LDL-C Lowering With Evolocumab in Hypercholesterolemia

Study Questions:

What is the durability of long-term efficacy and safety during long-term therapy with evolocumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9)?

Methods:

OSLER-1 (Open-Label Study of Long-Term Evaluation Against LDL Cholesterol) is an ongoing, randomized, open-label extension trial, being conducted at 192 sites in 18 countries. A total of 1,324 of 1,666 patients randomized into one of five 12-week double-blind phase 2 parent studies completed a parent study and chose to participate in OSLER-1; 1,255 received one or more evolocumab doses. As of August 2016, 812 of 1,324 (61%) had 208 weeks of follow-up. This current study was conducted from October 2011 to August 2016, with a data cutoff of August 26, 2016. During year 1, patients were randomized to evolocumab, 420 mg, plus standard of care (SOC) or SOC alone. After year 1, all patients continuing the study received evolocumab, 420 mg, plus SOC. The main outcome measures were lipids, safety, and tolerability every 12 weeks. A multivariate model identified factors associated with discontinuation of evolocumab.

Results:

At parent study baseline, the mean (standard deviation) age of the population was 57.1 (11.6) years, with 52.9% being women. The median low-density lipoprotein cholesterol (LDL-C) level was 133 mg/dl (to convert to millimoles per liter, multiply by 0.0259). After 52 weeks, evolocumab plus SOC was associated with a significant reduction in LDL-C level by 61% (95% confidence interval [CI], −63% to −60%) versus 2% (95% CI, −5% to −0.2%) with SOC alone (p < 0.001). At approximately 2, 3, and 4 years of study follow-up, the median LDL-C level was reduced by 59% (95% CI, −60% to −57%), 59% (95% CI, −61% to −58%), and 57% (95% CI, −59% to −55%), respectively, from parent study baseline. For patients receiving statin therapy unchanged from baseline, at week 208, the median LDL-C level reduction was 58%. No neutralizing antibodies to evolocumab were detected. The annualized incidence of new-onset diabetes was 4% in the SOC alone group and, adjusting for duration of evolocumab exposure, 2.8% in the evolocumab plus SOC group. Neurocognitive event rates were 0% (SOC alone) and 0.4% (evolocumab plus SOC). A total of 79% of patients persisted with evolocumab treatment, with a mean exposure duration of 44 months.

Conclusions:

The authors concluded that evolocumab produced sustained reductions in LDL-C levels.

Perspective:

This study reports sustained effectiveness of evolocumab for lowering LDL-C levels over an average of 44 months of exposure in a diverse patient population with hypercholesterolemia. The incidences of adverse events appear comparable between patients randomized to routine therapy alone and evolocumab plus standard of care during the first year of OSLER. Overall, there was no significant loss in efficacy or increasing annual rate of adverse effects from cumulative exposure. Cardiovascular outcome studies will help define the role of PCSK9 inhibitors for hypercholesterolemia in contemporary practice. For instance, the recent findings of the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial showed that evolocumab was superior to placebo at reducing adverse cardiovascular events with a 15% reduction in the primary endpoint. The magnitude of major cardiovascular event risk reduction will be key to wider use of these drugs.

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

Keywords: Antibodies, Monoclonal, Cholesterol, LDL, Diabetes Mellitus, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Lipids, Metabolic Syndrome X, Outcome Assessment (Health Care), Primary Prevention, Proprotein Convertases, Risk, Risk Reduction Behavior, Standard of Care, Subtilisins


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