Efficacy and Safety of a Novel Dual Modulator of Adenosine Triphosphate - Citrate Lyase and Adenosine Monophosphate - Activated Protein Kinase in Subjects With

Study Questions:

What is the effect of ETC-1002, a novel dual modulator of hepatic adenosine triphosphate and adenosine monophosphate-activated protein kinase, on serum lipids in subjects with hypercholesterolemia?

Methods:

A double-blind, parallel group, multicenter, placebo-controlled trial was conducted in persons (n = 177) with elevated low-density lipoprotein cholesterol (LDL-C) (130-220 mg/dl) who were stratified by baseline triglycerides (<150 or 150-399 mg/dl) and randomized to receive 40, 80, or 120 mg of ETC-1002 or placebo once daily for 12 weeks. Outcomes included changes in LDL-C (primary endpoint), other lipids, cardiometabolic risk factors, and safety.

Results:

Nearly 90% of participants were white, 45% were women; mean age was 57 years, and body mass index was 28 kg/m2. ETC-1002 40 mg, 80 mg, and 120 mg lowered LDL-C levels by 18% ± 2.2, 25% ± 2.1, and 27% ± 2.2, respectively (least squares mean ± standard error), versus a 2% ± 2.2 reduction by placebo (p < 0.0001); LDL-C lowering was similar in the <150 or 150-399 mg/dl groups. ETC-1002 also lowered apolipoprotein B, non–HDL-C, and LDL particle number (p < 0.0001) in a dose-dependent manner; HDL-C and triglyceride levels were relatively unchanged. Post-hoc analyses suggest that ETC-1002 may have favorable effects on other cardiometabolic risk factors. ETC-1002 and placebo groups did not demonstrate clinically meaningful differences in adverse events and other safety assessments.

Conclusions:

ETC-1002 significantly lowered LDL-C levels up to 27% across a broad range of baseline triglycerides, and was generally safe and well-tolerated. ETC-1002 has a novel mechanism of action, and may be useful for reducing LDL-C.

Perspective:

There is a considerable need for lipid-lowering agents beyond statins. While very effective at lowering the LDL-C, statins are associated with intolerable side effects in about 10% of persons, and increase the risk of diabetes, and there is a residual risk that could be further reduced by nonstatins. There are several very potent novel lipid-altering agents in outcome trials including PCSK-9 inhibitors and a cholesterol ester transfer protein inhibitor. Each appears much more potent than this new agent. But ETC-1002 is more potent than ezetimibe, colesevelam, and niacin. The efficacy and safety of ETC-1002 alone and in combination with other lipid-lowering agents will need to be studied in clinical trials followed by a large outcome trial.

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

Keywords: Hydroxymethylglutaryl-CoA Reductase Inhibitors, Multienzyme Complexes, Malignant Hyperthermia, Risk Factors, Hypercholesterolemia, Least-Squares Analysis, Protein Kinases, Cholesterol, Body Mass Index, Biological Markers, Azetidines, Oxo-Acid-Lyases, Niacin, Triglycerides, Diabetes Mellitus, Dicarboxylic Acids


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