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European Heart Journal. Cardiovascular... Sep 2022Many patients are unable to achieve guideline-recommended LDL cholesterol (LDL-C) targets, despite taking maximally tolerated lipid-lowering therapy. Bempedoic acid, a...
AIMS
Many patients are unable to achieve guideline-recommended LDL cholesterol (LDL-C) targets, despite taking maximally tolerated lipid-lowering therapy. Bempedoic acid, a competitive inhibitor of ATP citrate lyase, significantly lowers LDL-C with or without background statin therapy in diverse populations. Because pharmacodynamic interaction between statins and bempedoic acid is complex, a dose-response model was developed to predict LDL-C pharmacodynamics following administration of statins combined with bempedoic acid.
METHODS AND RESULTS
Bempedoic acid and statin dosing and LDL-C data were pooled from 14 phase 1-3 clinical studies. Dose-response models were developed for bempedoic acid monotherapy and bempedoic acid-statin combinations using previously published statin parameters. Simulations were performed using these models to predict change in LDL-C levels following treatment with bempedoic acid combined with clinically relevant doses of atorvastatin, rosuvastatin, simvastatin, and pravastatin. Dose-response models predicted that combining bempedoic acid with the lowest statin dose of commonly used statins would achieve a similar degree of LDL-C lowering as quadrupling that statin dose; for example, the predicted LDL-C lowering was 54% with atorvastatin 80 mg compared with 54% with atorvastatin 20 mg + bempedoic acid 180 mg, and 42% with simvastatin 40 mg compared with 46% with simvastatin 10 mg + bempedoic acid 180 mg.
CONCLUSION
These findings suggest bempedoic acid combined with lower statin doses offers similar LDL-C lowering compared with statin monotherapy at higher doses, potentially sparing patients requiring additional lipid-lowering therapies from the adverse events associated with higher statin doses.
Topics: Atorvastatin; Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
PubMed: 34448822
DOI: 10.1093/ehjcvp/pvab064 -
International Journal of Cardiology Jul 2024The effects of bempedoic acid on mortality in the secondary prevention setting have not been examined.
BACKGROUND
The effects of bempedoic acid on mortality in the secondary prevention setting have not been examined.
METHODS
We used data from the overall and primary prevention reports of CLEAR - Outcomes to reconstruct data for the secondary prevention population. A Bayesian analyses was employed to calculate the posterior probability of benefit or harm for the outcomes of all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACE). Relative effect sizes are presented as risk ratios (RR) with 95% credible intervals (CrI), which represent the intervals that true effect sizes are expected to fall in with 95% probability, given the priors and model.
RESULTS
In primary prevention, the posterior probability of bempedoic acid decreasing all-cause and cardiovascular mortality was 99.4% (RR: 0.70; 95% CrI: 0.51 to 0.92) and 99.7% (RR: 0.58; 95% CrI: 0.38 to 0.86) respectively. In secondary prevention, the posterior probability of bempedoic acid increasing all-cause and cardiovascular mortality was 96.6% (RR: 1.15; 95% CrI: 0.99 to 1.33) and 97.2% (RR: 1.21; 95% CrI: 1.00 to 1.45) respectively. The probability of bemepdoic acid reducing MACE in the primary and secondary prevention settings was 99.9% (RR: 0.70; 95% CrI: 0.54 to 0.88) and 95.8% (RR: 0.92; 95% CrI: 0.84 to 1.01) respectively.
CONCLUSION
In contrast to its effect in the primary prevention subgroup of CLEAR - Outcomes, bempedoic acid resulted in a more modest MACE reduction and a potential increase in mortality in the secondary prevention subgroup. Whether these findings represent true treatment effect heterogeneity or the play of chance requires further evidence.
Topics: Aged; Female; Humans; Male; Middle Aged; Cardiovascular Diseases; Dicarboxylic Acids; Double-Blind Method; Fatty Acids; Primary Prevention; Secondary Prevention; Treatment Outcome
PubMed: 38643794
DOI: 10.1016/j.ijcard.2024.132074 -
The New England Journal of Medicine Jun 2023
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Dicarboxylic Acids; Fatty Acids
PubMed: 37379145
DOI: 10.1056/NEJMc2305917 -
The New England Journal of Medicine Jun 2023
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Dicarboxylic Acids; Fatty Acids
PubMed: 37379143
DOI: 10.1056/NEJMc2305917 -
The New England Journal of Medicine Jun 2023
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Dicarboxylic Acids; Fatty Acids
PubMed: 37379144
DOI: 10.1056/NEJMc2305917 -
The New England Journal of Medicine Jun 2023
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Dicarboxylic Acids; Fatty Acids
PubMed: 37379142
DOI: 10.1056/NEJMc2305917 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Dec 2022Long-chain dicarboxylic acid (DCA), a building block for synthesizing a variety of high value-added chemicals, has been widely used in agriculture, chemical, and... (Review)
Review
Long-chain dicarboxylic acid (DCA), a building block for synthesizing a variety of high value-added chemicals, has been widely used in agriculture, chemical, and pharmaceutical industries. The global demand for DCA is increasing in recent years. Compared with chemical synthesis which requires harsh conditions and complicated processes, fermentative production of DCA has many unparalleled advantages, such as low cost and mild reaction conditions. In this review, we summarized the chemical and microbial synthesis methods for DCA and the commercialization status of the fermentation process. Moreover, the advances of using molecular and metabolic engineering to create high-yielding strains for efficient production of DCA were highlighted. Furthermore, the challenges remaining in the microbial fermentation process were also discussed. Finally, the perspectives for developing high titer DCA producing strains by synthetic biology were proposed.
Topics: Fermentation; Dicarboxylic Acids; Metabolic Engineering; Technology
PubMed: 36593186
DOI: 10.13345/j.cjb.220133 -
Cardiovascular Drugs and Therapy Aug 2021An elevated plasma low-density lipoprotein cholesterol (LDL-C) level is a well-established atherosclerotic cardiovascular disease (ACSVD) risk factor. Randomized studies... (Review)
Review
An elevated plasma low-density lipoprotein cholesterol (LDL-C) level is a well-established atherosclerotic cardiovascular disease (ACSVD) risk factor. Randomized studies with statins (alone or in combination with other lipid-lowering drugs) have demonstrated their clinical efficacy in lowering LDL-C. Several classes of new, non-statin agents have been successfully studied and used (e.g., ezetimibe and inhibitors of proprotein convertase subtilisin/kexin type 9 [i-PSCK9]). However, many high ACSVD risk patients remain at a high residual cardiovascular risk, with at least 10% being statin intolerant. Bempedoic acid (ETC-1002) is a new inhibitor of cholesterol synthesis that targets ATP citrate lyase (ACL). Importantly, ETC-1002 is only converted into an active form in the liver and is free of muscle side effects.Area Covered: Mechanism of action of ETC-1002, clinical pharmacology, completed clinical studies with bempedoic acid, lipid-lowering efficacy/safety issues, and recent meta-analyses of trials with ETC-1002.Expert Opinion: ETC-1002 has been extensively studied in phase I-III clinical studies in over 4000 individuals from different patient populations (statin intolerance, familial hypercholesterolemia, and high ACSVD risk patients), ETC-1002 has been demonstrated to have moderate cholesterol-lowering efficacy and a good safety profile at a dose of 180 mg/day as a monotherapy and in combination with statins and ezetimibe. The ongoing study CLEAR Outcomes, with composite cardiovascular endpoints, will elucidate the role of bempedoic acid in the management of high ACSVD risk and statin-intolerant patients with hypercholesterolemia. Long-term safety data on bempedoic acid are needed to fully establish this agent in evidence-informed guidelines for managing of patients with dyslipidemias.
Topics: Cholesterol, LDL; Dicarboxylic Acids; Drug Tolerance; Dyslipidemias; Fatty Acids; Heart Disease Risk Factors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Treatment Outcome
PubMed: 33502687
DOI: 10.1007/s10557-020-07139-x -
Applied Microbiology and Biotechnology Oct 2022The methylotrophic bacterium Methylorubrum extorquens AM1 has the potential to become a platform organism for methanol-driven biotechnology. Its ethylmalonyl-CoA pathway...
The methylotrophic bacterium Methylorubrum extorquens AM1 has the potential to become a platform organism for methanol-driven biotechnology. Its ethylmalonyl-CoA pathway (EMCP) is essential during growth on C1 compounds and harbors several CoA-activated dicarboxylic acids. Those acids could serve as precursor molecules for various polymers. In the past, two dicarboxylic acid products, namely mesaconic acid and 2-methylsuccinic acid, were successfully produced with heterologous thioesterase YciA from Escherichia coli, but the yield was reduced by product reuptake. In our study, we conducted extensive research on the uptake mechanism of those dicarboxylic acid products. By using 2,2-difluorosuccinic acid as a selection agent, we isolated a dicarboxylic acid import mutant. Analysis of the genome of this strain revealed a deletion in gene dctA2, which probably encodes an acid transporter. By testing additional single, double, and triple deletions, we were able to rule out the involvement of the two other DctA transporter homologs and the ketoglutarate transporter KgtP. Uptake of 2-methylsuccinic acid was significantly reduced in dctA2 mutants, while the uptake of mesaconic acid was completely prevented. Moreover, we demonstrated M. extorquens-based synthesis of citramalic acid and a further 1.4-fold increase in product yield using a transport-deficient strain. This work represents an important step towards the development of robust M. extorquens AM1 production strains for dicarboxylic acids. KEY POINTS: • 2,2-Difluorosuccinic acid is used to select for dicarboxylic acid uptake mutations. • Deletion of dctA2 leads to reduction of dicarboxylic acid uptake. • Transporter-deficient strains show improved production of citramalic acid.
Topics: Dicarboxylic Acids; Escherichia coli; Fumarates; Malates; Maleates; Methanol; Methylobacterium extorquens; Polymers; Succinates
PubMed: 36104545
DOI: 10.1007/s00253-022-12161-0 -
European Journal of Preventive... Jul 2021
Topics: Dicarboxylic Acids; Fatty Acids; Humans
PubMed: 33611517
DOI: 10.1177/2047487320929779