RedUction of LDL-C with PCSK9 InhibiTion in HEteRozygous Familial HyperchOlesteRolemia Disorder Study-2 - RUTHERFORD-2


Patients with heterozygous familial hypercholesterolemia (HeFH) have markedly elevated low-density lipoprotein cholesterol (LDL-C). Currently available medications, including statins, typically reduce LDL-C by 50-60%. The current trial sought to assess the safety and efficacy of evolocumab, a PCSK9 inhibitor, in further reducing LDL levels in patients with HeFH already on statin therapy.


Evolocumab would result in greater LDL reductions than placebo in patients with HeFH already on statin therapy.

Study Design

  • Placebo Controlled
  • Randomized
  • Parallel

Patient Populations:

  • 18-80 years of age
  • HeFH according to Simon-Broome criteria at screening and on a stable dose of a statin with or without other approved lipid-modifying therapy (e.g., ezetimibe, resins, stanols, or niacin, but excluding fibrates) for at least 4 weeks before screening

    Number of screened applicants: 415
    Number of enrollees: 331
    Duration of follow-up: 12 weeks
    Mean patient age: 51 years
    Percentage female: 42%


  • Diagnosis consistent with homozygous FH
  • Lipoprotein apheresis within the previous 4 months

Primary Endpoints:

  • Percent change in LDL from baseline at 12 weeks
  • Percent change in LDL from baseline at mean of weeks 10 and 12

Secondary Endpoints:

  • Absolute change in LDL from baseline at 12 weeks
  • Proportion of patients with LDL <70 mg/dl
  • Change in other lipoproteins from baseline

Drug/Procedures Used:

Patients were randomized in a 2:2:1:1 fashion to receive either evolocumab 140 mg subcutaneously every 2 weeks, 420 mg subcutaneously every month, placebo subcutaneously every 2 weeks, or placebo subcutaneously every month for 12 weeks.

Concomitant Medications:

Statins (100%; 87% on high-dose statins), ezetimibe (62%)

Principal Findings:

A total of 331 patients were randomized, 111 to evolocumab 140 mg every 2 weeks, 110 to evolocumab 420 mg every month, 55 to placebo every 2 weeks, and 55 to placebo every month. Baseline characteristics were fairly similar. The mean age was 51 years, and approximately 30% had coronary artery disease, and the majority (~80%) had a confirmed diagnosis of HeFH based on Simon-Broome criteria. Mean LDL at baseline was approximately 155 mg/dl, mean high-density lipoprotein (HDL) was 51 mg/dl, and apolipoprotein B (ApoB) was 115 mg/dl.

Evolocumab 140 mg subcutaneously every 2 weeks resulted in a 59.2% absolute reduction in LDL compared with its corresponding placebo at week 12 (95% confidence interval [CI] 53.4-65.1%, p < 0.001). Mean absolute LDL values were 64.6 vs. 144.4 mg/dl. At week 12, the proportion of patients with LDL <70 mg/dl was 68% vs. 2%, p < 0.001. The change from baseline for evolocumab 140 mg vs. placebo for ApoB: -49.8% vs. -0.7%, p < 0.0001; HDL: 8.1% vs. -1.2%, p < 0.0001; triglycerides: -16.1% vs. 3.5%; p < 0.0001; and Lp(a): -22.9% vs. 8.7%, p < 0.0001. Similarly, evolocumab 420 mg subcutaneously every month resulted in a 61.3% absolute reduction in LDL compared with its corresponding placebo at week 12 (95% CI 53.6-69.0%, p < 0.0001). Mean absolute LDL values were 68.4 vs. 155.8 mg/dl. At week 12, the proportion of patients with LDL <70 mg/dl was 63% vs. 2%, p < 0.001. The change from baseline for evolocumab 140 mg vs. placebo for ApoB: -44.8% vs. 4.6%, p < 0.0001; HDL: 5.4% vs. -3.7%, p = 0.0016; triglycerides: 5.1% vs. 6.4%, p < 0.02; and Lp(a): -21.6% vs. 6.7%, p < 0.0001.

The incidence of serious adverse events was 3.2% vs. 4.6%, with no fatalities in either arm. The most common adverse events in the evolocumab arm were nasopharyngitis (8.6%), headache (4.1%), contusion (4.1%), and muscle-related complaints (4.5%). There were three cardiovascular events during the trial, all three in the evolocumab arm. No patients developed neurocognitive adverse events or binding/neutralizing antibodies to evolocumab at 12 weeks.


The results of the RUTHERFORD-2 trial indicate that treatment of HeFH patients already on statins with evolocumab 140 mg every 2 weeks or 420 mg every month resulted in about a 60% greater reduction in LDL levels at 12 weeks compared with placebo. Nearly two thirds of patients were able to reduce LDL levels below 70 mg/dl. There were also favorable changes in other lipoproteins, including HDL, triglycerides, and Lp(a). Overall, it was well tolerated with a higher incidence of minor side effects such as nasopharyngitis and myalgias.

These are very interesting data and add to the evolving body of literature with PCSK9 inhibitors. PCSK9 promotes hepatic LDL receptor degradation, thereby reducing LDL receptor density and clearance of LDL particles. Evolocumab and others are monoclonal antibodies directed against PCSK9. It is unknown if the use of these agents will result in better cardiovascular outcomes in FH patients, and potentially non-FH patients with atherosclerosis. A number of other agents such as cholesteryl ester transfer protein inhibitors and niacin also favorably impacted on multiple lipoproteins, but did not improve cardiovascular outcomes.


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 2014;Oct 1:[Epub ahead of print].

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Atherosclerotic Disease (CAD/PAD), Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Coronary Artery Disease, Follow-Up Studies, Cholesterol, LDL, Hyperlipoproteinemia Type II, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Receptors, LDL, Headache, Apolipoproteins B, Contusions, Cholesterol Ester Transfer Proteins, Azetidines, Heterozygote, Niacin, Lipoproteins, HDL, Nasopharyngitis, Triglycerides, Myalgia

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