Hypercholesterolemic? Statin Sensitive? Bempedoic Acid May Be The Answer

Reductions in circulating cholesterol levels can have profound positive impacts on cardiovascular disease, particularly on atherosclerosis, as well as other metabolic disruptions of the vasculature. Control of dietary intake is one of the easiest and least cost intensive means to achieve reductions in cholesterol. However, in some individuals elevated levels of plasma cholesterol (hypercholesterolemia), especially that associated with very low density lipoprotein particles (VLDL) and low density lipoprotein particles (LDL, referred to as "bad" cholesterol), is the result of not only poor diet and lifestyle choices but is also exacerbated by genetics.

Drug treatment to lower plasma lipoproteins and/or cholesterol is primarily aimed at reducing the risk of atherosclerosis and subsequent coronary artery disease that exists in patients with elevated circulating lipids. Drug therapy usually is considered as an option only if non-pharmacologic interventions (altered diet and exercise) have failed to lower plasma lipids.

One of the most commonly prescribed drug class for individuals who are hypercholesterolemic is the statin class. The statins are fungal HMG-CoA reductase (HMGR) inhibitors. HMGR is the rate-limiting enzyme in the cellular synthesis of cholesterol. The net result of treatment is an increased cellular uptake of plasma LDL, since the intracellular synthesis of cholesterol is inhibited and cells are therefore dependent on extracellular sources of cholesterol. However, since mevalonate (the product of the HMGR reaction) is required for the synthesis of other important isoprenoid (lipid) compounds besides cholesterol, long-term treatments carry some risk of toxicity. In addition, statin therapy is associated with significant untoward side effects in the skeletal muscle. These toxicities can be mild such as muscle weakness and pain, or they can lead to significant skeletal muscle damage.

In addition to their role in lowering the endogenous synthesis of cholesterol, the statins have become recognized as a class of drugs capable of more pharmacologic benefits than just lowering blood cholesterol levels via their actions on HMGR. Part of the cardiac benefit of the statins relates to their ability to regulate the production of S-nitrosylated cycloxygenase 2 (COX-2 or PGS-2). COX-2 is an inducible enzyme involved in the synthesis of the prostaglandins and thromboxanes as well as the lipoxins and resolvins. The latter two classes of compounds are anti-inflammatory lipids discussed in the Bioactive Lipid Mediators of Inflammation page of my website. Evidence has shown that statins activate inducible nitric oxide synthase (iNOS) leading to nitrosylation of COX-2. The S-nitrosylated COX-2 enzyme produces the lipid compound 15R-hydroxyeicosatetraenoic acid (15R-HETE) which is then converted via the action of 5-lipoxygenase (5-LOX) to the epimeric lipoxin, 15-epi-LXA4. This latter compound is the same as the aspirin-triggered lipoxin (ATL) that results from the aspirin-induced acetylation of COX-2. Therefore, part of the beneficial effects of the statins are exerted via the actions of the lipoxin family of anti-inflammatory lipids.

Due to the negative effects of the statin class drugs on skeletal muscle they are not well tolerated in many individuals. There are numerous other classes of drug in the arsenal of medications for the treatment of hypercholesterolemia. Some of the newest drugs include the inhibitors of the enzyme (PCSK9: proprotein convertase subtilisin/kexin type 9) responsible for the degradation of the LDL receptor and the inhibitors of ATP citrate lyase (ACL), an enzyme critically involved in the conversion of carbohydrate carbons into fatty acids.

The PCSK9 inhibitors are injectable monoclonal antibodies that are sold by the trade names, Praluent and Repatha. The inhibitor of ACL is an orally administered compound called bempedoic acid. Bempedoic acid is a dicarboxylic acid that was demonstrated to inhibit fatty acid and cholesterol synthesis in experimental animals and these effects were correlated to reductions in plasma triglyceride and lipoprotein levels. Bempedoic acid is a pro-drug that is converted, exclusively in the liver, to its active CoA-derivative, bempedoyl-CoA. The CoA addition to bempedoic acid is catalyzed by very long-chain acyl-CoA synthetase-1 (ACSVL1) which is encoded by the SLC27A2 gene (for details go to the Lipolysis and the Oxidation of Fatty Acids page of my website). The SLC27A2 gene is highly expressed in the liver but is not expressed in adipose tissue, the intestines, nor in skeletal muscle. The conversion of bempedoic acid to its CoA derivative is required for its ability to suppress fatty acid and cholesterol synthesis and to also stimulate mitochondrial fatty acid β-oxidation.

One major advantage of bempedoic acid over the statin class of drugs in the treatment of hypercholesterolemia is that the lack of SLC27A2 expression in skeletal muscle prevents any adverse side effects in that tissue. The inhibition of muscle cholesterol synthesis by statins is a cause of the associated myotoxicity of that class of drug. Indeed, during clinical trials of bempedoic acid there was an absence of any muscle related symptoms. The US FDA approved the use of orally administered bempedoic acid alone (Nexletol™) or in combination with ezetimibe (Nexlizet™) in February of 2020. Ezetimibe blocks intestinal cholesterol uptake.

Bempedoic acid with a single daily dose (180 mg) reduces LDL-c by a mean 24.5% when given alone, by 18% when given on top of a major statin and by 38–40% when given in a fixed-dose combination with ezetimibe. Bempedoic acid treatment modestly improves glucose tolerance and also does not lead to the risk of new-onset diabetes.

A recent study was carried out with patients with plasma LDL-c levels of 130-189 mg/dL (optimal levels are less than 100 mg/dL) who were given a triple administration of bempedoic acid (180 mg), ezetimibe (10 mg), and atorvastatin (20 mg). After 6 weeks of once daily administration LDL-c levels dropped by 60.5% compared to placebo treatment. In greater than 90% of participants the level of LDL-c was less than 70 mg/dL. In addition, serum levels of C-reactive protein (CRP), a protein released from the liver in response to inflammation, was reduced in these patients by an average of 41.9%. This is significant given that hypercholesterolemia is associated with enhanced intravascular inflammation which significantly contributes to coronary artery disease and atherosclerosis.

In another study, bempedoic acid was co-administered with Repatha (evolocumab). In this study patients started with LDL-c levels greater than 160 mg/dL and were administered Repatha resulting in reductions in LDL-c to greater than 70 mg/dL. In these patients the administration of bempedoic acid resulted in 30.3% further reduction in LDL-c and a CRP by a further 28.5%.

The dramatic utility of bempedoic acid was demonstrated in one individual. This patient had a documented heterozygous frameshift deletion mutation the LDL receptor gene which represents a classic case of familial hypercholesterolemia. When this patient was treated with atorvastatin at 80 mg/day they developed severe skin lesions, lymphadenopathy, eosinophilia and abnormal liver functions test. The patient was switched to the PCSK9 inhibitor, alirocumab but their LDL-c remained elevated (139–250 mg/dL). The patient was then given bempedoic acid at 180 mg/day which resulted in a dramatic lowering of LDL-c to 51 mg/dL and, at a later evaluation, to 39 mg/dL. Importantly, this patient had no significant side effects.

It seems that more patients with poor statin tolerance and significantly elevated LDL-c levels should consider asking their physician to add bempedoic acid to their treatment plan.