Hyperlipidemia is a well-known cardiovascular disease risk factor. Lipid-lowering is important to prevent CVD in at-risk persons and also for secondary prevention in patients with diagnosed heart disease.

The 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitors, or statins are the cornerstone of the treatment of hyperlipidemia. A plethora of reliable and robust evidence exists justifying their choice as the first-line drugs to reduce the risk of atherosclerotic cardiovascular disease (ASCVD). However, some patients fail to respond to statin therapy while others experience adverse effects such as myalgia leading to non-adherence and often treatment discontinuation. Statin-associated muscle symptoms are the most common reason for patients stopping treatment. Patients with statin intolerance are at a higher risk of cardiovascular events because the atherosclerotic process is progressing unchecked due to the high cholesterol levels. In such patients a non-statin therapy to correct the dyslipidemia is required if despite dose adjustments or trial of another statin, they are still not able to tolerate statin therapy. These are the patients with true statin intolerance and achieving the recommended LDL targets is an onerous task.

Ezetimibe and proprotein convertase subtilsin-kexin type 9 (PCSK9) inhibitors like evolocumab and alirocumab are the non-statin options. Reduction in LDL-cholesterol with ezetimibe is only in the range of 15% to 25%, while PCSK9 inhibitors have proven to be the most potent by reducing LDL-cholesterol up to 60% in statin-intolerant patients. However, the subcutaneous route of administration and high costs deter the routine use of PCSK9 inhibitors. Also, their long-term safety and efficacy are still being studied.

This underscores the need for an effective non-statin drug, which can be orally administered and can be used as monotherapy or as combination therapy with other lipid lowering drugs like ezetimibe for patients intolerant to statins or who have severe hypercholesterolemia.

Bempedoic acid is a new class of nonstatin LDL-lowering drugs. It was FDA-approved in 2021 to be used either alone or in a fixed dose combination with ezetimibe as adjunct to diet and maximally tolerated statin therapy for patients with established ASCVD and/or heterozygous familial hypercholesterolemia, which requires substantial lowering of LDL-C.

Bempedoic acid is a first-in-class ACL (adenosine triphosphate-citrate lyase) inhibitor. It is a prodrug and its conversion to the active form is catalyzed by the enzyme acyl-CoA synthetase 1 (ACSL 1), which is expressed only in the liver and not in the skeletal muscle. It exerts its lipid lowering effect by inhibiting the enzyme ATP-citrate lyase (ACL) in the cholesterol synthesis pathway. Thus, similar to the statins, bempedoic acid too acts on the cholesterol synthesis pathway but at an early step “upstream” of HMG CoA reductase (the rate-limiting step in cholesterol biosynthesis), which is the target for statins. And, since bempedoic acid is not activated in the skeletal muscles, it is potentially free of the muscle related symptoms often associated with statins, which make it a useful alternative for statin-intolerant patients.

The safety and efficacy of bempedoic acid in statin intolerant patients have been evaluated in the phase III CLEAR trials (CLEAR Tranquility, CLEAR Serenity, CLEAR Wisdom, CLEAR Harmony trials). These trials have demonstrated that bempedoic acid added to standard therapy safely and effectively reduced LDL-C in patients with and without statin intolerance. The non-high-density lipoprotein (HDL) cholesterol, total cholesterol and apolipoprotein B also decreased significantly. The cholesterol-lowering effect was more pronounced when administered along with ezetimibe than either drug administered alone to standard therapy. Used alone, bempedoic acid reduced LDL-C by 15-20% and when given together with ezetimibe, the reduction in LDL-C increased to 25-30%.

In addition, bempedoic acid also has anti-inflammatory action, marking another point of difference with PCSK9 inhibitors. This effect was demonstrated in the CLEAR Serenity trial, where bempedoic acid was associated with 24.3% decrease in hsCRP, which is per se a marker of risk of ASCVD. Bempedoic acid was also well-tolerated in these trials. No increase in muscle-related adverse events was observed.

Would bempedoic acid reduce the CV risk in high risk patients with statin intolerance is a question still under investigation. The ongoing CLEAR Outcomes trial, the results of which are likely to be published next year, is expected to provide answers regarding CVD outcomes, which are currently lacking.

The approval of bempedoic acid in 2021 as an oral, non-statin drug has expanded the therapeutic armamentarium of lipid-lowering medications. It can be used as an adjunct to diet and statins or other lipid lowering drugs. It is a suitable alternative to statins in patients who are unable to tolerate statin due to muscle-related adverse effects. In all these groups of patients, bempedoic acid may help to attain the LDL-C goals. It can be safely used in normoglycemic persons including those with type 2 diabetes mellitus or prediabetes without adverse impact on glycemic control.