By Michael Crawford, MD
Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco
Dr. Crawford reports no financial relationships relevant to this field of study.
SYNOPSIS: In a meta-analysis of 17 studies, proprotein convertase subtilisin-kexin type 9 serine protease inhibitors markedly reduced low-density lipoprotein cholesterol levels and all-cause mortality, but was associated with a significant increase in neurocognitive adverse events.
SOURCE: Lipinski MJ, Benedetto U, Escarcega RO, et al. 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. Eur Heart J 2016;37:536-545.
Studies of proprotein convertase subtilisin-kexin type 9 serine protease (PCSK9) inhibitors demonstrate markedly reduced low-density lipoprotein (LDL) cholesterol and possibly improved outcomes. To further investigate potential outcomes, investigators from the United States, United Kingdom, and Italy performed a network meta-analysis of 17 trials of PCSK9 inhibitors vs. placebo or ezetimibe to assess whether PCSK9 inhibitors reduced all-cause mortality or cardiovascular (CV) events. They excluded studies involving patients homozygous for familial hypercholesterolemia. The outcomes analyzed included all-cause mortality, CV death, CV events, adverse events, and serious adverse events. The 17 randomized, controlled trials included 13,083 patients: 8,250 randomized to PCSK9 inhibitors, 3,957 to placebo, 846 to ezetimibe, and 30 to PCSK9 plus ezetimibe. The subjects’ mean age was 59 years and 52% were male, most of the subjects were Caucasian, and many had known coronary artery disease or risk factors for it. PCSK9 inhibitors reduced LDL cholesterol 57% from a mean baseline of 122 to 51 mg/dL, and increased HDL cholesterol 6%. PCSK9 inhibitors significantly reduced all-cause mortality (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.22-0.82; P = 0.01) but not CV death (HR, 0.50; CI, 0.22-1.13; P = 0.10) or CV events (HR, 0.67; CI, 0.43-1.04; P = 0.07) compared to placebo. PCSK9 inhibitors significantly increased neurocognitive events (HR, 2.31; CI, 1.11-4.93; P = 0.02). Other adverse events were not different on PCSK9 inhibitors compared to placebo. The authors concluded that PCSK9 inhibitors significantly improved lipid profiles and reduced all-cause mortality, but were associated with more neurocognitive adverse events than placebo.
COMMENTARY
Last year, the FDA approved PCSK9 inhibitors for patients with homozygous familial hypercholesterolemia and those intolerant to statins or statin failures who have compelling reasons to lower cholesterol. These drugs are monoclonal antibodies, which must be administered by subcutaneous injection every two-four weeks. They are very effective at lowering LDL cholesterol, even on top of other therapy, and many trial patients were found to have at least one LDL value below 25mg/dL. Naturally, there has been concern about potential neurocognitive adverse effects. The individual trials did not demonstrate an increase in neurocognitive adverse effects, but they were clearly apparent in this meta-analysis.
The significant reduction in all-cause mortality was mainly due to two large studies (ODYSSEY LONGTERM and OSLER 2), which had long follow-up periods. Although there was a trend toward reduced CV death and events, it was not statistically significant. Since the individual studies were not powered for outcomes, these results are hypothesis generating, and we must await the results of larger studies to confirm any outcome benefits.
This study fuels the debate about prescribing statins (or other LDL-lowering drugs) based on risk of vascular disease alone or treating to certain targeted LDL values. Proponents of the latter approach espouse that aggregating statin studies shows the lower the LDL, the better the outcomes. This also occurred in the recent IMPROVE IT study of adding ezetimibe to simvastatin. However, prior studies did not achieve the LDL levels that are possible with PCSK9 inhibitors, especially if they are added to statin plus ezetimibe therapy. Thus, many believe there is a lower limit to LDL lowering beyond which neurological adverse effects occur more commonly. The Cholesterol Treatment Trialists’ Collaboration has suggested that this may be 50 mg/dL. Since PCSK9 studies often achieved LDL levels below that in many patients, this may explain the meta-analysis results of more neurocognitive adverse events with PCSK9 inhibitors.
At this point, PCSK9 inhibitors are a reasonable alternative or additional therapy for those intolerant to statins or those in whom LDL cholesterol remains elevated despite statins plus ezetimibe. However, perhaps adjusting the dosage to keep the LDL in the 50-70 mg/dL range is prudent until further studies produce more data.
