In higher-risk, statin-intolerant adults with diabetes, bempedoic acid reduced MACE at a median 3 y.

SOURCE CITATION: Ray KK, Nicholls SJ, Li N, et al; CLEAR OUTCOMES Committees and Investigators. Efficacy and safety of bempedoic acid among patients with and without diabetes: prespecified analysis of the CLEAR Outcomes randomised trial. Lancet Diabetes Endocrinol. 2024;12:19-28. 38061370.

Efficacy and safety of bempedoic acid in patients with heterozygous familial hypercholesterolemia: analysis of pooled patient-level data from phase 3 clinical trials.

BACKGROUND: Patients with heterozygous familial hypercholesterolemia (HeFH) often cannot reach guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals despite multidrug therapy. OBJECTIVE: To evaluate the efficacy and safety of bempedoic acid as an add-on therapy for lowering LDL-C in patients with HeFH. METHODS: Pooled data from two 52-week phase 3 clinical trials of patients with atherosclerotic cardiovascular disease and/or HeFH receiving maximally tolerated statin therapy (randomized 2:1 to bempedoic acid or placebo) were analyzed by HeFH status. Endpoints included changes from baseline to week 12 (and up to week 52) in LDL-C and other lipid parameters, achievement of LDL-C goals, and safety. RESULTS: A total of 217 (bempedoic acid, 146; placebo, 71) patients with HeFH and 2,792 (bempedoic acid, 1,864; placebo, 928) without HeFH were included (mean baseline LDL-C, 172.8 mg/dL and 102.6 mg/dL, respectively). Bempedoic acid significantly lowered LDL-C at week 12 vs. placebo regardless of HeFH status (with HeFH, -21.2%; without HeFH, -18.2% [both P<0.0001]). Bempedoic acid significantly reduced other lipid parameters and high-sensitivity C-reactive protein vs. placebo regardless of HeFH status (all P≤0.01). Among patients with HeFH treated with bempedoic acid, 32% and 27% achieved LDL-C <100 mg/dL at weeks 12 and 52, respectively. Overall treatment-emergent adverse event incidence was comparable across all four groups (74.7-77.5%). CONCLUSION: Bempedoic acid significantly lowered LDL-C levels vs. placebo and was generally well tolerated in all patients, with no new safety findings in patients with HeFH, despite more intensive lipid-lowering therapy in patients with vs. without HeFH.

Safety and efficacy of bempedoic acid among patients with statin intolerance and those without: A meta-analysis and a systematic randomized controlled trial review.

OBJECTIVE: Bempedoic acid, an innovative oral medication, has garnered significant interest in recent times due to its potential as a therapeutic intervention for hypercholesterolemia. Nonetheless, the outcomes of the initial investigations might have been more definitive and coherent. Our objective was to perform a quantitative meta-analysis in order to evaluate bempedoic acid's safety and effectiveness. METHODS: A search was conducted on ClinicalTrials.gov, and PubMed from the time of inception until September 28, 2023. Randomized controlled trials comparing the safety and efficacy of bempedoic acid among patients with statin intolerance and those without were included in our analysis. The trial outcomes were summarized using a random effects model and were provided as mean differences or odds ratios (ORs) with a confidence interval of 95%. Additionally, trial heterogeneity and the possibility of bias were evaluated and investigated. RESULTS: Bempedoic acid treatment reduced low-density lipoprotein cholesterol levels more than placebo (mean difference -2.97%, 95% CI -5.89% to -0.05%), according to a pooled analysis of 16 eligible trials. The risk of death (OR 1.18, 95% CI 0.70 to 1.98) and muscle-associated occurrences (OR 1.00, 95% CI 0.77 to 1.31) was not impacted by bempedoic acid. In contrast, discontinuation of treatment was more frequently caused by adverse events in the bempedoic acid group (OR 1.13, 95% CI 1.01 to 1.27). CONCLUSIONS: In patients with statin intolerance as well as those without, bempedoic acid is a safe and efficacious lipid-lowering agent, according to findings from randomized controlled trials.

Safety of bempedoic acid in patients at high cardiovascular risk and with statin intolerance.

BACKGROUND: Bempedoic acid is an oral adenosine triphosphate citrate lyase (ACL) inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) blood levels. The Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes study demonstrated that bempedoic acid reduced cardiovascular (CV) risk in patients at high risk for CV events who were unwilling or unable to take guideline-recommended doses of statins. OBJECTIVE: To describe detailed safety information from CLEAR Outcomes, including events in the United States (US) prescribing information based on previous phase 3 hyperlipidemia studies. METHODS: CLEAR Outcomes was a double-blind trial conducted in 13,970 patients randomized to oral bempedoic acid 180 mg daily or placebo and followed for a median of 3.4 years. RESULTS: In patients who received at least one dose (7,001 bempedoic acid, 6,964 placebo), treatment emergent adverse events (AE) occurred in 86.3 % and 85 % of patients, respectively. COVID-19 was the most frequently reported AE in both groups. Changes in serum creatinine, blood urea nitrogen, hemoglobin, aminotransaminases, and uric acid were consistent with the known safety profile of bempedoic acid. Gout or gouty arthritis occurred in 3.2 % of bempedoic acid and 2.2 % of placebo patients. AE associated with tendinopathies, including tendon rupture, occurred in 2 % of patients in both treatment groups. Cholelithiasis occurred in 2.2 % of bempedoic acid and 1.2 % of placebo patients; AE related to gallbladder disease were similar between treatment groups. CONCLUSIONS: Bempedoic acid was well-tolerated compared with placebo. Safety data from the long-term CLEAR Outcomes study reinforce the positive benefit-risk profile of bempedoic acid.

Bempedoic acid and cardiovascular outcomes.

Overview of: Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med 2023;388:1353-64.

Efficacy and safety of bempedoic acid lipid-lowering therapy: a systematic review and meta-analysis of randomized controlled trials.

AIM: This systematic review and meta-analysis was conducted to synthesize the efficacy and safety of bempedoic acid in patients requiring lipid-lowering therapy. METHODS: PubMed, Embase, and Scopus databases were searched for randomized controlled trials from inception till June 2023. The primary outcome was major adverse cardiovascular events (MACE), and secondary outcomes were all-cause mortality, serum lipid profile, and adverse events between bempedoic acid and comparators. ROB2 was used for risk of bias assessment. We pooled mean differences or relative risks (RR) along with 95% confidence intervals (random-effects model). RESULTS: Five-hundred and thirty-one studies were screened and 17 (n = 21,131) were included for review. There was a significant reduction in the risk of MACE [RR, 0.88 (95% CI: 0.77 to 0.99), p = 0.03)] and all-cause mortality [RR, 0.90 (95% CI: 0.82 to 0.98), p = 0.02] following bempedoic acid treatment. Treatment with bempedoic acid led to a significant reduction in the mean serum total cholesterol [- 34.41 mg/dl (95% CI: - 42.43 to - 26.39), p < 0.001], low-density lipoprotein cholesterol (LDL-C) [- 33.91 mg/dl (95% CI: - 39.66 to - 28.17), p < 0.001], as well as high-density lipoprotein cholesterol (HDL-C) [- 2.40 mg/dl (95% CI: - 3.09 to - 1.71), p < 0.001] levels. However, there was a significant increase in the risk of hyperuricemia [RR, 2.05 (95% CI: 1.81 to 2.33), p < 0.001] following bempedoic acid treatment. The number needed to harm was large for all safety outcomes. The GRADE of evidence was moderate for all outcomes. CONCLUSION: Bempedoic acid reduces the risk of MACE and all-cause mortality, lowers serum total cholesterol and LDL-C levels, and has a favorable safety profile. Trial registration ClinicalTrial.gov Identifier: CRD42023412837.

Evaluation of the efficacy and safety of bempedoic acid in women and men: Pooled analyses from phase 3 trials.

BACKGROUND AND AIMS: Sex-specific differences in the response to lipid-lowering therapies have been reported. Here, we assessed the effect of bempedoic acid in women and men using pooled, patient-level data from four phase 3 clinical trials of bempedoic acid. METHODS: Patients were grouped into two pools: 1) atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) "on statins" and 2) "low-dose or no statin". Percent changes from baseline to at least week 12 in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B (Apo B), and high-sensitivity C-reactive protein (hsCRP), as well as safety, were analyzed by statin pool and sex. RESULTS: Overall, 3623 patients were included (bempedoic acid, 2425; placebo, 1198). Significant reductions in lipid parameters and hsCRP were observed with bempedoic acid vs. placebo in both sexes in the ASCVD and/or HeFH on statins (n = 3009) and the low-dose or no statin (n = 614) pools (p ≤ 0.002). Compared with men, women had significantly greater placebo-corrected reductions in LDL-C (-21.2% vs. -17.4%; p = 0.044), non-HDL-C (-17.3% vs. -12.1%; p = 0.003), TC (-13.8% vs. -10.5%; p = 0.012), and Apo B (-16.0% vs. -11.3%; p = 0.004) in the ASCVD and/or HeFH on statins pool. Women had similar reductions to men in lipid parameters in the low-dose or no statin pool and hsCRP in both pools. The safety of bempedoic acid was comparable between sexes. CONCLUSIONS: In this pooled analysis, women experienced significant improvements in levels of LDL-C and other lipid parameters with bempedoic acid.

In statin-intolerant adults with, or at risk for, CV disease, bempedoic acid reduced MACE at a median 41 mo.

SOURCE CITATION: Nissen SE, Lincoff MA, Brennan D, et al; CLEAR Outcomes Investigators. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023;388:1353-1364. 36876740.

Bempedoic Acid: A Contemporary Review of Its Pharmacology, Efficacy, and Safety Profile, Including Recent Data from the CLEAR Outcomes Clinical Trial.

PURPOSE OF REVIEW: To provide an updated review of bempedoic acid's clinical application in lowering LDL-C in the setting of statin intolerance and the recent findings in the CLEAR Outcomes trial as well as summarize and synthesize the current state of knowledge regarding bempedoic acid while providing an in-depth analysis of the drug's pharmacological properties, mechanism of action, clinical trials, safety, and efficacy. RECENT FINDINGS: The CLEAR Outcomes trial has provided evidence to support bempedoic acid as a viable alternative to statins for the primary and secondary prevention of cardiovascular disease. Bempedoic acid is a promising treatment option for patients with hypercholesterolemia who are unable to tolerate statin therapy or require additional LDL-C reduction in the treatment of cardiovascular disease, with the newest lipid-lowering cardiovascular outcomes trials expanding on their generalizability particularly in the inclusion of women.

Efficacy and safety of bempedoic acid in patients with and without metabolic syndrome: Pooled analysis of data from four phase 3 clinical trials.

BACKGROUND AND AIMS: Bempedoic acid significantly lowers low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia but its effects in patients with metabolic syndrome (MetS) have not been well characterized. We sought to determine the efficacy and safety of bempedoic acid in patients with hypercholesterolemia by baseline MetS status. METHODS: This study used pooled data from four phase 3 studies. Using modified International Atherosclerosis Society guidelines, patients were grouped into two pools: those with and those without MetS. Patients with diabetes were excluded. Endpoints assessed change from baseline to week 12 in lipid and glycemic parameters and high-sensitivity C-reactive protein (hsCRP), and safety. RESULTS: The study included 936 patients with MetS (bempedoic acid, 648; placebo, 288) and 1573 without MetS (bempedoic acid, 1037; placebo, 536). Significant placebo-corrected reductions in LDL-C were observed with bempedoic acid (p < 0.0001), with a slightly larger decrease in patients with vs. without MetS (-22.3% vs. -18.4%; interaction p = 0.0472). Compared with placebo, bempedoic acid significantly (p < 0.0001) lowered total cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, and hsCRP, with a similar magnitude of benefit observed between MetS categories. Triglycerides increased with bempedoic acid but only to a lesser extent than with placebo in patients without MetS (placebo-corrected difference, -4.4%; p = 0.02). Only patients with MetS experienced decreases in glycated hemoglobin (-0.07%; p < 0.0001) and fasting plasma glucose (-2.4 mg/dL; p = 0.002). Safety was comparable between MetS categories and treatment groups. CONCLUSIONS: These data suggest that bempedoic acid is a suitable therapy for patients with and without MetS who require additional lipid lowering.

A pilot study of vidofludimus calcium for treatment of primary sclerosing cholangitis.

The purpose of this pilot study was to explore the efficacy, safety, and tolerability of vidofludimus calcium (VC) in the treatment of primary sclerosing cholangitis (PSC). This was a single-arm open-label pilot study with a cohort of 18 patients with PSC. Study patients received VC for a period of 6 months. The study was undertaken at two sites, Mayo Clinic, Rochester, MN, and Mayo Clinic, Phoenix, AZ. The primary endpoint of the study was improvement of serum alkaline phosphatase (ALP) at the end of the study. Secondary endpoints included assessment of other liver biomarkers (bilirubin, alanine aminotransferase, and aspartate aminotransferase). Of 18 patients enrolled, 11 completed the 6 months of study treatment. Patients who completed treatment versus those who did not were similar other than a significantly higher direct bilirubin at baseline in the group that completed treatment (mean ± SD, 0.4 ± 0.3 versus 0.1 ± 0.1, p = 0.04). By intent to treat analysis, the primary outcome was met in 16.7% (3/18) of patients. By per-protocol analysis, including only patients who completed treatment, normalization of ALP occurred in 27.7% (3/11) at week 24 (95% confidence interval, 6.0% to 61.0%). VC was well tolerated with no drug-related serious adverse events. Conclusion: This proof of concept study provides support for further exploration of VC in patients with PSC.

Clinical efficacy and safety outcomes of bempedoic acid for LDL-C lowering therapy in patients at high cardiovascular risk: a systematic review and meta-analysis.

OBJECTIVES: Bempedoic acid (BA) is a novel oral low-density lipoprotein cholesterol lowering drug. This systematic review and meta-analysis aims to assess efficacy and safety for clinical outcomes in high cardiovascular (CV) risk patients. DATA SOURCES: MEDLINE, Cochrane Central Register of Controlled Trials, Google Scholar, Embase, ClinicalTrials.gov, Clinical Trial Results and the American College of Cardiology web site were searched. STUDY SELECTION: Randomised controlled trials (RCTs) of BA versus placebo in high CV risk patients reporting clinical outcomes were included. MAIN OUTCOMES AND MEASURES: Primary efficacy outcomes were major adverse cardiovascular events (MACE), all-cause mortality, CV mortality and non-fatal myocardial infarction (MI). Safety outcomes included new onset or worsening of diabetes mellitus (DM), muscular disorders, gout and worsening of renal function. RESULTS: Six RCTs with a total of 3956 patients and follow-ups of four to 52 weeks were identified. Heterogeneity mainly derived from differing follow-up duration and baseline CV risk. No difference in MACE (OR 0.84; 95% CI 0.61 to 1.15), all-cause mortality (OR 2.37; CI 0.80 to 6.99) and CV mortality (OR 1.66; CI 0.45 to 6.04) for BA versus placebo was observed. BA showed beneficial trends for non-fatal MI (OR 0.57; CI 0.32 to 1.00) and was associated with a lower risk of new-onset or worsening of DM (OR 0.68; CI 0.49 to 0.94), but higher risk of gout (OR 3.29; CI 1.28 to 8.46) and a trend for muscular disorders (OR 2.60; CI 1.15 to 5.91) and worsening of renal function (OR 4.24; CI 0.98 to 18.39). CONCLUSION: BA in high CV risk patients showed no significant effects on major CV outcomes in short-term follow-up. Unfavourable effects on muscular disorders, renal function and gout sound a note of caution. Hence, further studies with longer term follow-up in carefully selected populations are needed to clarify the risk/benefit ratio of this novel therapy.

Real-world utilization of bempedoic acid in an academic preventive cardiology practice.

BACKGROUND: Lipid management for prevention and treatment of cardiovascular disease remains insufficient for many with currently available therapies. OBJECTIVE: Evaluate real-world use of bempedoic acid. METHODS: Retrospective study of patients in our Center for Preventive Cardiology who were prescribed bempedoic acid between February 2020 and July 2021. Patients were managed according to clinical standards of care, with lipid assessments at months ≤3, 6, and 12 post-bempedoic acid initiation. RESULTS: Seventy-three patients were prescribed bempedoic acid, with 64 initiating therapy. The majority had atherosclerosis (89%), familial hypercholesterolemia (64%), and statin intolerance (74%), with baseline low-density lipoprotein cholesterol (LDL-C) 120 mg/dL. Prior authorization requests and appeals of denials were required in 90% and 19% of cases, respectively. Cost-mitigating strategies reduced median monthly drug costs from $432 pre-insurance approval to $80 post-insurance approval, to $10 after financial assistance intervention. Bempedoic acid reduced LDL-C by -36.7%, -31%, and -20.3% at ≤3, 6, and 12, respectively, with >20% achieving LDL-C <70 mg/dL. There was substantial inter-individual heterogeneity in LDL-C lowering. We observed high rates of drug discontinuation (35.9%), mostly related to treatment-emergent adverse events (TEAEs) (32.8%), primarily musculoskeletal complaints. Use of reduced dose bempedoic acid (<180 mg) was associated similar LDL-C lowering but TEAE and drug discontinuation were still common. CONCLUSIONS: Real-world use of bempedoic acid was limited by insurance and cost barriers requiring substantial post-prescription interventions. In patients at heightened risk for atherosclerotic events and statin intolerance, bempedoic acid was associated with clinically meaningful LDL-C lowering, but high rates of TEAEs and drug discontinuations.

Pharmacokinetics of bempedoic acid in patients with renal impairment.

Bempedoic acid is an ATP citrate lyase inhibitor approved for the treatment of hypercholesterolemia. The objective of this phase I study was to assess the pharmacokinetics (PKs) and safety of bempedoic acid in 24 subjects with normal renal function or mild, moderate, or severe renal impairment. All subjects received a single oral bempedoic acid 180-mg dose and PK parameters were monitored for up to 23 days. Resulting estimates of area under the concentration-time curve exposure following bempedoic acid treatment were 1.5-fold, 2.2-fold, and 2.2-fold higher in subjects with mild, moderate, or severe renal impairment, respectively, compared with subjects with normal renal function. With decreases in renal function, plasma free fraction was increased up to 20.1%, whereas total and unbound clearances were decreased by 55.2% and 62.6%, respectively, in subjects with severe renal impairment relative to those with normal renal function. These observed decreases in total and unbound oral clearance in subjects with decreased renal function are not explained by the increases in free fraction and might therefore also be attributable to changes in bioavailability or intrinsic clearance. Bempedoic acid was generally well-tolerated and the incidence and type of adverse events were not affected by the degree of renal impairment. In conclusion, bempedoic acid exposures in subjects with renal impairment were increased up to approximately two-fold with no safety signals identified, consistent with findings in phase III patients with mild or moderate renal impairment. No dose adjustments are necessary for patients with mild or moderate renal impairment.

Evaluating pharmacokinetics of bempedoic acid in the treatment of hypercholesterolemia.

Introduction: Bempedoic acid is a first-in-class low-density lipoprotein cholesterol (LDL-C) lowering agent which offers an important opportunity for further LDL-C lowering in statin-intolerant patients or in patients requiring further LDL-C reduction despite maximally tolerated statin therapy.Areas covered: In this review, we examined the pharmacodynamics, pharmacokinetics, clinical efficacy, and safety of bempedoic acid, based on randomized clinical phase III clinical studies and their meta-analyses.Expert opinion: Unlike statins, bempedoic acid is administered as a prodrug and is converted to active form by a liver-specific enzyme. For the liver-specific mechanism of action, bempedoic acid has the potential to reduce the risk of muscle-related adverse events which can limit the utilization and effectiveness of statin therapy.

Clinical development of bempedoic acid: phase 2 and phase 3 clinical trials. / Desarrollo clínico de ácido bempedoico: estudios fase 2 y fase 3.

We review all the phase II and III studies carried out with bempedoic acid at the dose of 180mg, alone or in combination with different lipid-lowering drugs and in different subgroups of patients that unequivocally show the efficacy and safety of the drug. We point out some of the potential advantages of its use in clinical practice in patients with statin intolerance and the efficacy in reducing LDL-c when combined with statins, and with statins and ezetimibe, as well as in reducing inflammation markers pending the results of the CV Clear Outcomes trial that will end in 2022.

Bempedoic Acid for Heterozygous Familial Hypercholesterolemia: From Bench to Bedside.

Bempedoic acid is a first-in-class, oral, inhibitor of cholesterol biosynthesis that is approved for use in patients with atherosclerotic cardiovascular disease (ASCVD) and for primary prevention in individuals with heterozygous familial hypercholesterolemia (HeFH) by the United States Food and Drug Administration. Pooled data from the phase III clinical trials, CLEAR Harmony and CLEAR Wisdom, have demonstrated the safety and efficacy of bempedoic acid with regard to lowering of low-density lipoprotein cholesterol (LDL-C) in patients with HeFH as an adjunct or alternative to currently existing lipid-lowering therapies. CLEAR Outcomes is a cardiovascular outcomes trial that is currently underway that will provide additional insight as to where bempedoic acid will fit into treatment regimens among the non-statin lipid-lowering therapy options. Patients who might particularly benefit from bempedoic acid are those with HeFH and those unable to take adequate doses of statins or take any statin therapy altogether who need additional LDL-C lowering. In this review, we will discuss the profile of bempedoic acid from its design, development, and its place in therapy for the management of LDL-C for the purposes of ASCVD prevention.