Mipomersen, an Apolipoprotein B Synthesis Inhibitor, Reduces Atherogenic Lipoproteins in Patients With Severe Hypercholesterolemia at High Cardiovascular Risk: A Randomized, Double-Blind, Placebo-Controlled Trial

Study Questions:

What is the efficacy and safety of mipomersen for reducing atherogenic lipids/lipoproteins in persons with or at high risk for coronary heart disease (CHD)?


A randomized, double-blind, multicenter study was conducted in 158 patients with baseline low-density lipoprotein cholesterol (LDL-C) ≥100 mg/dl and triglycerides <200 mg/dl with, or at high risk for, CHD. All were on a low-fat diet and taking maximally tolerated lipid-lowering therapy. Patients received weekly subcutaneous mipomersen 200 mg (n = 105) or placebo (n = 52) for 26 weeks with a 24-week follow-up. Randomization was stratified by type 2 diabetes status with target minimal of 40%.


Mean age was 59 years and 43% were on maximal approved statin dosing. Sixty mipomersen and 44 placebo patients completed treatment. Mean baseline LDL-C was 123 mg/dl in both groups. Mipomersen reduced LDL-C by -36.9% compared with placebo at -4.5% (p < 0.001). Target LDL-C <100 mg/dl was attained in 76% of mipomersen versus 38% of placebo patients and LDL-C <70 mg/dl in 51% on mipomersen and 8% of placebo. Maximal effect was at about week 17 and returned to baseline by week 50. Mipomersen also reduced apolipoprotein (apo) B (-38%) and Lp(a) (-24%) (p < 0.001 for each). Common adverse events included injection site reactions (78% mipomersen, 31% placebo) and flu-like symptoms (34% mipomersen, 21% placebo). Elevations in transaminases and liver fat also occurred in some patients, and returned toward baseline after treatment cessation.


Mipomersen significantly reduced LDL-C, apo B, and Lp(a) in patients with, or at risk for, CHD whose LDL-C was not controlled by existing therapies.


Mipomersen is an apo B anti-sense to mRNA with great promise to lower the LDL-C to target with statins and in statin-intolerant patients. Among concerns is accumulation of hepatic fat. There was a strong correlation between increasing alanine aminotransferase and liver fat fraction, which correlated with reduction in apo B and LDL-C. The significance of this needs to be assessed in patients treated long-term. Five-fold more of the mipomersen group discontinued the study, which included 25% for liver enzyme elevation.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Atherosclerotic Disease (CAD/PAD), Homozygous Familial Hypercholesterolemia, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Diet

Keywords: Oligonucleotides, Coronary Artery Disease, Follow-Up Studies, Atherosclerosis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Diabetes Mellitus, Type 2, Lipoproteins, Risk Factors, Hypercholesterolemia, RNA, Messenger, Cholesterol, Dyslipidemias, Biological Markers, Troponin I, Liver, Diet, Fat-Restricted, Triglycerides

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