Long-term PCSK9 inhibitor safe and effective in HeFH

Long-term Safety, Tolerability, and Efficacy of Evolocumab in Patients With Heterozygous Familial Hypercholesterolemia

Literature - Hovingh GK, Raal FJ, Dent R, et al. - J Clin Lipidol (2017), doi: 10.1016/j.jacl.2017.09.003


Patients with heterozygous familial hypercholesterolemia (HeFH) have increased plasma low-density lipoprotein cholesterol (LDL-C) levels, mainly due to genetic mutations in the LDL receptor gene [1], resulting in an increased cardiovascular (CV) risk. Of the estimated 34 million patients [2,3] worldwide, a large portion is not treated. Another part uses lipid lowering agents, such as statins, which do not result in sufficient reduction of LDL-C levels. Therefore, there is an unmet need for additional therapies to reduce the residual CV risk in this patient population.

Although it has been demonstrated that the PCSK9 antibody evolocumab safely lowered LDL-C levels in HeFH patients in phase II and III RUTHERFORD trials [4,5], long-term effects are not known yet. These long-term effects were evaluated in the evolocumab open-label extension (OLE) trial program (OSLER-1 and OSLER-2).

After completion of the RUTHERFORD trial, patients were enrolled in the OLE program and re-randomized 2:1 to receive evolocumab in addition to standard of care (SOC) or SOC alone for 48 weeks. Of the 440 enrolled patients, 289 were enrolled in the evolocumab plus SOC group and 151 in the SOC alone group.

Main results

  • 281 patients in the evolocumab plus SOC group completed the OLE program and 144 in the SOC alone group, resulting in discontinuation rates of 2.8% and 4.6%, respectively.
  • Patients who received evolocumab plus SOC for 48 weeks showed a mean reduction of 53.5% in calculated LDL-C levels (mean: -2.1 [SD: 0.07] mmol/L) compared to the levels at baseline of the parent study. The group with SOC alone had an increase of 2.1% after 48 weeks (0.03 [0.09] mmol/L).
  • Similar patterns were observed for other lipid parameters; a decrease for apolipoprotein B, non-high-density lipoprotein-C , triglycerides and lipoprotein(a) and an increase in HDL-C in patients who received evolocumab plus SOC.
  • Adverse event (AE) rates for the group of evolocumab plus SOC and SOC alone were 79.9% and 66.9%, respectively, without any permanent discontinuation in both groups due to AE.
  • Infections and infestations (47.8% vs 37.1%), musculoskeletal and connective tissue disorders (33.2% vs. 21.9%), general disorders and administration site conditions (25.3% vs. 7.3%), gastrointestinal disorders (19.7% vs. 12.6%) and nervous system disorders (14.5% vs. 7.9%) were more common in the evolocumab plus SOC group compared to the SOC alone group.
  • No differences in the number of serious AE was observed between the two groups.


This open-label extension trial of evolocumab demonstrated that long-term use (48 weeks) of this PCSK9 inhibitor in combination with SOC reduced the levels of LDL-C and was well tolerated in a HeFH patient population of , who need additional therapy to reduce their CV risk.


1. Leigh SE, Foster AH, Whittall RA, et al. Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. Ann Hum Genet 2008;72:485-498.

2. de Ferranti SD, Rodday AM, Mendelson MM, et al. Prevalence of Familial Hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES). Circulation 2016;133:1067-1072.

3. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478-3490a.

4. Raal F, Scott R, Somaratne R, et al. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation 2012;126(20):2408-2417.

5. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, doubleblind, placebo-controlled trial. Lancet 2015;385:331-340.

Find this article online at Lipid Journal

Facebook Comments


We’re glad to see you’re enjoying PACE-CME…
but how about a more personalized experience?

Register for free