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Aims The aim of this study was to evaluate the low-density lipoprotein cholesterol lowering efficacy and safety of a bempedoic acid 180 mg and ezetimibe 10 mg fixed-dose combination in patients with hypercholesterolemia and a high risk of cardiovascular disease receiving maximally tolerated statin therapy. Methods This phase 3, double-blind clinical trial enrolled adult patients at high risk of cardiovascular disease due to atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or multiple cardiovascular disease risk factors. Patients were randomly assigned (2:2:2:1) to treatment with the fixed-dose combination, bempedoic acid 180 mg, ezetimibe 10 mg or placebo added to stable background statin therapy for 12 weeks. The primary efficacy endpoint was the percentage change from baseline to week 12 in low-density lipoprotein cholesterol. Results Among the 301 patients included in the primary analysis, the mean baseline low-density lipoprotein cholesterol level was 3.87 mmol/L (149.8 mg/dL). At week 12, the fixed-dose combination lowered low-density lipoprotein cholesterol (–36.2%) significantly more than placebo (1.8% (placebo-corrected difference –38.0%); P < 0.001), ezetimibe alone (–23.2%; P < 0.001) or bempedoic acid alone (–17.2%; P < 0.001). The fixed-dose combination lowered low-density lipoprotein cholesterol levels similarly across subgroups, including patients receiving high-intensity, other-intensity or no statin therapy. Improvements with the fixed-dose combination were also observed in secondary efficacy endpoints, including high-sensitivity C-reactive protein. In this trial, fixed-dose combination treatment had a generally similar safety profile compared with bempedoic acid, ezetimibe or placebo. Conclusion The bempedoic acid and ezetimibe fixed-dose combination significantly lowered low-density lipoprotein cholesterol versus placebo or other oral monotherapies and had a favourable safety profile when added to maximally tolerated statin therapy in patients with hypercholesterolemia and high cardiovascular disease risk. Trial Registration ClinicalTrials.gov identifier: NCT03337308.

Phytosterols (plant sterols), abundant in fat-soluble fractions of plants, are consumed at levels of 200-400 mg/day in Western diets. Chemically resembling cholesterol, phytosterols inhibit the absorption of cholesterol. Phytosterol consumption in human subjects under a wide range of study conditions has been shown to reduce plasma total and low density lipoprotein (LDL) cholesterol levels; however, the response varies widely. Greater cholesterol-lowering efficacy occurs with consumption of the saturated phytosterol sitostanol versus sitosterol or campesterol. Most studies report no effect of phytosterol administration in high density lipoprotein (HDL) cholesterol or triglyceride levels, although certain evidence exists for an HDL cholesterol raising effect of sitostanol. Phytosterol absorption is limited, although serum phytosterol levels have proven to be important indicators of both cholesterol absorption and synthesis. Serum phytosterols correlate with HDL cholesterol level. In addition, higher phytosterol/cholesterol ratios appear in HDL versus LDL particles, suggesting the existence of an intrinsic phytosterol action, in addition to the extrinsic effect on cholesterol absorption. In conclusion, addition to diet of the phytosterol sitostanol represents an effective means of improving circulating lipid profiles to reduce risk of coronary heart disease.

Objective-8-Hydroxy-2,2,14,14-tetramethylpentadecanedioic acid (ETC-1002) is a small molecule with a unique mechanism of action shown in nonclinical studies to modulate pathways of cholesterol, fatty acid, and carbohydrate metabolism. In previous phase 2 clinical trials, once daily oral treatment with ETC-1002 significantly reduced low-density lipoprotein-cholesterol in patients with hypercholesterolemia. In this trial, the lipid-lowering efficacy of ETC-1002 was evaluated in patients with type 2 diabetes mellitus and hypercholesterolemia. Additional cardiometabolic biomarkers, including glycemic measures, were also assessed. Approach and Results-A single-center, double-blind, placebo-controlled trial evaluated 60 patients with type 2 diabetes mellitus and elevated low-density lipoprotein-cholesterol. Patients discontinued all diabetes mellitus and lipid-regulating drugs and were randomized to receive ETC-1002 80 mg QD for 2 weeks followed by 120 mg QD for 2 weeks or placebo for 4 weeks. ETC-1002 lowered low-density lipoprotein-cholesterol levels by 43±2.6% (least squares mean±SE), compared with a reduction of 4±2.5% by placebo at day 29 (P<0.0001; primary end point). Non-high-density lipoproteincholesterol and total cholesterol were also significantly lowered by ETC-1002 compared with placebo (P<0.0001). Highsensitivity C-reactive protein was reduced by 41% (median) compared with a placebo reduction of 11% (P=0.0011). No clinically meaningful safety findings were observed. Conclusions-ETC-1002 lowered low-density lipoprotein-cholesterol and other lipids and demonstrated improvement inhigh-sensitivity C-reactive protein in patients with type 2 diabetes mellitus and hypercholesterolemia without worsening glycemic control. ETC-1002 was well tolerated in this population.

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. (A Study to Assess the Efficacy and Safety of ETC-1002 in Subjects With Elevated Blood Cholesterol and Either Normal or Elevated Triglycerides; NCT01262638).