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Bempedoic acid added to PCSK9 inhibitor therapy lowered LDL-C by 30.3% vs placebo.
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Bempedoic acid significantly lowered Apo B, non-HDL-C, total cholesterol, and hsCRP.
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The safety profile of bempedoic acid in combination with a PCSK9i was generally comparable to placebo.
Background
Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is) lower low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia. However, some patients receiving PCSK9i therapy might require additional lipid-lowering therapy (LLT) to reach LDL-C goals. Bempedoic acid is an oral, once-daily, ATP-citrate lyase inhibitor that significantly lowers LDL-C in patients with hypercholesterolemia when given alone or as add-on therapy to statins and/or ezetimibe.
Objective
Assess safety and efficacy of bempedoic acid added to PCSK9i (evolocumab) background therapy in patients with hypercholesterolemia.
Methods
This phase 2, randomized, double-blind, placebo-controlled study was conducted in three phases: 1.5-month screening/washout period including discontinuation of all LLTs, a 3-month period wherein patients initiated background PCSK9i therapy, and a 2-month treatment period in which patients were randomized 1:1 to receive bempedoic acid 180 mg or placebo once daily while continuing PCSK9i therapy.
Results
Of 59 patients randomized, 57 completed the study. Mean baseline LDL-C after 3 months of PCSK9i background therapy was 103.1 ± ± 30.4 mg/dL. Bempedoic acid added to background PCSK9i therapy significantly lowered LDL-C by 30.3% (P < .001) vs placebo. Compared with placebo, bempedoic acid significantly lowered apolipoprotein B, non–high-density lipoprotein cholesterol, and total cholesterol (nominal P < .001 for all), and high-sensitivity C-reactive protein (P = .029). When added to background PCSK9i therapy, the safety profile of bempedoic acid was comparable to that observed for placebo.
Conclusions
When added to a background of PCSK9i therapy, bempedoic acid significantly lowered LDL-C levels with a safety profile comparable to placebo in patients with hypercholesterolemia.
Although often used for the treatment of hypertension and diabetes, combination pharmacotherapy for patients with elevated low-density lipoprotein cholesterol (LDL-C) levels remains underutilized in both the United States and Europe.
Underuse of combination pharmacotherapy for management of dyslipidemia versus diabetes and hypertension among patients with atherosclerotic cardiovascular disease (ASCVD): insights from the Getting to an Improved Understanding of Low-density Lipiprotein-cholesterol and Dyslipidemia Management (GOULD) registry.
Statins are considered a first-line therapy for lowering LDL-C. However, many patients cannot take statins and fewer than half of eligible patients receive recommended high-intensity statin therapy.
Getting to an ImprOved understanding of low-density lipoprotein-cholesterol and dyslipidemia management (GOULD): methods and baseline data of a registry of high cardiovascular risk patients in the United States.
Therefore, combination therapies, with and without, statin therapy need to be investigated.
Bempedoic acid is an oral, once-daily, first-in-class adenosine triphosphate (ATP)–citrate lyase inhibitor that significantly lowers LDL-C in patients with hypercholesterolemia when given alone or as add-on therapy to statins and/or ezetimibe.
Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study.
Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy.
Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR wisdom randomized clinical trial.
AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism.
Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance.
Bempedoic acid is indicated in the United States as an adjunct to diet and maximally tolerated statin therapy to treat adults with heterozygous familial hypercholesterolemia (FH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL-C. Bempedoic acid is also approved in the European Union as an adjunct to diet for adults with primary hypercholesterolemia or mixed dyslipidemia in combination with a statin in patients unable to reach LDL-C goals with maximally tolerated statin, and alone or in combination with other lipid-lowering therapies in patients who are unable to take a statin. Bempedoic acid is a prodrug that is converted to its active form (bempedoyl-CoA) in the liver by very-long-chain acyl-CoA synthetase 1, which is mainly present in the liver and is not detectible in skeletal muscle.
Activated bempedoic acid inhibits ATP-citrate lyase, an enzyme that acts two steps upstream of 3‑hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase (the target of statins) in the cholesterol synthesis pathway.
Inhibition of cholesterol synthesis by bempedoyl-CoA triggers upregulation and expression of hepatic LDL receptors (LDLRs), increasing uptake and clearance of LDL and lowering plasma LDL-C levels.
Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance.
In phase 3 studies, bempedoic acid provides significant additional LDL-C lowering (range, 17.4% to 28.5%) compared with placebo when added to background treatment with maximally tolerated statin with or without other lipid-lowering therapies (LLTs) in patients with hypercholesterolemia (bempedoic acid vs placebo, P < .001).
Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study.
Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR wisdom randomized clinical trial.
Bempedoic acid and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is) both upregulate levels of hepatic LDLRs, but by two different mechanisms—one increasing expression and the other inhibiting degradation, respectively. In addition, the inhibition of cholesterol synthesis by statins increases expression of PCSK9 through effects on sterol regulatory elements.
When bempedoic acid is used in combination with a PCSK9i, the inhibition of PCSK9 may enhance the effects of bempedoic acid on upregulation of LDLR. It is hypothesized that treatment with these two medications with complementary mechanisms may lead to further lowering of LDL-C levels. This phase 2 study (NCT03193047) in patients with elevated LDL-C was designed to characterize safety and efficacy of bempedoic acid when added to PCSK9i background therapy.
Methods
Study population
The study population included men and nonlactating, nonpregnant women aged 18 years and older who had fasting LDL-C levels ≥160 mg/dL prior to initiating PCSK9i therapy and after washout of other lipid-regulating drugs and supplements during the run-in period and LDL-C levels ≥70 mg/dL while they received stable PCSK9i therapy prior to randomization. Women were required to be either postmenopausal, surgically sterile, or use two acceptable methods of birth control, if they were of childbearing potential. Patients were excluded from the study if they had homozygous or heterozygous FH, fasting triglyceride levels ≥500 mg/dL at month –3, a history of type 1 or type 2 diabetes, or laboratory evidence of diabetes at month –4.5. Patients were also excluded if they had known cardiovascular disease (CVD), peripheral arterial disease or cerebrovascular disease, uncontrolled hypertension, uncontrolled hypothyroidism, renal dysfunction (estimated glomerular filtration rate <30 mL/min/1.73 m2), glomerular nephropathy, liver disease or dysfunction, history of malignancy (except nonmetastatic basal or squamous cell carcinoma of the skin and cervical carcinoma in situ), history of hematologic or coagulation disorders or a hemoglobin level <10 g/dL at month –4.5, gastrointestinal conditions or procedures that could affect drug absorption, unexplained creatine kinase levels >3 times the upper limit of normal (ULN), or a history of drug or alcohol abuse in the last 2 years. Patients were prohibited from using any experimental or investigational drugs within 30 days or five half-lives (whichever was longer), a cholesteryl ester transfer protein inhibitor in the last 12 months prior to screening, a PCSK9i (within the past 16 weeks at screening), or prohibited therapies/supplements (including mipomersen, lomitapide, apheresis therapy, products containing red yeast rice, and/or LLTs or supplements). All patients provided written informed consent.
Study design and treatment
This was a phase 2, randomized, double-blind, placebo-controlled, parallel-group study conducted at 16 sites in the United States from April 7, 2017, to January 29, 2018. The study consisted of three phases (Fig. 1): (1) a 1.5-month screening/washout period during which all lipid-modifying drugs, including statins and nutritional supplements, were discontinued; (2) a 3-month lipid stabilization period wherein patients initiated background therapy with subcutaneous evolocumab 420 mg/3.5 mL administered via the Pushtronex system (Amgen, Thousand Oaks, CA, USA) once monthly; and (3) a 2-month, double-blind treatment period in which patients were randomized 1:1 to treatment with bempedoic acid 180 mg or placebo once daily (same time each day with or without food) added to background PCSK9i therapy. There were seven planned study visits: one at month –4.5 (screening); three screening, once-monthly visits during the PCSK9i run-in period where PCSK9i was administered at months –3, –2, and –1; randomization visit and initiation of treatment with bempedoic acid or placebo and continuing PCSK9i administration at month 0; visit at month 1 (with continued PCSK9i administration) and visit at month 2 (end of study).
The protocol and informed consent documents were reviewed and approved by the institutional review board at each site prior to initiation of the study. This trial was designed, conducted, and monitored in accord with procedures that comply with the ethical principles of Good Clinical Practice as required by the major regulatory authorities, and in accord with the Declaration of Helsinki.
Assessments and endpoints
Samples were collected and analyzed by a central clinical laboratory (ICON Laboratory Services, Inc., Farmingdale, NY, USA) for LDL-C and lipid and cardiometabolic biomarkers, including high-density lipoprotein cholesterol (HDL-C), non–high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B (Apo B), lipoprotein (a) (Lp[a]), triglycerides (TG), and high-sensitivity C-reactive protein (hsCRP). Blood draws for lipid analysis were collected at each visit after a minimum 10-hour fast (water was allowed). Blood samples to determine clinical safety were collected at each study visit.
Efficacy and exploratory assessments
The primary endpoint was the percent change from baseline in LDL-C at month 2 during the double-blind period. Secondary efficacy endpoints for the double-blind period included percent change from baseline to month 1 in LDL-C levels, and percent change from baseline to month 2 in Apo B, non-HDL-C, TC, and hsCRP levels. The exploratory endpoints were the percent change from baseline to month 2 in TG, Lp(a), and HDL-C levels, and plasma concentrations of bempedoic acid at select time points.
Safety assessment
Safety and tolerability of bempedoic acid were assessed by adverse events (AEs) and clinical laboratory values. All AEs were coded by system organ class and preferred term using the Medical Dictionary for Regulatory Affairs, version 20.1. Treatment-emergent AEs (TEAEs) were defined as AEs that began or worsened after administration of the first dose of the investigational medical product (IMP). Adverse events of special interest included metabolic acidosis (identified by clinical laboratory evaluation), hypoglycemia, new-onset or worsening diabetes mellitus and/or hyperglycemia, musculoskeletal events (by reports of AEs and evaluations of creatine kinase levels), hepatic disorders, renal events, and neurocognitive/neurologic events. All reports of AEs were collected from the time of informed consent until 30 days after the last dose of the IMP.
Statistical analysis
A sample size of 52 randomized patients (26 assigned to bempedoic acid and 26 assigned to placebo) was planned in order to provide 90% power to detect a difference of 15% in the percent change from baseline to month 2 in LDL-C levels between the two treatment groups during the double-blind period. This calculation was based on a two-sided t test at the 5% level of significance (α = 0.05), a common standard deviation of 15%, and a dropout rate of 10%.
The safety population included all randomized patients who received at least one dose of the IMP. The analysis population was the modified intent-to-treat (mITT) population—all randomized patients who received at least one dose of the IMP and who had a baseline lipid value, at least one postbaseline lipid value, and who took the IMP within 2 days before the lipid measurement and received an evolocumab 420 mg/3.5 mL injection within 30 days (± 3 days) before the lipid measurement.
An analysis of covariance with treatment group as factor and baseline LDL-C as a covariate was performed to compare bempedoic acid with placebo for the primary endpoint using the mITT population. The least square (LS) mean and standard error were calculated for both treatment groups, along with the placebo-corrected LS mean, its 95% CI, and associated P value for primary and secondary endpoints. Statistical testing of the primary and secondary efficacy endpoints was two-sided, and each test was conducted at a nominal 5% level of significance, with no adjustments for multiplicity. Missing data for the primary endpoint were imputed using the last-observation-carried-forward procedure (only postbaseline values were carried forward). All P values for secondary endpoints are considered descriptive only. Analyses using observed data only were also performed for the primary and secondary efficacy endpoints as sensitivity analyses.
Results
Patient disposition and characteristics
Of the 170 patients screened and included in the evolocumab run-in period, 59 patients were randomized (28 to bempedoic acid and 31 to placebo) at 16 sites in the United States. Fifty-seven patients completed the study, all 28 in the bempedoic acid group and 29 in the placebo group (two patients in the placebo group discontinued study treatment [1 patient missed a visit and later discontinued because of physician decision and another patient received only 1 dose before moving out of state]). The mITT population included 27 patients from the bempedoic acid group and 26 patients from the placebo group. Patient demographic characteristics in the safety population (28 receiving bempedoic acid and 30 receiving placebo) were generally comparable between treatment groups (Table 1). A higher percentage of women (62.1% overall) than men (37.9% overall) were included in the safety population, and the percentage of women was higher in the bempedoic acid group (75.0%) than in the placebo group (50.0%). Fifty-eight patients received at least one dose of the IMP and were included in the safety population.
Table 1Baseline demographics and characteristics (safety population).
When added to PCSK9i therapy for 2 months, bempedoic acid treatment resulted in significantly greater lowering of LDL-C levels (–27.5% LS mean change from baseline) compared with placebo (2.8%) (Fig. 2). The difference in LS means between bempedoic acid and placebo at month 2 (ie, primary endpoint, mITT population) was –30.3% (P < .001). The proportion of patients who achieved LDL-C levels <70 mg/dL was greater with bempedoic acid treatment vs placebo (1 month: bempedoic acid, 61.5% vs placebo, 0%; 2 months: bempedoic acid, 40.7% vs placebo, 3.8%). Treatment with bempedoic acid for 2 months also resulted in significantly greater reductions in Apo B (P < .001), non-HDL-C (P < .001), TC (P < .001), and hsCRP (P = .029) levels compared with placebo (Fig. 3). The percent changes from baseline in Lp(a), HDL-C, and TG levels were comparable between treatment groups (Table 2).
Fig. 2Percent change from baseline in LDL-C at month 2, mITT population. LDL-C, low-density lipoprotein cholesterol; mITT, modified intent to treat; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor; Data are least squares means ± SE.
Fig. 3Percent changes from baseline in key secondary endpoints at month 2, mITT population. Apo B, apolipoprotein B; hsCRP, high-sensitivity C-reactive protein; mITT, modified intent to treat; non-HDL-C, non–high-density lipoprotein cholesterol; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor; TC, total cholesterol. Data for Apo B, non-HDL-C, and TC are least squares means ± SE. Data for hsCRP are medians. *P = .029; **P < .001 for the comparison of bempedoic acid and placebo.
Overall, 22 patients (37.9%) experienced an adverse event during the evolocumab run-in period; these events were considered related to the treatment with evolocumab in six patients (10.3%). All adverse events during the run-in period were mild or moderate in intensity. The most common categories of AEs during the run-in period were “infections and infestations” and “musculoskeletal and connective tissue disorders” categories. No patients experienced a serious adverse event during the run-in period.
The addition of bempedoic acid to stable evolocumab therapy was well tolerated, with a safety profile generally comparable with that observed in the PCSK9i plus placebo group (Table 3). Rates of TEAEs were comparable in the bempedoic acid and placebo treatment groups, and TEAEs were generally mild or moderate in intensity. No TEAEs occurred in more than one patient, except for urinary tract infection (one patient in each treatment group). No patients discontinued treatment due to a TEAE. One patient in each treatment group experienced a TEAE considered by the investigator to be related to the IMP: one patient in the bempedoic acid group experienced moderate dyspepsia (administration of bempedoic acid was unchanged due to the event; the event resolved 57 days after onset) and one patient in the placebo group experienced mild ejaculation failure (IMP was interrupted because of the event; the event did not resolve). There was one serious TEAE of influenza, which was considered severe and unrelated to the IMP, that occurred in the bempedoic acid group. There were no deaths in the study. Three patients had TEAEs of special interest, none of which were considered related to IMP by the investigator. Patients treated with bempedoic acid experienced mild elevations in uric acid compared with placebo, with a mean change from baseline at month 1 of 0.40 ± 0.94 mg/dL (bempedoic acid) vs –0.16± 0.60 mg/dL (placebo) and at month 2 of 0.56± 0.77 mg/dL (bempedoic acid) vs –0.03± 0.56 mg/dL (placebo). One patient (3.6%) in the bempedoic acid group experienced mild gout; the patient's urate levels at screening were 7.1 mg/dL and were 11.4 mg/dL at the time of the event. One patient (3.3%) in the placebo group experienced mild muscle spasms and another experienced mild amnesia. There were no treatment-related trends in mean vital signs or changes from baseline, and no patients experienced a meaningful clinical change at physical examination.
Table 3Summary of treatment-emergent adverse events occurring during the double-blind period.
There were no other treatment-related trends in mean chemistry, hematology, coagulation, or urinalysis values or changes from baseline. Shifts to high or low values postbaseline in clinical laboratory evaluations were sporadic and not considered clinically meaningful. No patient had alanine aminotransferase or aspartate aminotransferase values ≥3 × ULN, total bilirubin levels ≥2 × ULN, or creatine kinase levels ≥5 × ULN postbaseline. These were predefined thresholds for laboratory parameters of interest. There were no patients with laboratory abnormalities related to renal function (>1 mg/dL increase from baseline in creatinine levels or <30 mL/min/1.73 m2 estimated glomerular filtration rate).
Discussion
When added to background PCSK9i therapy for 2 months, bempedoic acid 180 mg once daily significantly lowered LDL-C levels by 30.3% compared with placebo (P < .001). Apo B, non-HDL-C, TC, and hsCRP levels were also significantly lowered with bempedoic acid treatment. Bempedoic acid in addition to PCSK9i therapy did not significantly affect Lp(a), HDL-C, and TG levels. The addition of bempedoic acid to a PCSK9i was well tolerated, with a safety profile comparable to that observed in the PCSK9i plus placebo group. Results from previous studies have shown that bempedoic acid is effective when added to statins, ezetimibe, and statins plus ezetimibe.
Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study.
Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy.
Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR wisdom randomized clinical trial.
Findings from this study indicate that bempedoic acid added to PCSK9i is effective and well-tolerated.
Bempedoic acid inhibits cholesterol synthesis in the liver, which leads to increased transcriptional expression of hepatic LDLR, resulting in an increase in LDL-C uptake and a lowering of plasma LDL-C.
Therapy with PCSK9is raises the level of hepatic LDLRs by inhibiting LDLR degradation, which increases uptake of LDL from plasma and lowers LDL-C levels.
The additional LDL-C lowering capability provided by bempedoic acid when added to a PCSK9i demonstrates complementary mechanisms of these two treatments. Bempedoic acid increases the expression of PCSK9 mRNA in primary human hepatocytes.
Although untested, it is reasonable to hypothesize that the complementary lowering of LDL-C with bempedoic acid in combination with a PCSK9i may be due to synergistic effects involving PCSK9 levels between the two treatments.
The inflammatory biomarker hsCRP helps classify CVD risk and independently predicts future vascular events.
Adding bempedoic acid to a PCSK9i significantly lowered hsCRP levels vs placebo by 28.5% (95% CI, −51.5%, −3.9%; P = .029). These results, along with evidence from previous studies, demonstrate that when bempedoic acid is given alone, with a statin and/or with ezetimibe, hsCRP levels are effectively lowered.
Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy.
Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR wisdom randomized clinical trial.
Not all high-risk patients with elevated LDL-C levels treated with a PCSK9i achieve LDL-C levels <70 mg/dL. In two clinical trials with PCSK9is as monotherapy and in combination with statins, between 25% and 33% of patients did not reach the <70 mg/dL threshold.
Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody alirocumab vs placebo in patients with heterozygous familial hypercholesterolemia.
Results from this study demonstrate that bempedoic acid can provide significant additional LDL-C lowering capabilities for patients treated with a background PCSK9i who are still not at their goal for suitable LDL-C levels and are not taking a statin, with significantly more patients achieving LDL-C <70 mg/dL with bempedoic acid treatment than placebo. The combination of bempedoic acid and a PCSK9i in the absence of a statin may be an attractive treatment option for patients who cannot tolerate taking statins because of statin-associated muscle adverse events. This is the first study where a cholesterol-lowering agent has been studied as an add on to PCSK9i therapy. However, PCSK9i has been studied as monotherapy and as an add on to patients taking maximum-dose statin therapy with or without ezetimibe.
Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial.
The efficacy and safety of bempedoic acid among patients receiving background maximally tolerated statin therapy, which could mean no statins, was investigated in four phase 3 studies, two of which were 52 weeks in duration.
Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study.
Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR wisdom randomized clinical trial.
Bempedoic acid was generally well tolerated among the 3621 patients studied. Bempedoic acid was associated with mild increases in blood urea nitrogen, creatinine, and uric acid and decreases in hemoglobin, which were reversible after treatment was stopped.
Patients treated with bempedoic acid had a higher rate of gout than did patients receiving placebo (1.6 per 100 patient-years vs 0.5 per 100 patient-years).
The incidence of gout was greatest among patients who had a history of gout or those who had elevated uric acid levels at baseline. It is possible that a similar incidence of laboratory abnormalities and gout associated with bempedoic acid treatment and more adverse reactions associated with evolocumab would have been observed in our study if it had been of longer duration.
Limitations of the study include the relatively small sample size, the lack of data for long-term treatment (beyond 2 months), the lack of data on groups of special interest (such as patients with FH), and the lack of outcome data on cardiovascular events. Outcomes with bempedoic acid therapy in high-risk, statin-intolerant patients are currently being investigated in the ongoing CLEAR Outcomes trial (NCT02993406).
Rationale and design of the CLEAR-outcomes trial: evaluating the effect of bempedoic acid on cardiovascular events in patients with statin intolerance.
Results from this study demonstrate that bempedoic acid therapy can provide significant additional LDL-C lowering for high-risk patients who are receiving background PCSK9i therapy. In addition to lowering LDL-C, bempedoic acid also significantly lowered Apo B, non-HDL-C, TC, and hsCRP levels. No new safety issues with bempedoic acid were identified with regard to its use with the PCSK9i evolocumab during the 2-month double-blind period or 30 days after the last dose. Bempedoic acid is an effective add-on therapy not only with statins and/or ezetimibe,
Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study.
Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR wisdom randomized clinical trial.
but, as these data demonstrate, also with PCSK9is.
Disclosures
John Rubino reports receiving funding from Abbott, Allergan, Astellas, Biohaven, Guardant Health, Merck, Novo Nordisk, Novavax, Pfizer, Sanofi, and Teva. Lulu Ren Sterling is a former employee of Esperion Therapeutics, Inc., and may hold stock or stock options; she is now with Sterling Bio-science Analytics, Los Gatos, CA, USA. James M. McKenney is an employee of National Clinical Research, Inc., which has received funding for lipid modifying research from Sanofi, Regeneron, Esperion Therapeutics, Inc., Merck, Amgen, Pfizer, and Lilly. Stephanie E. Kelly is a current employee of Esperion Therapeutics, Inc. and may hold stock and/or stock options. Diane E. MacDougall and Narendra D. Lalwani are former employees of Esperion Therapeutics, Inc., and may hold stock and/or stock options.
Data sharing statement
The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedures.
CRediT authorship contribution statement
John Rubino: Conceptualization, Visualization, Data curation, Writing – review & editing, Writing – original draft. Diane E. MacDougall: Conceptualization, Visualization, Formal analysis, Data curation, Writing – review & editing, Writing – original draft. Lulu Ren Sterling: Data curation, Formal analysis, Writing – review & editing, Writing – original draft. Stephanie E. Kelly: Conceptualization, Visualization, Data curation, Writing – review & editing, Writing – original draft. James M. McKenney: Data curation, Writing – review & editing, Writing – original draft. Narendra D. Lalwani: Conceptualization, Methodology, Visualization, Data curation, Writing – review & editing, Writing – original draft.
Acknowledgments
This study was supported by Esperion Therapeutics, Inc., Ann Arbor, Michigan. Medical writing support was provided by James Bergstrom, PhD, and Kelly M Cameron, PhD, CMPP™, of JB Ashtin, who received compensation for contributing to this work.
References
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et al.
Underuse of combination pharmacotherapy for management of dyslipidemia versus diabetes and hypertension among patients with atherosclerotic cardiovascular disease (ASCVD): insights from the Getting to an Improved Understanding of Low-density Lipiprotein-cholesterol and Dyslipidemia Management (GOULD) registry.
Getting to an ImprOved understanding of low-density lipoprotein-cholesterol and dyslipidemia management (GOULD): methods and baseline data of a registry of high cardiovascular risk patients in the United States.
Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study.
Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy.
Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR wisdom randomized clinical trial.
AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism.
Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance.
Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody alirocumab vs placebo in patients with heterozygous familial hypercholesterolemia.
Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial.
Rationale and design of the CLEAR-outcomes trial: evaluating the effect of bempedoic acid on cardiovascular events in patients with statin intolerance.
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