The impact of proprotein convertase subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: a network meta-analysis

Lipinski, Michael J.; Benedetto, Umberto; Escárcega, Ricardo O.; Biondi‐Zoccai, Giuseppe; Lhermusier, Thibault; Baker, Nevin C.; Torguson, Rebecca; Brewer, H. Bryan; Waksman, Ron

doi:10.1093/eurheartj/ehv563

Cited by 230 publications

(183 citation statements)

References 46 publications

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“…Until recently, the highest quality of evidence surrounding alirocumab and evolocumab stemmed from phase 2 and 3 lipid‐lowering trials and their meta‐analyses 46, 47. The encouraging results led to the 2015 US Food and Drug Administration fast‐track approval for use of PCSK9 inhibitors as adjuncts to diet and maximally tolerated statin for patients with FH and clinical ASCVD.…”

Section: Discussionmentioning

confidence: 99%

“…De novo glial synthesis of cholesterol in the brain is postulated to be important for synapse formation and function; observational studies and RCTs of statins have been inconsistent in their demonstration of an association between statin utilization and impaired neurocognitive function 52, 53, 54, 55. PCSK9 inhibitors are not known to inhibit de novo cholesterol synthesis or to cross the blood–brain barrier; nevertheless, imbalances in neurocognitive side effects between PCSK9 inhibitors and control groups were detected in OSLER (Open‐Label Study of Long‐Term Evaluation Against LDL‐C) 1 and 2 (pooled rate: 0.9% versus 0.3%) and in ODYSSEY LONG‐TERM (1.2% versus 0.5%), as well as 2 large meta‐analyses of lipid‐lowering trials 46, 56. However, these findings were limited by heterogeneity of the examined populations, small numbers of events, and differences in the definition and assessment of neurocognitive events.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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

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“…PCSK9-The recent FDA approval of two proprotein convertase subtilisin/kexintype (PCSK9) inhibitors (alirocumab and evolocumab) provides the physician with a potent class of medications to lower LDL-c levels if a statin and ezetimibe do not achieve the <50 mg/dl goal [116] [117]. PCSK9 inhibitors prevent the binding of the PCSK9 protein with the LDL-c receptor, thereby preventing the catabolism of hepatic LDL-c receptors and thus significantly lowering circulating LDL-c [78] [118].…”

Section: Medicationsmentioning

confidence: 99%

The Application of the LDL Principle

Schade¹,

Cavanaugh²,

Ramo³

et al. 2016

WJCD

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The LDL Principle has recently been invoked to describe the observation that lowering the LDL cholesterol (by whatever means) results in a lowering of atherosclerotic cardiovascular events. The scientific basis of the LDL Principle dates back to the discovery that the LDL receptor is the prime determinant of the circulating LDL-c concentration. Since that time, major advances have been made at both the basic and clinical science level in our understanding of the pathogenesis and reversal of atherosclerosis. The incorporation of atherogenic lipoproteins plus inflammatory mediators into plaque formation permits the targeted intervention into preventing plaque rupture. In addition, genetic studies identifying individuals with unique phenotypes of either abnormally high or low LDL-c concentrations have provided insight into possible therapeutic modalities that have recently provided the physician with the tools necessary to apply the LDL Principle to achieve reversal of atherosclerosis. The epidemic of atherosclerotic cardiovascular disease has resulted in numerous randomized controlled intervention trials in an attempt to identify approaches to reduce ASCD morbidity and mortality. Recently published data indicate that circulating LDL-c levels of 50 mg/dl or less are not only physiologic at birth but also effective in greatly reducing cardiovascular disease. In addition, the recent availability of two PCSK9 inhibitors provides the primary care physician with the possibility of achieving this low level of LDL-c even in statin intolerant patients. The widespread availability of the coronary artery calcium scan plus the inclusion of traditional cardiovascular risk factors in risk assessment has enabled the physician to readily identify asymptomatic individuals at high risk for cardiovascular events. Aggressively applying the LDL Principle to these individuals has the potential of greatly reducing cardiovascular mortality. This review will document the scientific basis for this principle and provide the arguments in favor of its aggressive application.

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“…Drugs that were recently associated with better cardiovascular outcomes (such as PCSK9 inhibitors, colchicine, semaglutide and empaglifosin) should also be tested for this purpose [2,[21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%