PCSK9 and Clinical Outcomes in Hypercholesterolemia

Study Questions:

Does proprotein convertase subtilisin-kexin type 9 serine protease (PCSK9) improve lipids and cardiovascular outcomes better than placebo or ezetimibe?

Methods:

This was a meta-analysis of randomized controlled trials (RCTs), which included patients with primary hypercholesterolemia and compared PCSK9 inhibitors with placebo and ezetimibe. Outcomes included change in lipids, and trials were identified through MEDLINE/PubMed, Cochrane CENTRAL, and ClinicalTrials.gov. A total of 920 citations were identified, and 34 full-text publications were reviewed. Those which included patients with homozygosity for genes implicated in familial hypercholesterolemia and/or lacked data on lipids and/or clinical outcomes were excluded. Outcomes included were all-cause mortality, cardiovascular death, cardiovascular events, any adverse events, serious adverse events, events leading to drug discontinuation, and three-fold elevation of liver function tests. Network meta-analysis with both a frequentist approach and a Bayesian framework was performed to directly and indirectly compare PCSK9 inhibition on lipid levels with ezetimibe and placebo.

Results:

A total of 17 RCTs with 13,083 patients that were randomized to PCSK9 inhibitors (n = 8,250), placebo (n = 3,957), ezetimibe (n = 846), or PCSK9 inhibitors and ezetimibe (n = 30) were included in this analysis. The mean age was 59 ± 10 years, and 52% were male. The prevalence of coronary artery disease was 34%, hypertension was 51%, and diabetes mellitus was 19%. Mean lipid levels at baseline included a low-density lipoprotein (LDL) of 122 ± 36 mg/dl, total cholesterol of 199 ± 39 mg/dl, and high-density lipoprotein (HDL) of 51 ± 14 mg/dl. PCSK9 inhibitors significantly reduced LDL cholesterol by 57% relative to placebo (p < 0.001) and 36.1% relative to ezetimibe (p < 0.001). A significant reduction in all-cause mortality was observed with PCSK9 inhibitors (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.22-0.82; p = 0.01). A trend toward reduced cardiovascular disease death (OR, 0.50; 95% CI, 0.22-1.13; p = 0.10) and reduced cardiovascular disease events (OR, 0.67; 95% CI, 0.43-1.04; p = 0.07) was observed as well. However, an increased incidence of neurocognitive adverse events (OR, 2.34; 95% CI, 1.11-4.93; p = 0.02) was observed for PCSK9 inhibitors when compared with placebo.

Conclusions:

The investigators concluded that PCSK9 inhibition significantly improved lipid profiles and reduced the incidence of all-cause mortality compared with placebo, but had a higher rate of neurocognitive adverse events. PCSK9 inhibitor therapy may serve as an alternative for patients with statin intolerance and for those who do not respond to other lipid reduction therapy.

Perspective:

This meta-analysis demonstrates clinical benefits related to PCSK9 inhibitors including all-cause mortality, and offers an alternative therapy to statins. However, neurocognitive adverse effects are concerning, and support the need for continued assessment of cognitions among patients taking PCSK9 inhibitors.

Clinical Topics: Diabetes and Cardiometabolic Disease, Clinical Topic Collection: Dyslipidemia, Prevention, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Cholesterol, LDL, Coronary Artery Disease, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type II, Lipoproteins, HDL, Lipoproteins, LDL, Primary Prevention, Proprotein Convertases, Serine Proteinase Inhibitors, Subtilisins


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