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Current Atherosclerosis Reports Oct 2022The aim of creating an orally active non-statin cholesterol-lowering drug was achieved with bempedoic acid, a small linear molecule providing both a significant... (Review)
Review
PURPOSE OF REVIEW
The aim of creating an orally active non-statin cholesterol-lowering drug was achieved with bempedoic acid, a small linear molecule providing both a significant low-density lipoprotein cholesterol (LDL-C) reduction and an anti-inflammatory effect by decreasing high-sensitivity C-reactive protein. Bempedoic acid antagonizes ATP citrate-lyase, a cytosolic enzyme upstream of HMGCoA reductase which is the rate-limiting step of cholesterol biosynthesis. Bempedoic acid is a pro-drug converted to its active metabolite by very-long-chain acyl-CoA synthetase 1 which is present mostly in the liver and absent in skeletal muscles. This limits the risk of myalgia and myopathy. The remit of this review is to give clinical insights on the safety and efficacy of bempedoic acid and to understand for whom it should be prescribed.
RECENT FINDINGS
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 does not lead to the risk of new-onset diabetes, and moderately improves the glycaemic profile. The extensive knowledge on bempedoic acid mechanism, metabolism and side effects has led to an improved understanding of the potential benefits of this agent and offers a possible alternative to cardiologists and clinical practitioners somewhat worn out today by the occurrence of the muscular side effects of statins.
Topics: Anticholesteremic Agents; Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 35900636
DOI: 10.1007/s11883-022-01054-2 -
Journal of the American Heart... Apr 2019Background Inability to tolerate statins because of muscle symptoms contributes to uncontrolled cholesterol levels and insufficient cardiovascular risk reduction.... (Randomized Controlled Trial)
Randomized Controlled Trial
Background Inability to tolerate statins because of muscle symptoms contributes to uncontrolled cholesterol levels and insufficient cardiovascular risk reduction. Bempedoic acid, a prodrug that is activated by a hepatic enzyme not present in skeletal muscle, inhibits ATP -citrate lyase, an enzyme upstream of β-hydroxy β-methylglutaryl-coenzyme A reductase in the cholesterol biosynthesis pathway. Methods and Results The phase 3, double-blind, placebo-controlled CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen) Serenity study randomized 345 patients with hypercholesterolemia and a history of intolerance to at least 2 statins (1 at the lowest available dose) 2:1 to bempedoic acid 180 mg or placebo once daily for 24 weeks. The primary end point was mean percent change from baseline to week 12 in low-density lipoprotein cholesterol. The mean age was 65.2 years, mean baseline low-density lipoprotein cholesterol was 157.6 mg/dL, and 93% of patients reported a history of statin-associated muscle symptoms. Bempedoic acid treatment significantly reduced low-density lipoprotein cholesterol from baseline to week 12 (placebo-corrected difference, -21.4% [95% CI, -25.1% to -17.7%]; P<0.001). Significant reductions with bempedoic acid versus placebo were also observed in non-high-density lipoprotein cholesterol (-17.9%), total cholesterol (-14.8%), apolipoprotein B (-15.0%), and high-sensitivity C-reactive protein (-24.3%; P<0.001 for all comparisons). Bempedoic acid was safe and well tolerated. The most common muscle-related adverse event, myalgia, occurred in 4.7% and 7.2% of patients who received bempedoic acid or placebo, respectively. Conclusions Bempedoic acid offers a safe and effective oral therapeutic option for lipid lowering in patients who cannot tolerate statins. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02988115.
Topics: Administration, Oral; Canada; Dicarboxylic Acids; Double-Blind Method; Drug Hypersensitivity; Fatty Acids; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Male; Middle Aged; Muscular Diseases; Treatment Outcome; United States
PubMed: 30922146
DOI: 10.1161/JAHA.118.011662 -
Atherosclerosis Oct 2018Patients with hyperlipidemia who are unable to tolerate optimal statin therapy are at increased cardiovascular risk due to ongoing elevations in low-density lipoprotein... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIMS
Patients with hyperlipidemia who are unable to tolerate optimal statin therapy are at increased cardiovascular risk due to ongoing elevations in low-density lipoprotein cholesterol (LDL-C). The objective of CLEAR Tranquility (NCT03001076) was to evaluate the efficacy and safety of bempedoic acid when added to background lipid-modifying therapy in patients with a history of statin intolerance who require additional LDL-C lowering.
METHODS
This phase 3, multicenter, randomized, double-blind, placebo-controlled study enrolled patients with a history of statin intolerance and an LDL-C ≥100 mg/dL while on stable lipid-modifying therapy. After a 4-week ezetimibe 10 mg/day run-in period, patients were randomized 2:1 to treatment with bempedoic acid 180 mg or placebo once daily added to ezetimibe 10 mg/day for 12 weeks. The primary endpoint was the percent change from baseline to week 12 in LDL-C.
RESULTS
The study population comprised 269 patients (181 bempedoic acid, 88 placebo). Bempedoic acid added to background lipid-modifying therapy that included ezetimibe reduced LDL-C by 28.5% more than placebo (p < 0.001; -23.5% bempedoic acid, +5.0% placebo). Significant reductions in secondary endpoints, including non-high-density lipoprotein cholesterol (-23.6%), total cholesterol (-18.0%), apolipoprotein B (-19.3%), and high-sensitivity C-reactive protein (-31.0%), were observed with bempedoic acid vs. placebo (p < 0.001). Bempedoic acid was well tolerated; rates of treatment-emergent adverse events, muscle-related adverse events, and discontinuations were similar in the bempedoic acid and placebo treatment groups.
CONCLUSIONS
Bempedoic acid may provide an oral therapeutic option complementary to ezetimibe in statin intolerant patients who require additional LDL-C lowering.
Topics: Aged; Biomarkers; Canada; Cholesterol, LDL; Dicarboxylic Acids; Double-Blind Method; Down-Regulation; Drug Therapy, Combination; Europe; Ezetimibe; Fatty Acids; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Male; Middle Aged; Time Factors; Treatment Outcome; United States
PubMed: 29910030
DOI: 10.1016/j.atherosclerosis.2018.06.002 -
Clinica E Investigacion En... May 2021Bempedoic acid acts by inhibiting adenosine triphosphate-citrate lyase (ACL) and consequently cholesterol biosynthesis, leading to increased expression of LDL receptors...
Bempedoic acid acts by inhibiting adenosine triphosphate-citrate lyase (ACL) and consequently cholesterol biosynthesis, leading to increased expression of LDL receptors and increasing low-density lipoproteins (LDL-C) plasma clearence. It is a prodrug for oral administration with intracellular activation. It is activatedin liver cells and to a lesser extent in kidney cells, being absent in adipose tissue and muscle cells. Therefore, unlike statins, its potential myotoxic effect is very limited. It has recently been approved as a lipid-lowering drug in combination with diet, with statins, or with other lipid-lowering drugs in patients with hypercholesterolaemia, mixed dyslipidaemia, statin intolerance, or when these are contraindicated. The marketing of bempedoic acid implies, in clinical practice, having a new family of lipid-lowering drugs.
Topics: Dicarboxylic Acids; Drug Therapy, Combination; Dyslipidemias; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents
PubMed: 33966814
DOI: 10.1016/j.arteri.2021.02.012 -
European Journal of Preventive... Apr 2020The 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... (Randomized Controlled Trial)
Randomized Controlled Trial
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%); < 0.001), ezetimibe alone (-23.2%; < 0.001) or bempedoic acid alone (-17.2%; < 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.
Topics: Aged; Anticholesteremic Agents; Biomarkers; Cardiovascular Diseases; Cholesterol, LDL; Dicarboxylic Acids; Double-Blind Method; Down-Regulation; Drug Combinations; Ezetimibe; Fatty Acids; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Middle Aged; Time Factors; Treatment Outcome; United States
PubMed: 31357887
DOI: 10.1177/2047487319864671 -
The Biochemical Journal May 2023Mitochondrial β-oxidation is the most prominent pathway for fatty acid oxidation but alternative oxidative metabolism exists. Fatty acid ω-oxidation is one of these... (Review)
Review
Mitochondrial β-oxidation is the most prominent pathway for fatty acid oxidation but alternative oxidative metabolism exists. Fatty acid ω-oxidation is one of these pathways and forms dicarboxylic acids as products. These dicarboxylic acids are metabolized through peroxisomal β-oxidation representing an alternative pathway, which could potentially limit the toxic effects of fatty acid accumulation. Although dicarboxylic acid metabolism is highly active in liver and kidney, its role in physiology has not been explored in depth. In this review, we summarize the biochemical mechanism of the formation and degradation of dicarboxylic acids through ω- and β-oxidation, respectively. We will discuss the role of dicarboxylic acids in different (patho)physiological states with a particular focus on the role of the intermediates and products generated through peroxisomal β-oxidation. This review is expected to increase the understanding of dicarboxylic acid metabolism and spark future research.
Topics: Microbodies; Fatty Acids; Oxidation-Reduction; Mitochondria; Liver; Dicarboxylic Acids
PubMed: 37140888
DOI: 10.1042/BCJ20230041 -
Scientific Reports Jul 2020Chemical peels are widely used as therapeutic agents in dermatology and cosmetology. This study aims to explore the differences in the effectiveness of azelaic and... (Comparative Study)
Comparative Study Randomized Controlled Trial
Chemical peels are widely used as therapeutic agents in dermatology and cosmetology. This study aims to explore the differences in the effectiveness of azelaic and pyruvic acid peels in the treatment of acne vulgaris. Eligibility criteria for participants were: female gender, 18-25 years of age, no dermatological treatment within the last 12 months and mild to moderate papulopustular acne. We treated 120 young women (with a mean age of 22 years old) with six peeling sessions at 2-week intervals. In the parallel clinical study design, one randomized group (n = 60, 50%) was treated using azelaic acid (AA), whereas the second group participated in pyruvic acid (PA) sessions. We evaluated the patients clinically twice (before and after treatment), using the Scale of Hellegren-Vincent Severity Symptoms to assess the acne diagnosis, and the Nati Analyzer to estimate the skin properties (oily skin, desquamation, porosity, and moisture). The clinical evaluation of the patients demonstrated a significant reduction of acne severity symptoms in both the AA and PA groups, after the peeling sessions. An effect was also found in terms of decreasing desquamation and the oiliness of the skin. PA showed a more significant reduction of greasy skin than AA. In conclusion, after the six peeling sessions using AA and PA, all patients showed better skin parameters in term of reduced oiliness and desquamation. Both AA and PA peelings are a safe and efficient treatment for mild acne, however, during the selection of one of the two acids, side effects, skin properties, and patients' preferences should be taken into account. This study was registered in the ISRCTN registry (registration number ISRCTN79716614, 17/01/2020).
Topics: Acne Vulgaris; Adult; Analysis of Variance; Dicarboxylic Acids; Female; Humans; Porosity; Pyruvic Acid; Skin; Treatment Outcome; Young Adult
PubMed: 32724156
DOI: 10.1038/s41598-020-69530-w -
Nature Communications Nov 2016Despite widespread use of statins to reduce low-density lipoprotein cholesterol (LDL-C) and associated atherosclerotic cardiovascular risk, many patients do not achieve...
Despite widespread use of statins to reduce low-density lipoprotein cholesterol (LDL-C) and associated atherosclerotic cardiovascular risk, many patients do not achieve sufficient LDL-C lowering due to muscle-related side effects, indicating novel treatment strategies are required. Bempedoic acid (ETC-1002) is a small molecule intended to lower LDL-C in hypercholesterolemic patients, and has been previously shown to modulate both ATP-citrate lyase (ACL) and AMP-activated protein kinase (AMPK) activity in rodents. However, its mechanism for LDL-C lowering, efficacy in models of atherosclerosis and relevance in humans are unknown. Here we show that ETC-1002 is a prodrug that requires activation by very long-chain acyl-CoA synthetase-1 (ACSVL1) to modulate both targets, and that inhibition of ACL leads to LDL receptor upregulation, decreased LDL-C and attenuation of atherosclerosis, independently of AMPK. Furthermore, we demonstrate that the absence of ACSVL1 in skeletal muscle provides a mechanistic basis for ETC-1002 to potentially avoid the myotoxicity associated with statin therapy.
Topics: ATP Citrate (pro-S)-Lyase; Adenylate Kinase; Animals; Atherosclerosis; Cholesterol, LDL; Dicarboxylic Acids; Disease Progression; Enzyme Activation; Enzyme Inhibitors; Fatty Acids; Hepatocytes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipid Metabolism; Liver; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Organ Specificity; Receptors, LDL; Up-Regulation
PubMed: 27892461
DOI: 10.1038/ncomms13457 -
European Journal of Preventive... Apr 2020
Topics: Cardiovascular Diseases; Dicarboxylic Acids; Ezetimibe; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia
PubMed: 31311303
DOI: 10.1177/2047487319864672 -
Journal of Translational Medicine Sep 2017This review based on translational research predicts that the transcription factor p53 is the key effector of all anti-acne therapies. All-trans retinoic acid (ATRA) and... (Review)
Review
This review based on translational research predicts that the transcription factor p53 is the key effector of all anti-acne therapies. All-trans retinoic acid (ATRA) and isotretinoin (13-cis retinoic acid) enhance p53 expression. Tetracyclines and macrolides via inhibiting p450 enzymes attenuate ATRA degradation, thereby increase p53. Benzoyl peroxide and hydrogen peroxide elicit oxidative stress, which upregulates p53. Azelaic acid leads to mitochondrial damage associated with increased release of reactive oxygen species inducing p53. p53 inhibits the expression of androgen receptor and IGF-1 receptor, and induces the expression of IGF binding protein 3. p53 induces FoxO1, FoxO3, p21 and sestrin 1, sestrin 2, and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), the key inducer of isotretinoin-mediated sebocyte apoptosis explaining isotretinoin's sebum-suppressive effect. Anti-androgens attenuate the expression of miRNA-125b, a key negative regulator of p53. It can thus be concluded that all anti-acne therapies have a common mode of action, i.e., upregulation of the guardian of the genome p53. Immortalized p53-inactivated sebocyte cultures are unfortunate models for studying acne pathogenesis and treatment.
Topics: Acne Vulgaris; Dicarboxylic Acids; Humans; Isotretinoin; Models, Biological; Photochemotherapy; Tetracyclines; Tumor Suppressor Protein p53
PubMed: 28927457
DOI: 10.1186/s12967-017-1297-2