Background Bempedoic acid (BA) is an oral first-in-class, ATP-citrate lyase inhibitor that lowers... more Background Bempedoic acid (BA) is an oral first-in-class, ATP-citrate lyase inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) levels in adults with hypercholesterolemia. In the phase 3 CLEAR Harmony study (NCT02666664, n=2230), BA 180 mg for 52 weeks significantly lowered LDL-C at week 12 compared with placebo and was maintained for 52 weeks in hypercholesterolemic patients with atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) on stable, maximally tolerated statins. Purpose To report long-term safety, tolerability, and efficacy of BA from the CLEAR Harmony open-label extension (OLE) study (NCT03067441). Methods After completing the 52-week placebo-controlled CLEAR Harmony study, patients immediately entered the OLE and received BA for 78 weeks, followed by a 4-week washout period; the potential cumulative exposure to BA was 2.5 years. The primary endpoint was long-term safety of BA in the OLE. Results A total of 1462 patients enrolled in the OLE (BA n=970; placebo n=492 from CLEAR Harmony). At OLE baseline, mean (SD) age was 66.9 (8.7) years, 73.9% were male, 96.3% had ASCVD, 3.7% had HeFH with or without ASCVD, and all were receiving statins (93.5% moderate or high intensity). At baseline of CLEAR Harmony, patients had mean (SD) LDL-C of 102.9 (29.9) mg/dL (BA) and 99.0 (24.2) mg/dL (placebo). The majority of OLE patients (86.2%, n=1260) completed 78 weeks of BA treatment. At week 12 and 78 of OLE treatment, respectively, mean LDL-C lowering from CLEAR Harmony baseline was –14.9% and –14.4%. A total of 1143 patients (78.2%) reported a treatment-emergent adverse event (TEAE), and 299 (20.5%) reported a serious TEAE. TEAEs of special interest, determined by the therapeutic area or prior observations in preclinical or early clinical studies, occurred at similar rates as CLEAR Harmony (creatine kinase elevations, 1.8%; gout, 2.6%; hepatic enzyme elevations, 2.0%; hypoglycemia, 1.2%; muscular disorders, 8.5%; neurocognitive disorders, 0.9%; new onset/worsening diabetes mellitus, 5.5%; renal disorders, 2.8%) with biochemical changes that were stable over the course of the study and approached baseline levels after treatment discontinuation. Overall, 114 patients (7.8%) reported a TEAE leading to discontinuation of BA (most common: myalgia [0.6%], muscle spasm [0.5%]). Conclusion Durable lipid lowering was observed through 78 weeks of BA treatment and patient adherence to BA therapy was high (86.2%). Overall safety during the OLE was similar to results reported in the 52-week-long CLEAR Harmony study and the overall BA phase 3 clinical program, with no new safety findings. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Esperion Therapeutics, Inc., funded the research for this study and provided writing support for this abstract. Medical writing assistance was provided by Agnella Izzo Matic, PhD, CMPP, and Kelly M Cameron, PhD, CMPP, of JB Ashtin.
This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evi... more This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosc...
AimTo evaluate the effect of bempedoic acid on glycaemic and lipid variables in patients with hyp... more AimTo evaluate the effect of bempedoic acid on glycaemic and lipid variables in patients with hypercholesterolaemia.MethodsA patient‐level pooled analysis of four phase 3, randomized, double‐blind, placebo‐controlled trials evaluated changes in glycaemia, change from baseline in LDL‐C, and adverse events. Patients (N = 3621) on maximally tolerated statins were randomized 2:1 to oral bempedoic acid 180 mg or placebo once daily for 12 to 52 weeks with the results analysed by baseline glycaemic status (diabetes, prediabetes, or normoglycaemia).ResultsThe annual rate of new‐onset diabetes for bempedoic acid versus placebo in patients with normoglycaemia at baseline (n = 618) was 0.3% versus 0.8%, and for patients with prediabetes at baseline (n = 1868) it was 4.7% versus 5.9%. In patients with diabetes or prediabetes, bempedoic acid significantly (P < .0001) reduced HbA1c by −0.12% and −0.06%, respectively, and did not worsen fasting glucose versus placebo. Bempedoic acid significant...
Introduction: Some patients cannot tolerate statins mainly because of statin-associated muscle sy... more Introduction: Some patients cannot tolerate statins mainly because of statin-associated muscle symptoms (SAMS). Bempedoic acid (BA) is a prodrug activated in the liver and not in skeletal muscle. B...
Despite consensus that excessive circulating concentrations of apoB‐lipoproteins is a key driver ... more Despite consensus that excessive circulating concentrations of apoB‐lipoproteins is a key driver for the atherosclerotic process and that treatments that low‐density lipoprotein cholesterol lowering by up‐regulation of low‐density lipoprotein cholesterol receptor expression reduces that risk, divergent viewpoints on interpretation of study data have resulted in substantial differences in European and American lipid guideline recommendations. This article explores those differences and highlights the importance of understanding guideline‐based lipid management to improve patient care and reduce the risk of clinical atherosclerotic cardiovascular disease.
Many patients do not achieve optimal low-density lipoprotein cholesterol (LDL-C) levels with stat... more 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 c...
Background/Introduction Bempedoic acid (BA), an oral, first-in-class, ATP-citrate lyase inhibitor... more Background/Introduction Bempedoic acid (BA), an oral, first-in-class, ATP-citrate lyase inhibitor, lowers low-density lipoprotein cholesterol (LDL-C) in patients who do not achieve sufficient lipid lowering with guideline-recommended first-line therapies. Purpose We evaluated the safety profile of BA in phase 3 trials. Methods Data were pooled from 4 randomised, double-blind, placebo-controlled studies that enrolled patients with hyperlipidaemia who were receiving stable lipid-lowering therapy (LLT; maximally tolerated statins +/− nonstatin therapies) and required additional LDL-C lowering. Patients were randomised (2:1) to BA 180 mg or placebo daily for 12 to 52 weeks. Results Median exposure for 3621 patients (2424 BA, 1197 placebo) was 363 days. Background LLT included a statin +/− other LLT (83.8%), nonstatin LLT alone (9.4%), or none (6.8%). Adverse event (AE) and serious AE rates were similar between groups (Table). The most common AEs in the BA and placebo groups were nasopha...
Background Bempedoic acid (BA) is an oral first-in-class, ATP-citrate lyase inhibitor that lowers... more Background Bempedoic acid (BA) is an oral first-in-class, ATP-citrate lyase inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) levels in adults with hypercholesterolemia. In the phase 3 CLEAR Harmony study (NCT02666664, n=2230), BA 180 mg for 52 weeks significantly lowered LDL-C at week 12 compared with placebo and was maintained for 52 weeks in hypercholesterolemic patients with atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) on stable, maximally tolerated statins. Purpose To report long-term safety, tolerability, and efficacy of BA from the CLEAR Harmony open-label extension (OLE) study (NCT03067441). Methods After completing the 52-week placebo-controlled CLEAR Harmony study, patients immediately entered the OLE and received BA for 78 weeks, followed by a 4-week washout period; the potential cumulative exposure to BA was 2.5 years. The primary endpoint was long-term safety of BA in the OLE. Results A total of 1462 patients enrolled in the OLE (BA n=970; placebo n=492 from CLEAR Harmony). At OLE baseline, mean (SD) age was 66.9 (8.7) years, 73.9% were male, 96.3% had ASCVD, 3.7% had HeFH with or without ASCVD, and all were receiving statins (93.5% moderate or high intensity). At baseline of CLEAR Harmony, patients had mean (SD) LDL-C of 102.9 (29.9) mg/dL (BA) and 99.0 (24.2) mg/dL (placebo). The majority of OLE patients (86.2%, n=1260) completed 78 weeks of BA treatment. At week 12 and 78 of OLE treatment, respectively, mean LDL-C lowering from CLEAR Harmony baseline was –14.9% and –14.4%. A total of 1143 patients (78.2%) reported a treatment-emergent adverse event (TEAE), and 299 (20.5%) reported a serious TEAE. TEAEs of special interest, determined by the therapeutic area or prior observations in preclinical or early clinical studies, occurred at similar rates as CLEAR Harmony (creatine kinase elevations, 1.8%; gout, 2.6%; hepatic enzyme elevations, 2.0%; hypoglycemia, 1.2%; muscular disorders, 8.5%; neurocognitive disorders, 0.9%; new onset/worsening diabetes mellitus, 5.5%; renal disorders, 2.8%) with biochemical changes that were stable over the course of the study and approached baseline levels after treatment discontinuation. Overall, 114 patients (7.8%) reported a TEAE leading to discontinuation of BA (most common: myalgia [0.6%], muscle spasm [0.5%]). Conclusion Durable lipid lowering was observed through 78 weeks of BA treatment and patient adherence to BA therapy was high (86.2%). Overall safety during the OLE was similar to results reported in the 52-week-long CLEAR Harmony study and the overall BA phase 3 clinical program, with no new safety findings. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Esperion Therapeutics, Inc., funded the research for this study and provided writing support for this abstract. Medical writing assistance was provided by Agnella Izzo Matic, PhD, CMPP, and Kelly M Cameron, PhD, CMPP, of JB Ashtin.
This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evi... more This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosc...
AimTo evaluate the effect of bempedoic acid on glycaemic and lipid variables in patients with hyp... more AimTo evaluate the effect of bempedoic acid on glycaemic and lipid variables in patients with hypercholesterolaemia.MethodsA patient‐level pooled analysis of four phase 3, randomized, double‐blind, placebo‐controlled trials evaluated changes in glycaemia, change from baseline in LDL‐C, and adverse events. Patients (N = 3621) on maximally tolerated statins were randomized 2:1 to oral bempedoic acid 180 mg or placebo once daily for 12 to 52 weeks with the results analysed by baseline glycaemic status (diabetes, prediabetes, or normoglycaemia).ResultsThe annual rate of new‐onset diabetes for bempedoic acid versus placebo in patients with normoglycaemia at baseline (n = 618) was 0.3% versus 0.8%, and for patients with prediabetes at baseline (n = 1868) it was 4.7% versus 5.9%. In patients with diabetes or prediabetes, bempedoic acid significantly (P < .0001) reduced HbA1c by −0.12% and −0.06%, respectively, and did not worsen fasting glucose versus placebo. Bempedoic acid significant...
Introduction: Some patients cannot tolerate statins mainly because of statin-associated muscle sy... more Introduction: Some patients cannot tolerate statins mainly because of statin-associated muscle symptoms (SAMS). Bempedoic acid (BA) is a prodrug activated in the liver and not in skeletal muscle. B...
Despite consensus that excessive circulating concentrations of apoB‐lipoproteins is a key driver ... more Despite consensus that excessive circulating concentrations of apoB‐lipoproteins is a key driver for the atherosclerotic process and that treatments that low‐density lipoprotein cholesterol lowering by up‐regulation of low‐density lipoprotein cholesterol receptor expression reduces that risk, divergent viewpoints on interpretation of study data have resulted in substantial differences in European and American lipid guideline recommendations. This article explores those differences and highlights the importance of understanding guideline‐based lipid management to improve patient care and reduce the risk of clinical atherosclerotic cardiovascular disease.
Many patients do not achieve optimal low-density lipoprotein cholesterol (LDL-C) levels with stat... more 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 c...
Background/Introduction Bempedoic acid (BA), an oral, first-in-class, ATP-citrate lyase inhibitor... more Background/Introduction Bempedoic acid (BA), an oral, first-in-class, ATP-citrate lyase inhibitor, lowers low-density lipoprotein cholesterol (LDL-C) in patients who do not achieve sufficient lipid lowering with guideline-recommended first-line therapies. Purpose We evaluated the safety profile of BA in phase 3 trials. Methods Data were pooled from 4 randomised, double-blind, placebo-controlled studies that enrolled patients with hyperlipidaemia who were receiving stable lipid-lowering therapy (LLT; maximally tolerated statins +/− nonstatin therapies) and required additional LDL-C lowering. Patients were randomised (2:1) to BA 180 mg or placebo daily for 12 to 52 weeks. Results Median exposure for 3621 patients (2424 BA, 1197 placebo) was 363 days. Background LLT included a statin +/− other LLT (83.8%), nonstatin LLT alone (9.4%), or none (6.8%). Adverse event (AE) and serious AE rates were similar between groups (Table). The most common AEs in the BA and placebo groups were nasopha...
Uploads
Papers