Atorvastatin with or without an Antibody to PCSK9 in Primary Hypercholesterolemia

Roth, Eli M.; McKenney, James M.; Hanotin, Corinne; Asset, Gaëlle; Stein, Evan A.

doi:10.1056/nejmoa1201832

Cited by 432 publications

(308 citation statements)

References 16 publications

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“…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

163

104

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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.

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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

163

104

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“…Key design features of each study, general entry criteria, patient characteristics, and leadin background lipid therapy are summarized in Figure 2. More specific entry and exclusion criteria are described in detail in the publications from each trial [6][7][8].…”

Section: Study Design and Patientsmentioning

confidence: 99%

“…All patients provided written informed consent. The Phase II trials were registered with ClinicalTrials.gov (Sponsor protocol numbers: 11565 [NCT01288443] [6], 11566 [NCT01288469] [7], and 1003 [NCT01266876] [8]). …”

Section: Study Design and Patientsmentioning

confidence: 99%

“…Phase II trials with alirocumab evaluated different doses and dosing schedules in patients with non-familial hypercholesterolemia (non-FH) on different but stable doses of atorvastatin [6,7], or in patients with FH on stable doses of any statin with or without ezetimibe [8] (Table 1). The individual results from each trial demonstrated robust, consistent, and statistically significant reductions in LDL-C (Supplement Table) with good tolerability.…”

Section: Introductionmentioning

confidence: 99%

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Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: A Phase II pooled analysis

Koren

Roth

McKenney

et al. 2015

Postgraduate Medicine

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Background. Alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/ kexin type 9, is in Phase III development for the treatment of hypercholesterolemia. In Phase II studies, 150 mg every 2 weeks (Q2W) was the highest Q2W dose studied, and it is currently the highest Q2W dose under development. To better assess the safety and efficacy of this dose, data across three Phase II studies were pooled. Methods. We analyzed data from three double-blind, randomized, placebo-controlled Phase II studies of 8 or 12 weeks' duration. In the current analysis, 77 patients were randomized to the control group and 108 were randomized to alirocumab 150 mg Q2W administered via a single 1 mL subcutaneous injection. Results. Adverse events (AEs) occurred in 58.3% of alirocumab patients compared with 54.5% of placebo-controlled patients. The most common AE was mild, transient injection-site reactions. No signal for muscle symptoms such as myalgia and no cases of neurocognitive effects were reported or observed. One alirocumab patient, also receiving atorvastatin 80 mg/day, had an increase in aspartate transaminase 3 to 5 times the upper limit of normal. Alirocumab 150 mg Q2W reduced low-density lipoprotein cholesterol (LDL-C) from baseline by 68.4% compared with 10.5% for the control group. More than 90% of patients achieved an LDL-C target of < 70 mg/dL with alirocumab versus 8% with control. Marked reductions in other atherogenic lipids and modest increases in high-density lipoprotein cholesterol were also observed. Conclusion. At the highest Q2W dose under development (150 mg), alirocumab appears well tolerated and produces robust LDL-C reductions. These data suggest that alirocumab 150 mg Q2W is an appropriate dose for further evaluation in Phase III trials.

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“…10, 618-619 [2013]), 1 Davidson discussed the successful experience with strategies to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), particularly using monoclonal antibodies (mAbs), and the value of this therapeutic approach as an example of translational research from genomics. PCSK9 mAbs (such as AMG145 and REGN727) have shown promise in randomized, controlled trials, [2][3][4][5] and are currently being investigated in long-term clinical outcome studies. 6,7 Interestingly, percentage reductions in levels of LDL cholesterol with PCSK9 mAbs reported in phase I and phase II trials are the largest ever achieved by a p harmacotherapeutic agent.…”

mentioning

confidence: 99%

Beyond anti-PCSK9 therapies: the potential role of resistin inhibitors

Sahebkar

2013

Nat Rev Cardiol

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Atorvastatin with or without an Antibody to PCSK9 in Primary Hypercholesterolemia

Cited by 432 publications

References 16 publications

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

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

Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: A Phase II pooled analysis

Beyond anti-PCSK9 therapies: the potential role of resistin inhibitors

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