Long-term safety and LDL lowering with PCSK9 inhibition in hypercholesterolemic patients

Long-Term Efficacy and Safety of Evolocumab in Patients With Hypercholesterolemia

Literature - Koren MJ, Sabatine MS, Giugliano RP et al. - J Am Coll Cardiol 2019: 74(17). DOI: https://doi.org/10.1016/j.jacc.2019.08.1024

Introduction and methods

Evolocumab is one of the two regulatory approved PCSK9 inhibitors and has been shown to reduce LDL-C by approximately 60% as monotherapy or in combination with other lipid-lowering therapies in patients with hypercholesterolemia [1-6]. Results from the FOURIER trial recently demonstrated that the beneficial effect of PCSK9 inhibition on lipid levels improved cardiovascular outcomes and suggested that persistently low lipid levels lead to an increased benefit over time [7].

This report of the OSLER-1 study (Open Label Study of Long-Term Evaluation Against LDL-C Trial) describes the efficacy and safety of evolocumab for up to 5 years. Patients who enrolled in OSLER-1, had previously participated in 1 of 5 phase 2 studies of evolocumab. In the first year of OSLER-1, patients (n=1255) were randomized in a 2:1 ratio to either treatment with evolocumab (420 mg very 4 weeks) plus standard of care (SOC) (n=882) or only SOC (n=442).After the first year, all patients received treatment with evolocumab. For the safety analysis, 1255 patients were included who received at least one dose of evolocumab. Data were available of 1151 patients for the efficacy analysis (year 2 to 5). 659 patients had more than 4 years of exposure to evolocumab.

The primary goal of the OSLER-1 study was to characterize the incidence of adverse events (AEs), SAEs and events leading to treatment discontinuation during long-term exposure to evolocumab. Presence of binding anti-drug antibody (ADA), and of neutralizing ADAs that interfere with the function of the therapeutic agent [8] was assessed. Secondary efficacy study objectives included the yearly changes in LDL-C, ApoB, Lp(a), triglycerides, ApoA1 and HDL-C, as compared with baseline before evolocumab parent study enrollment.

Main results

Safety results

  • During 5 years,1179 of 1255 patients (94%) reported ≥1 AE and 293 (23%) patients reported an SAE. 71 patients discontinued evolocumab due to AEs.
  • The rate of AEs in year 5 (65%) was similar to those in years 2 to 4 (67% to 80%), as well as to the rate in year 1 in the SOC control group (74%). Likewise, the rate of SAEs in year 5 (7%) was similar to rates of year 2 to 4 (7% to 8%) and year 1 in the SOC control (7%).
  • 4 Patients tested positively for ADAs. For all, this resolved after a few weeks and thereafter. None experienced a loss in treatment efficacy. No neutralizing ADAs were detected during the 5-year course of this study.
  • Annualized rates of injection-site reactions decreased from 4.1% in the first year of exposure to evolocumab to 0.2% in year 4 and beyond.
  • Adjudicated CV events occurred in 1.0% (12 of 1255) of the study participants during the first year of evolocumab exposure. Incidence rates of adjudicated CV events remained low during years 2, 3, 4 and 5 of the study; 1.2%, 1.3%, 1.9%, and 1.7%, respectively.

Efficacy results

  • In the efficacy group, mean absolute LDL levels were 61, 61, 62, and 61 mg/dl at the end of year 2, 3, 4 and 5 of the study, respectively. LDL-C at baseline at the time of enrollment in the parent studies was 140 ± 39 mg/dl (mean ± SD).
  • 67.0% Of patients on evolocumab achieved LDL-C levels<70 mg/dl and 87.6% had <100 mg/dl.
  • Mean ApoB reduced at years 2, 3, 4 and 5 with 46%, 45%, 45%, and 43%, respectively. Median Lp(a) reduced with 31%, 29%, 36% and 36%, respectively. Mean ApoA1 increased by 7%, 8%, 9% and 9%, respectively. HDL-C increased with 11%, 10%, 11% and 9%, respectively. Mean triglycerides reduced in year 2, 3 and 4 with 5%, 3% and 1%, respectively, and increased at year 5 by 1%.


This study presented persistent effectiveness and good tolerance of evolocumab over a 5-year period in patients with hypercholesterolemia. LDL-C reduction was consistent without attenuation. AE incidence rates did not increase over time and were similar during extended exposure to evolocumab compared to the SOC control group in the first year of the OSLER-1 trial. ADAs occurred rarely and did not interfere with treatment efficiency. No ADAs were detected after the first year of exposure.

Editorial comment

In their editorial comment [9], Chapman and Ginsberg emphasize the high incidence and associated costs of CVD. Atherosclerotic CVD (ASCVD) is caused by elevated blood pressure and high LDL-C levels. The absolute reduction in LDL-C and the cumulative duration of lower LDL levels is proportional to the reduction in ASCVD events [10]. Chapman and Ginsberg welcome the findings of Koren et al. on the long-term efficacy and safety of the PCSK9 inhibitor evolocumab in this context, because the large randomized, placebo-controlled FOURIER CV outcome trial of evolocumab had a relatively short duration of a mean of 2.2 years.

Over the 5-year time course, reduction of LCL-C levels was maintained. Rates of SAEs were comparable to those in the control group in the first year of the OSLER-1 trial and remained constant over time.

It is noteworthy that 71% of the patients in the evolocumab plus SOC group received background statin treatment. The study did not include a statin control group. For this reason, AE rates should be considered with caution. It is reassuring that patients who achieved LDL-c <40 mg/dL in the evolocumab plus SOC group had a similar safety profile to those with LDL-c >40 mg/dL.

Chapman and Ginsberg conclude that these findings bode well for the use of PCSK9 inhibitors in long-term treatments in patients with hypercholesterolemia. This will be particularly the case for patients with a residual CV risk and in whom treatment with statin or statin-ezetimibe has not led to a guideline-recommended LCL-C level of <70 mg/dl.


1. Stein EA, Giugliano RP, Koren MJ, et al. Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials. Eur Heart J 2014;35:2249–59.

2. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385:331–40.

3. Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA part B): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385:341–50.

4. Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med 2014;370:1809–19.

5. Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA 2014;311:1870–82.

6. Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 2014;63:2541–8.

7. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22.

8. Kuriakose A, Chirmule N, Nair P. Immunogenicity of biotherapeutics: causes and association with posttranslational modifications. J Immunol Res 2016;2016:1298473.

9. M. John Chapman, Henry N. Ginsberg. Evolocumab Treatment of Hypercholesterolemia in OSLER-1. J Am Coll Cardiol. 2019 Oct, 74 (17) 2147-2149.

10. Ference BA, Ginsberg HN, Graham I, et al. Lowdensity lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459–72.

11. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias:lipid modification to reduce cardiovascular risk. Eur Heart J Aug 31.

Find this article online at J. Am. Coll. Cardiol.

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