Emerging Non-statin Treatment Options for Lowering Low-Density Lipoprotein Cholesterol

Abstract

Low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for the development of atherosclerotic cardiovascular disease. Statins have been the gold standard for managing cholesterol levels and reducing the risks associated with atherosclerotic cardiovascular disease; however, many patients do not achieve their cholesterol goals or are unable to tolerate this drug class due to adverse drug events. Recent studies of non-statin cholesterol lowering drugs (i.e., ezetimibe, PCSK9 inhibitors) have demonstrated cardiovascular benefits; and new drugs [i.e., bempedoic acid (BDA), inclisiran] have produced promising results in pre-clinical and clinical outcome trials. This narrative review aims to discuss the place in therapy of ezetimibe, PCSK9 inhibitors, BDA, and inclisiran and describe their relative pharmacokinetic (PK) profiles, efficacy and safety as monotherapy and combination therapy, and cardiovascular benefit(s) when used for hypercholesterolemia.

New Therapeutic Approaches in Treatment of Dyslipidaemia—A Narrative Review

“…Inhibition of ATP citrate lyase prevents endogenous cholesterol synthesis and indirectly increases the expression of LDL receptors, thereby increasing the clearance of LDL cholesterol [ 29 ]. Bempedoic acid is a prodrug that requires activation, and the active metabolite ESP15228 inhibits ATP citrate lyase [ 30 ]. It is administered orally once a day at a dose of 180 mg and is approved by the FDA and EMA for the treatment of hypercholesterolemia [ 30 , 31 ].…”

“…Bempedoic acid is a prodrug that requires activation, and the active metabolite ESP15228 inhibits ATP citrate lyase [ 30 ]. It is administered orally once a day at a dose of 180 mg and is approved by the FDA and EMA for the treatment of hypercholesterolemia [ 30 , 31 ]. Efficacy and safety of bempedoic acid have been evaluated in five clinical trials: HARMONY, WISDOM, SERENITY, TRANQUILITY and OUTCOMES.…”

“…An important finding was the lack of myopathies that are sometimes observed with prolonged statin therapy [ 35 ]. Most common side effects include upper respiratory tract infection, urinary tract infection, arthralgia, muscle spasms and diarrhoea; however, it is worth mentioning that similar occurrences of these symptoms were observed in the placebo groups [ 30 ]. In the SERENITY trial, one observation was an increase in uric acid levels in the blood, but other trials did not support this finding [ 23 ].…”

“…The mechanism of action of ezetimibe is mediated by targeting the sterol transporter Neimann-Pick C1 Like 1 (NPC1L1), which is localized at the border cells in the small intestine. Binding to the transporter inhibits it and decreases the absorption of cholesterol, further decreasing cholesterol circulation through the liver, and finally increasing the clearance of cholesterol from blood [ 30 ]. It is orally administered at a daily dose of 10 mg.…”

The Role of Endothelial Progenitor Cells in Atherosclerosis and Impact of Anti-Lipemic Treatments on Endothelial Repair

“…PCSK9 modulating agents form a new class of anti-lipemic drugs, suitable as add-on treatment to statins and ezetimibe, but also as monotherapy in statin and/or ezetimibe intolerant patients at increased cardiovascular risk [ 107 ]. By structure, they are either PCSK9 monoclonal antibodies interfering with circulatory PCSK9 (alirocumab, evolocumab) or small interfering ribonucleic acids (siRNA), modulating PCSK9 synthesis (inclisiran) [ 108 , 109 ].…”