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Bempedoic acid for the treatment of dyslipidemia.

ABSTRACT: Cardiovascular disease (CVD) is the leading cause of death worldwide and one key factor associated with the increased CVD risk is dyslipidemia. Statin therapy remains the first-line treatment to manage dyslipidemia, yet many patients do not achieve optimal low-density lipoprotein-cholesterol (LDL-C) levels even after taking moderate- or high-intensity statins; therefore, additional, non-statin therapy is often needed. Bempedoic acid is a prodrug that, once activated, decreases LDL-C levels by the inhibition of adenosine triphosphate citrate lyase in the liver. Five clinical trials have demonstrated the safety and efficacy of bempedoic acid and the bempedoic acid/ezetimibe combination in lowering LDL-C in patients with atherosclerotic CVD and heterozygous familial hypercholesterolemia and also in high-risk primary prevention, and statin-intolerant patients. Bempedoic acid has been demonstrated to lower LDL-C levels by 15-25% in clinical trials and up to 38% when combined with ezetimibe. In 2020, the FDA approved bempedoic acid. Furthermore, the combination of bempedoic acid with ezetimibe is FDA approved for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic CVD who require additional LDL-C lowering after maximally tolerated statin therapy. The ongoing CLEAR OUTCOMES trial aims to evaluate whether bempedoic acid can reduce cardiovascular events in patients with statin intolerance and results will be available in the next 3 years. This outcomes trial will be pivotal for determining the role of bempedoic acid in the non-statin lipid-lowering armamentarium.

SUBMITTER: Marrs JC

PROVIDER: S-EPMC7449648 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Bempedoic acid for the treatment of dyslipidemia.

Marrs Joel C JC Anderson Sarah L SL

Drugs in context 20200824

Cardiovascular disease (CVD) is the leading cause of death worldwide and one key factor associated with the increased CVD risk is dyslipidemia. Statin therapy remains the first-line treatment to manage dyslipidemia, yet many patients do not achieve optimal low-density lipoprotein-cholesterol (LDL-C) levels even after taking moderate- or high-intensity statins; therefore, additional, non-statin therapy is often needed. Bempedoic acid is a prodrug that, once activated, decreases LDL-C levels by th ...[more]

PMID: 32922503

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Project description:Diabetes is a major risk factor for atherosclerotic cardiovascular disease (ASCVD) in which dyslipidaemia plays a crucial role. Statins are first line therapy for primary and secondary prevention of ASCVD; however, adverse events include reversible musculoskeletal and liver side effects in addition to a diabetogenic association. In this short review, we provide a succinct narrative of the future role and current trial data of a novel first-in-class molecule, bempedoic acid. The authors provide their expert insight with a focus on Phase III randomised controlled trials (RCT) of bempedoic acid. Bempedoic acid was approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in February and March 2020, respectively, and is a novel molecule which inhibits cholesterol biosynthesis in the same mechanistic pathway as statins. It is a first-in-class small molecule, delivered as a prodrug and administered as an oral, once-daily dose that decreases low-density lipoprotein cholesterol (LDL-C) levels. Phase II and III RCTs have demonstrated efficacy with adequate safety data as mono- or combination therapy with statins and ezetimibe. Bempedoic acid is hepatically converted to the active drug with a lack of activation in skeletal muscle. Due to this novel mechanism, musculoskeletal-related adverse events exhibit a lower prevalence providing an alternative pharmacotherapy in statin-intolerant patients. Bempedoic acid may be used as an adjunct to diet and maximally tolerated statin therapy or in statin-intolerant patients for the treatment of dyslipidaemia. The recent National Institute of Health and Care Excellence (NICE) (UK) technology appraisal guidance [TA694] published in April 2021 recommended bempedoic acid with ezetimibe as a treatment option for primary hypercholesterolaemia or mixed dyslipidaemia if statins are not tolerated or contraindicated and if there is inadequate control of LDL-C with ezetimibe alone. Additionally, outcomes trials evaluating 'hard' endpoints in statin-intolerant patients or those with ASCVD are currently underway.

Project description:ADPKD has few therapeutic options. Tolvaptan slows disease but has side effects limiting its tolerability. Bempedoic acid (BA), an ATP citrate-lyase (ACLY) inhibitor FDA-approved for hypercholesterolemia, catalyzes a key step in fatty acid/sterol synthesis important for cell proliferation. BA is activated by very long-chain acyl-CoA synthetase (FATP2) expressed primarily in kidney and liver. BA also activates AMPK. We hypothesized that BA could be a novel ADPKD therapy by inhibiting cyst growth, proliferation, injury, and metabolic dysregulation via ACLY inhibition and AMPK activation. Pkd1-null kidney cell lines derived from mouse proximal tubule (PT) and collecting duct (IMCD) were grown in 2D or 3D Matrigel cultures and treated ± BA, ± SB-204990 (another ACLY inhibitor) or with Acly shRNA before cyst analysis, immunoblotting or mitochondrial assays using MitoSox and MitoTracker staining. Pkd1 fl/fl ; Pax8-rtTA; Tet-O-Cre C57BL/6J mice were induced with doxycycline injection on postnatal days 10 and 11 (P10-P11) and then treated ± BA (30 mg/kg/d) ± tolvaptan (30-100 mg/kg/d) by gavage from P12-21. Disease severity was determined by % total-kidney-weight-to-bodyweight (%TKW/BW) and BUN levels at euthanasia (P22). Kidney and liver homogenates were immunoblotted for expression of key biomarkers. ACLY expression and activity were upregulated in Pkd1-null PT and IMCD-derived cells vs. controls. Relative to controls, both BA and SB-204990 inhibited cystic growth in Pkd1-null kidney cells, as did Acly knockdown. BA inhibited mitochondrial superoxide production and promoted mitochondrial elongation, suggesting improved mitochondrial function. In ADPKD mice, BA reduced %TKW/BW and BUN to a similar extent as tolvaptan vs. untreated controls. Addition of BA to tolvaptan caused a further reduction in %TKW/BW and BUN vs. tolvaptan alone. BA generally reduced ACLY and stimulated AMPK activity in kidneys and livers vs. controls. BA also inhibited mTOR and ERK signaling and reduced kidney injury markers. In liver, BA treatment, both alone and together with tolvaptan, increased mitochondrial biogenesis while inhibiting apoptosis. We conclude that BA and ACLY inhibition inhibited cyst growth in vitro, and BA decreased ADPKD severity in vivo. Combining BA with tolvaptan further improved various ADPKD disease parameters. Repurposing BA may be a promising new ADPKD therapy, having beneficial effects alone and along with tolvaptan.

Project description:Many patients do not achieve optimal low-density lipoprotein cholesterol (LDL-C) levels with statins alone; others are unable to tolerate statin therapy. Additional non-statin treatment options including ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and bile acid sequestrants are often necessary to further reduce the risk of atherosclerotic cardiovascular disease. This review provides practical guidance as to the use of bempedoic acid to lower LDL-C and includes direction as to which patients may benefit and advice for safety monitoring during treatment. Bempedoic acid, a new class of agent, is a prodrug converted to bempedoyl-CoA by very long-chain acyl-CoA synthetase 1, an enzyme with high expression in the liver but that is undetectable in the skeletal muscle. Bempedoic acid inhibits the enzyme adenosine triphosphate (ATP)-citrate lyase, which lies two steps upstream from β-hydroxy β-methylglutaryl-CoA reductase in the cholesterol biosynthesis pathway. In clinical trials conducted in patients with or at risk for atherosclerotic cardiovascular disease or familial heterozygous hypercholesterolemia, bempedoic acid in combination with statins and/or ezetimibe significantly reduced LDL-C, apolipoprotein B, and high-sensitivity C-reactive protein compared with placebo. Bempedoic acid is generally well tolerated with no clinically meaningful increase in muscle-related symptoms relative to placebo, even in patients taking maximally tolerated statins. A small increase in serum uric acid (mean increase 0.8 mg/dL) is the most noteworthy adverse effect. Bempedoic acid provides an effective and generally well-tolerated medication to further reduce LDL-C in patients taking maximally tolerated statins or manage LDL-C levels in those who are unable to take statins. The potential for a reduced incidence of major cardiovascular events with bempedoic acid is being investigated in the CLEAR Outcomes trial, with results expected in 2023.

Dataset Information

Bempedoic acid for the treatment of dyslipidemia.

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Bempedoic acid for the treatment of dyslipidemia.

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