 539 patients (mean follow‐up: 85.5 weeks) were included. Mean age was 61.0±2.8 years, and mean baseline low‐density lipoprotein cholesterol was 106±22 mg/dL. Compared with no PCSK9 inhibitor therapy, treatment with a PCSK9 inhibitor was associated with a lower rate of myocardial infarction (2.3% versus 3.6%; odds ratio [OR]: 0.72 [95% confidence interval (CI), 0.64–0.81]; P<0.001), stroke (1.0% versus 1.4%; OR: 0.80 [95% CI, 0.67–0.96]; P=0.02), and coronary revascularization (4.2% versus 5.8%; OR: 0.78 [95% CI, 0.71–0.86]; P<0.001). Overall, no significant change was observed in all‐cause mortality (OR: 0.71 [95% CI, 0.47–1.09]; P=0.12) or cardiovascular mortality (OR: 1.01 [95% CI, 0.85–1.19]; P=0.95). A significant association was observed between higher baseline low‐density lipoprotein cholesterol and benefit in all‐cause mortality (P=0.038). No significant change was observed in neurocognitive adverse events (OR: 1.12 [95% CI, 0.88–1.42]; P=0.37), myalgia (OR: 0.95 [95% CI, 0.75–1.20]; P=0.65), new onset or worsening of preexisting diabetes mellitus (OR: 1.05 [95% CI, 0.95–1.17]; P=0.32), and increase in levels of creatine kinase (OR: 0.84 [95% CI, 0.70–1.01]; P=0.06) or alanine or aspartate aminotransferase (OR: 0.96 [95% CI, 0.82–1.12]; P=0.61).ConclusionsTreatment with a PCSK9 inhibitor is well tolerated and improves cardiovascular outcomes. Although no overall benefit was noted in all‐cause or cardiovascular mortality, such benefit may be achievable in patients with higher baseline low‐density lipoprotein cholesterol.

show abstract

“…Alirocumab and evolocumab, either alone or in combination with statins and/or other lipid‐lowering therapies, have been shown in their respective phase 3 clinical trial programs (ODYSSEY and PROFICIO [Program to Reduce LDL‐C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different Populations]) to significantly reduce LDL‐C levels by up to 60% from baseline (depending on dosing regimen; Table) in patients with hypercholesterolemia, including those with familial hypercholesterolemia, moderate to very high cardiovascular risk, and statin intolerance 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62. The inclusion/exclusion criteria and other details of each phase 3 ODYSSEY and PROFICIO trial are shown in Table S2.…”

Section: Pcsk9 Inhibitors and Their Effects In Patients With Diabetesmentioning

confidence: 99%

PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review

Handelsman

Lepor

2018

JAHA

View full text Add to dashboard Cite

A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia

Abstract: At 52 weeks, evolocumab added to diet alone, to low-dose atorvastatin, or to high-dose atorvastatin with or without ezetimibe significantly reduced LDL cholesterol levels in patients with a range of cardiovascular risks. (Funded by Amgen; DESCARTES ClinicalTrials.gov number, NCT01516879.).

Cited by 630 publications

References 15 publications

Evaluation of Evolocumab (AMG 145), a Fully Human Anti‐PCSK9 IgG2 Monoclonal Antibody, in Subjects With Hepatic Impairment

Evaluation of Evolocumab (AMG 145), a Fully Human Anti‐PCSK9 IgG2 Monoclonal Antibody, in Subjects With Hepatic Impairment

Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta‐Analysis of 35 Randomized Controlled Trials

PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review

Contact Info

Product

Resources

About