Abstract
Background
Elevated low-density lipoprotein cholesterol (LDL-C) is directly associated with cardiovascular disease, with the risk level determined by the magnitude and duration of exposure. In routine practice, there are limited data on the expected LDL-C lowering with bempedoic acid (BA) alone or in combination with ezetimibe (BA + EZE).
Methods
Patients initiating BA or BA + EZE were identified in the Veradigm Network EHR linked to claims (index). LDL-C levels were evaluated at baseline, 3, 6, and 12 months. To further examine BA and BA + EZE efficacy, patients were stratified by background statin use (12 months pre-index) and by continuous index therapy use (no therapy gap >45 days).
Results
Of the 900 BA and 615 BA + EZE patients identified, median baseline LDL-C was 137 mg/dL and 127 mg/dL, respectively. By 3 months, BA (21%) and BA + EZE (33%, p < 0.0001 for both) were associated with significant reductions in median LDL-C levels. At baseline, only 6.3% of BA and 8.5% of BA + EZE patients had LDL-C <70 mg/dL; by 3 months, this increased to 16.8% and 33.3%. Over 12 months, 18.0% and 27.5% of patients had LDL-C <70 mg/dL. When stratified, the median reductions by 3 months highlighted use of BA and BA + EZE in patients without background statin use (BA: 24.2%; BA + EZE: 36.7%) and with continuous use (BA: 26.1%; BA + EZE: 40.2%).
Conclusions
Patients initiating BA and BA + EZE experienced early and sustained LDL-C improvements. The greatest reductions were in patients with continuous use and patients with no evidence of prior statin use, underscoring the importance of long-term adherence and treating patients not on statin therapy.
Keywords: Bempedoic acid, Non-statin therapies, Lipid-lowering, LDL-C, Real-world evidence
Graphical abstract
Highlights
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A real-world, retrospective study of 1,515 patients newly initiating BA and BA + EZE.
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Median LDL-C >130 mg/dL and 27% had an ASCVD event within 12 months pre-index.
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Initiation of BA was associated with 21% lower LDL-C levels by 3 months.
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Initiation of BA + EZE was associated with 33% lower LDL-C levels by 3 months.
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Goal LDL-C <70 mg/dL and <100 mg/dL thresholds met during 1 year of follow-up.
Glossary
- ASCVD:
atherosclerotic cardiovascular disease
- BA:
bempedoic acid
- BA + EZE:
bempedoic acid plus ezetimibe
- BMI:
body mass index
- CLEAR :
Cholesterol Lowering via Bempedoic Acid (ETC-1002), an ACL-Inhibiting Regimen
- CV:
cardiovascular
- CVD:
cardiovascular disease
- EHR:
electronic health records
- FDA:
Federal Drug Administration
- HeFH:
heterozygous familial hypercholesterolemia
- HIPAA:
Health Insurance Portability and Accountability Act
- IQR:
interquartile range
- LDL-C:
low-density lipoprotein cholesterol
- LLT:
lipid-lowering therapy
- MI:
myocardial infarction
- PCSK9:
proprotein convertase subtilisin/kexin type 9
- US:
United States
1. Introduction
Cardiovascular disease (CVD) is the leading cause of mortality in the United States (US), and is on the rise, with a prevalence of almost 50% in adults ≥20 years of age, or approximately 127.9 million people in 2020 [1]. By 2050, more than 184 million adults (61%) are predicted to have CVD [2]. An extensive body of evidence has consistently established low-density lipoprotein cholesterol (LDL-C) is directly implicated in the development and progression of atherosclerosis and CVD, and the effects on cardiovascular (CV) risk are determined by the magnitude and duration of exposure to elevated LDL-C [3,4]. Reducing LDL-C through proven therapies has been linked with incrementally lower CV risk. As such, timely initiation of LDL-C lowering therapy with a sufficient level-lowering response may provide greater protective benefit.
Statin therapies are considered the first-line lipid-lowering therapy (LLT) for the treatment of elevated LDL-C levels and the prevention of CVD. For patients who have not achieved their therapeutic targets with statins alone, clinical practice guidelines on lipid management by the American College of Cardiology, the American Diabetes Association, and the European Society of Cardiology and European Atherosclerosis Society recommend treatment intensification by increasing statin dosage or with the addition of non-statin LLTs [[5], [6], [7]]. Moreover, for patients who are statin intolerant, guidelines also recommend non-statin LLTs as a treatment alternative to reduce adverse CV risk [5,6]. This subgroup represents a substantial number of patients (as many as 30% who may have some degree of statin intolerance) who are also at an increased risk for CV events [8]. However, despite guideline recommendations, 60% to 70% of patients receiving statin therapy do not meet their LDL-C targets [9,10]. Observational studies have also shown that patients at high risk for CVD often do not have their LLT intensified in clinical practice, despite not achieving goal LDL-C levels [11].
Bempedoic acid (BA) is an oral ATP citrate lyase inhibitor approved to lower LDL-C levels and reduce the risk of major adverse CV events in primary and secondary prevention patients who are unable or unwilling to take recommended statin therapy [12,13]. The LDL-C lowering efficacy of BA and the fixed-dose combination with ezetimibe (BA + EZE) have been established in clinical trials. In adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic CVD (ASCVD) who were on maximally tolerated statin therapy, BA provided additional LDL-C reduction of 15% to 17% from baseline to week 12 [14,15]. The fixed-dose combination demonstrated a mean reduction of 36% from baseline in patients with HeFH, CVD or risk factors for CVD on maximally tolerated statin therapy [16]. In the Cholesterol Lowering via Bempedoic Acid (ETC-1002), an ACL-Inhibiting Regimen (CLEAR) Outcomes trial (NCT02993406), the use of BA in primary and secondary prevention patients who were unable or unwilling to take guideline-recommended doses of statins reduced LDL-C levels by a mean of 21%, and significantly reduced the risk of the composite endpoint of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization by 13% compared to placebo [17]. Bempedoic acid significantly reduced the risk of MI (fatal and nonfatal) and coronary revascularization by 23% and 19%, respectively.
However, there are limited data on LDL-C lowering with BA or BA + EZE in the US real-world clinical setting among broader populations who may have been less well represented in pivotal randomized clinical trials and may face unique treatment hurdles. Treatment challenges may include clinical inertia to intensify therapy or monitor treatment success, difficulties in access, poor adherence, and early treatment discontinuation. As such, we sought to characterize the patient population of new initiators of BA and combination BA + EZE and evaluate the association of new initiation with BA and BA + EZE on LDL-C values over 1 year of treatment. In addition, this study also investigated the effectiveness of these therapies when stratified by (1) evidence of prior statin use and (2) by the continuous or non-continuous use of treatment.
2. Methods
2.1. Study design and data sources
This retrospective, observational study used electronic health records (EHR) from the Veradigm Network EHR database (Veradigm, Chicago, IL) linked to open healthcare claims from the Komodo Healthcare Map (Komodo Health Inc., San Francisco, CA) to identify individuals who were being treated with BA monotherapy or BA + EZE fixed-dose combination following the US Food and Drug Administration (FDA) approval on February 21, 2020 and February 26, 2020, respectively. The EHR component of the dataset consisted of de-identified data collected from patients in the ambulatory/outpatient primary care and specialty settings that were deterministically linked to medical and pharmacy insurance claims data. This linked dataset only used de-identified patient data in accordance with the de-identification standard defined in Section §164.514(a) of the Health Insurance Portability and Accountability Act of 1996 (HIPAA) Privacy Rule. As such, this data from a certified HIPAA-compliant de-identified research database did not require approval from an institutional review board.
2.2. Patient population
Patients ≥18 years of age with evidence of ≥1 pharmacy claim for BA (NDCs: 72426011803, 72426011809, 72426011899) or BA + EZE fixed-dose combination (NDCs: 72426081803, 72426081809, 72426081899) between March 1, 2020 and March 25, 2024 were eligible for inclusion. The index date was defined as the earliest date indicating a prescription fill for either medication following the February 2020 approval date. Patients were required to have ≥1 medical encounter with LDL-C lab results on or within 6 months prior to the index date and ≥2 separate medical visits with LDL-C lab results following the index date (follow-up period). At least 1 LDL-C lab result was required to be within the 12 months ± 60-day window in follow-up. To evaluate the effectiveness of the fixed-dose combination, patients in the BA + EZE cohort with documented use of ezetimibe on or within 6 weeks prior to their index date were excluded from this study.
As BA and BA + EZE have been studied in statin intolerant patients, we also evaluated LDL-C lowering by patients with evidence of statin use history in the previous 12 months and by those with no evidence of use. Evidence of statin use history was defined as an EHR record or pharmacy claim of statin therapy at any dose, alone or in combination with a non-statin LLT. In order to more closely assess the LDL-C lowering effects after treatment initiation, we identified an additional subgroup of patients with continuous use of index medication. For this analysis, patients who had a treatment gap (defined as an interruption in the administration or refill of the index medication) of >45 days were considered to be non-continuous users. Patients who discontinued and later restarted or switched therapies were also considered to be non-continuous. Continuous (and non-continuous/gap) use was measured at every timepoint captured in the follow-up period.
2.3. Covariates
We assessed baseline demographics and clinical characteristics (including CV risk factors and history of ASCVD events) on or during the 12 months prior to the index date (baseline period). History of CVD and use of LLT were evaluated at any time during the baseline period. LLT medication classes included use of statins (at any dose), PCSK9 inhibitors, ezetimibe, and other LLT (defined as bile acid sequestrants, fibrates, niacin, omega-3 fatty acids). The full list of patient characteristics are presented in Table 1, Table 2.
Table 1.
Baseline patient demographics.
| BA N = 900 |
BA + EZE N = 615 |
|
|---|---|---|
| Age (Median, IQR) | 64.0 (57-71) | 62.0 (56-69) |
| Gender (n, %) | ||
| Male | 386 (42.9%) | 298 (48.5%) |
| Female | 514 (57.1%) | 317 (51.5%) |
| Race (n, %) | ||
| White | 624 (69.3%) | 400 (65.0%) |
| Black | 74 (8.2%) | 56 (9.1%) |
| Asian | 36 (4.0%) | 26 (4.2%) |
| Other | 74 (8.2%) | 53 (8.6%) |
| Unknown/Not Reported | 92 (10.2%) | 80 (13.0%) |
| Ethnicity (n, %) | ||
| Hispanic | 27 (3.0%) | 23 (3.7%) |
| Non-Hispanic | 702 (78.0%) | 514 (83.6%) |
| Unknown/Not Reported | 171 (19.0%) | 78 (12.7%) |
| Geographic Region (n, %) | ||
| Northeast | 130 (14.4%) | 84 (13.7%) |
| Midwest | 90 (10.0%) | 77 (12.5%) |
| South | 484 (53.8%) | 339 (55.1%) |
| West | 196 (21.8%) | 115 (18.7%) |
BA, bempedoic acid; BA + EZE, bempedoic acid plus ezetimibe; IQR, interquartile range.
Table 2.
Baseline clinical characteristics.
| BA N = 900 |
BA + EZE N = 615 |
|
|---|---|---|
| BMI (Median, IQR) | 30.0 (26.6-34.0) | 30.3 (27.0-35.0) |
| LDL-C (Median, IQR) | 137 (100-167) | 127 (93-163) |
| Total Cholesterol (Median, IQR) | 220 (181-254) | 211 (170-251) |
| CVD (n, %)a | 731 (81.2%) | 512 (83.3%) |
| CV Risk Factors (n, %) | ||
| ASCVD | 407 (45.2%) | 287 (46.7%) |
| Diabetes | 349 (38.8%) | 286 (46.5%) |
| HeFH | 32 (3.6%) | 31 (5.0%) |
| Hypertension | 640 (71.1%) | 453 (73.7%) |
| Any ASCVD Event (n, %) | 242 (26.9%) | 168 (27.3%) |
| Stroke | 28 (3.1%) | 23 (3.7%) |
| Transient Ischemic Attack | 29 (3.2%) | 25 (4.1%) |
| Unstable Angina | 10 (1.1%) | 5 (0.8%) |
| Myocardial Infarction | 23 (2.6%) | 20 (3.3%) |
| Heart Failure | 73 (8.1%) | 54 (8.8%) |
| CV-related Hospitalization | 32 (3.6%) | 29 (4.7%) |
| Coronary Revascularization | 99 (11.0%) | 65 (10.6%) |
| Antihyperlipidemic Medication Classes (n, %) | ||
| Statins (Any Dose) | 524 (58.2%) | 391 (63.6%) |
| PCSK9 inhibitors (PCSK9i) | 105 (11.7%) | 74 (12.0%) |
| Ezetimibeb | 322 (35.8%) | 79 (12.9%)† |
| Otherc | 0 (0.0%) | 1 (0.2%) |
ASCVD, atherosclerotic cardiovascular disease; BA, bempedoic acid; BA + EZE, bempedoic acid plus ezetimibe; BMI, body mass index; CV, cardiovascular; CVD, cardiovascular disease; HeFH, heterozygous familial hypercholesterolemia; IQR, interquartile range; LDL-C, low-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin/kexin type 9.
CVD is not restricted to the 12-month pre-index period and was assessed in all of available patient history.
Includes ezetimibe use in the 12-month baseline period, excluding the 6 weeks prior to the index event.
Other includes bile acid sequestrants, fibrates, niacin, and omega-3 fatty acids.
2.4. Outcomes
Change in LDL-C values was the primary outcome in this study. The association between BA and BA + EZE initiation was assessed as of the index date and in follow-up among those with valid lab test values at 3 months ± 30 days (noted as “3 months”), 6 months ± 60 days (noted as “6 months”), and 12 months ± 60 days (noted as “12 months”). LDL-C values in the overall treatment cohorts, stratified by evidence of prior statin use, and stratified by continuous use of index medication were reported continuously and categorically. The LDL-C thresholds were defined as <70 mg/dL, 70-99 mg/dL, 100-129 mg/dL, 130-159 mg/dL, and ≥160 mg/dL. As a secondary outcome of interest, change in total cholesterol lab values were described at index and in follow-up (among those with available lab values) at 3 months ± 30 days (noted as “3 months”), 6 months ± 60 days (noted as “6 months”), and 12 months ± 60 days (noted as “12 months”). To evaluate the robustness of the study results, a sensitivity analysis was conducted using closed healthcare claims data from Komodo Healthcare Map on a subset of patients from the overall cohorts. These patients were required to have continuous claims enrollment for more than 12 months prior to and following the index date. Sensitivity analysis results are reported continuously throughout the study period.
The code sets used to identify index and baseline medications are reported in Supplemental Table S1.
2.5. Data analysis
Patient demographics and clinical characteristics are reported descriptively. Categorical variables were reported using counts and percentages while continuous variables were reported using median and interquartile ranges (IQR). As patients were not required to have lab tests available at every timepoint in follow-up, to assess a statistical change in laboratory measures over time, a chi-square test was applied to categorized LDL-C values and unpaired sample t-tests were used for continuous values (i.e., LDL-C, total cholesterol). Significance was set to p < 0.05. For descriptive reporting in this paper, median laboratory levels are described though mean lipid values were used for inferential testing. All statistics were performed using SAS V9.4 (SAS Institute Inc., Cary, NC).
3. Results
3.1. Baseline demographics and clinical characteristics
This study included 1,515 patients who initiated BA or BA + EZE (BA, n = 900; BA + EZE, n = 615) and met all the study inclusion criteria (Fig. 1). The median age was 64 years for patients initiating BA and 62 years for those initiating BA + EZE; most patients were female (57% and 52%, respectively) (Table 1). At baseline, a high cardiometabolic comorbidity burden was observed in both groups. The majority of patients had existing CVD and hypertension in their patient history; more than a third had diabetes, more than a quarter had a prior ASCVD event, and the median BMI was >30 kg/m2 (Table 2). During the baseline period, 58.2% and 63.6% of BA and BA + EZE patients, respectively, received statin therapy. As shown in Table 2, approximately 12% of patients had taken PCSK9 inhibitors in both cohorts and 35.8% of BA patients had a history of ezetimibe use.
Fig. 1.
Patients selected for inclusion in the study.
3.2. LDL-C reduction in the overall cohorts
The median LDL-C values at baseline were 137 (100-167) mg/dL for BA and 127 (93-163) mg/dL for BA + EZE. Following BA initiation, median (IQR) LDL-C levels significantly decreased in the first 3 months to 108 (80-138) mg/dL (21.2% reduction) and was maintained at 6 and 12 months (p < 0.0001 at every time point vs the index; Fig. 2A) despite the proportion of patients with available lab results varying (Supplemental Table S2). LDL-C lowering was greater after initiation with BA + EZE at 3 months, with median (IQR) levels reduced to 85 (61-114) mg/dL (33.1% reduction); by 12 months, the median LDL-C was 96 (67-128) mg/dL (22.4% reduction) (p < 0.0001 at every time point vs the index).
Fig. 2.
Median and percent change in LDL-C lab values in (A) overall therapy cohorts, (B) stratified by evidence of prior statin use, and (C) stratified by continuous use of index medication.
∗p < 0.0001 vs the index. †Continuous use defined as a gap in coverage of the index medication of ≤45 days duration.
BA, bempedoic acid; BA + EZE, bempedoic acid plus ezetimibe; LDL-C, low-density lipoprotein cholesterol.
There was a significant shift observed in LDL-C thresholds from baseline to the 3-, 6-, and 12-month time points for both BA and BA + EZE (p < 0.0001 for every time point vs the index; Fig. 3). After 3 months of treatment, 16.8% and 33.3% of BA and BA + EZE patients, respectively, had LDL-C <70 mg/dL. Over 1 year of treatment, 18.0% and 27.5% of patients reached LDL-C <70 mg/dL (Fig. 3). Across both cohorts, the percentage of patients with LDL-C <100 mg/dL also notably increased from baseline through month 12 (BA: 24.5% to 42.8%; BA + EZE: 30.1% to 55.3%).
Fig. 3.
Shift in the proportion of patients in LDL-C categories by therapy cohort.
∗p < 0.0001 vs the index.
BA, bempedoic acid; BA + EZE, bempedoic acid plus ezetimibe.
3.3. Total cholesterol reduction in the overall cohorts
Total cholesterol reductions were also evaluated as a secondary outcome. The initiation of BA and BA + EZE was associated with lower subsequent total cholesterol throughout the follow-up period. At baseline, median total cholesterol were >210 mg/dL (BA: 220 mg/dL; BA + EZE: 211 mg/dL) (Supplemental Table S3). By 3 months in follow-up, total cholesterol levels dropped 14.5% for BA and 23.7% for BA + EZE and remained ≤190 mg/dL through the end of follow-up (p < 0.0001 at every time point vs the index).
3.4. LDL-C reduction stratified by evidence of prior statin use
When stratified by evidence of prior statin use, 41.8% of BA patients and 36.4% of BA + EZE patients had no evidence of statin use in the 12 months prior to their index date (Table 2). Median baseline (IQR) LDL-C levels for these patients were (149 (121-177) mg/dL for BA and 139 (103-170) mg/dL for BA + EZE. For patients who had evidence of prior statin use, median levels were 126 (90-160) mg/dL and BA + EZE: 121 (89-157) mg/dL (Supplemental Table S2). By 3 months, the percent change in LDL-C in patients without evidence of prior statin use was −24.2% and −36.7% for BA and BA + EZE, respectively, and −16.7% and −29.8% in patients with evidence of prior statin use (p < 0.0001 at every time point vs the index) (Fig. 2B).
For patients without evidence of prior statin use, a clear shift in LDL-C thresholds was observed in the BA + EZE cohort. In these patients, the proportion with LDL-C <70 mg/dL increased almost 6-fold (from 5.0% to 29.6% at 3 months); similarly, there was a 5-fold increase for BA patients (from 1.9% at baseline to 10.8%; p < 0.0001 for BA vs the index) (Supplemental Figure S1). The percentage with LDL-C <100 mg/dL notably increased from baseline through month 12 (BA: 11.2% to 35.1%; BA + EZE: 24.9% to 49.3%). In patients with evidence of prior statin use, the proportion of those who achieved LDL-C <70 mg/dL also increased from baseline to 3 months for both BA and BA + EZE patients.
3.5. LDL-C reduction stratified by continuous use of BA or BA + EZE
Approximately one-third of patients met the study definition of continuous use (≤45-day gap in index medication) (BA: 29%; BA + EZE: 30%). Over the 12-month follow-up period, 15% and 19% of patients in each cohort, respectively, discontinued and later restarted after more than a 45-day gap, and 18% and 16% of patients switched therapies (most commonly to statin or ezetimibe monotherapy).
Median baseline LDL-C levels were similar between continuous use and non-continuous use/gap patients for both the BA cohort (134 [96-165] mg/dL and 139 [103-168] mg/dL, respectively) and the BA + EZE cohort (127 [91-167] mg/dL and 126 [94-160] mg/dL) (Supplemental Table S2). As expected, greater LDL-C reductions were observed in continuous users, with 26.1% and 40.2% reduction in LDL-C by 3 months for BA and BA + EZE, respectively (p < 0.0001 for both vs the index) (Fig. 2C). These reductions were generally maintained over 1 year of treatment. Interestingly, there was still a significant and clinically relevant lowering in LDL-C values in non-continuous use/gap patients, with LDL-C reductions at 3 months of 18.7% and 29.4% for BA and BA + EZE (p < 0.0001 for both vs the index).
When evaluated by LDL-C thresholds, the shift was most evident in continuous users. In these patients, the proportion with LDL-C <70 mg/dL increased 4-fold for BA (from 5.4% at baseline to 24.2% at 12 months; p < 0.0001 vs the index), and 5-fold for BA + EZE (from 7.7% to 42.0%) (Supplemental Figure S2). By 12 months, 56.5% and 73.9% of continuous BA and BA + EZE patients, respectively, had LDL-C <100 mg/dL. There was a significant reduction in the percentage of patients with LDL-C ≥130 mg/dL across both cohorts (BA: 53.5% to 20% at 12 months; BA + EZE: 49.4% to 10.8%). These trends were still observable even in non-continuous use/gap patients.
3.6. Closed claims sensitivity analysis
In a sensitivity analysis using the Veradigm Network EHR data linked to closed healthcare claims from Komodo Healthcare Map, the number of eligible patients in each cohort was substantially smaller (BA: n = 178; BA + EZE: n = 163). Median baseline LDL-C levels (BA: 143 mg/dL; BA + EZE 131 mg/dL) were slightly higher than in the overall cohort, and changes in LDL-C thresholds in the BA and BA + EZE cohorts followed similar trends to the overall cohorts (Supplemental Table S2). LDL-C improvements were observed at 3 months (BA: 24.5%; BA + EZE: 28.4%) and maintained through 12 months post-initiation (p < 0.0001 at every time point vs the index).
4. Discussion
This study describes the characteristics of patients who newly initiated BA or BA + EZE between March 1, 2020 and March 15, 2024, and provides evidence of LDL-C outcomes in a real-world patient population in the US. Overall, the observed patient population had an increased CV risk profile (age, history of CVD, and presence of risk factors such as high BMI, diabetes, and hypertension), similar to the patient populations of the phase 3 studies [[14], [15], [16], [17]]. The results showed that BA and BA + EZE therapies were associated with clinically and statistically relevant LDL-C reductions with meaningful shifts in LDL-C categorical thresholds. Three months after initiation, median LDL-C reductions were 21.2% for BA and 33.1% for BA + EZE. Despite the high median baseline LDL-C levels, 33.3% of BA + EZE patients had LDL-C <70 mg/dL by 3 months. The results of this study also suggest that the LDL-C lowering is durable, with the initial reduction over 3 months maintained through 6 and 12 months for BA. Although some waning was observed for BA + EZE users, it may be in part attributable to treatment discontinuation. In addition, more than half of BA + EZE patients had no evidence of subsequent LLTs (56%; 49% for BA) (Supplemental Table S4) despite these patients having an increase proportion of cardiometabolic comorbidities and pre-existing ASCVD at a baseline. It is possible that these clinical characteristics, in addition to patient behavior, may have contributed to differences in treatment over time.
Unfortunately, poor adherence and treatment discontinuation have been well-documented in patients taking chronic medications and are challenges to achieving treatment goals. Previous studies have found low rates of continuous cardiometabolic medication use [[18], [19], [20], [21]]. In Koenig et al. [18], over the course of the 1.3-year follow-up period, only 39% of patients newly initiating statin or ezetimibe treatment were persistent at 12 months. Similarly, in a study of oral antidiabetic medication users, Choe et al. [19] observed that only 22% of patients maintained continuous use of their index medication (no gap >60 days) and only 12% stayed on the index medication for a median 2.3 years. In our study, approximately one-third of patients continuously used their index medication as prescribed (≤45-day gap in medication). The observed median LDL-C changes were highest in these patients (−26.1% for BA and −40.2% for BA + EZE) and greater than current guideline recommendations of LDL-C lowering for BA and BA + EZE [22]. By 12 months, ∼39% of BA + EZE patients with continuous therapy had LDL-C <70 mg/dL and 74% had LDL-C <100 mg/dL. It is of interest that meaningful LDL-C reductions were still observed in patients who discontinued use or had a gap in their index therapy; the observed reductions (BA: 18.7%; BA + EZE: 29.4%) were consistent with the CLEAR clinical trials, suggesting that even patients who skip doses or prematurely stop therapy may still benefit from the initial treatment [16,17]. A distressing finding, however, is that more than one-third of patients who discontinued BA or BA + EZE therapy had no evidence of a follow-on LLT (38% and 34% for BA and BA + EZE, respectively).
Less than two-thirds of patients in our study were on statin therapy at baseline (BA: 58.2%; BA + EZE: 63.6%); a lower treatment rate than that reported by Navar et al. in patients with ASCVD (76.1%), yet higher than Chan et al. in a high CV risk population (37.6%) [23,24]. Of note, baseline rates of PCSK9 inhibitor (12% in both cohorts) and ezetimibe use (BA: 35.8%, BA + EZE: 12.9%) were considerably higher in the current study than what has been reported in other real-world studies in the US, where <5% of patients were receiving a non-statin LLT [23,24]. The higher proportion of patients treated with non-statins in the current study may be due to physicians using BA in statin intolerant patients. This is supported by much higher rates of non-statin use also observed in a small single-center study, in which the majority of BA users were statin intolerant [25]. In our current study, no formal definition of statin intolerance was applied as an inclusion criterion, and instead, patients were stratified by evidence of statin use in the 12 months prior to initiating BA or BA + EZE. Whether the patients in our study are statin intolerant could not be definitively confirmed. Patients with statin intolerance may represent a challenging patient population, with higher rates of discontinuation and non-adherence, all of which may make achieving therapeutic goals challenging [8,25]. The observed LDL-C reductions in our study were numerically greater in patients without evidence of prior statin use (24.2% for BA and 36.7% for BA + EZE at 3 months), although as expected, these patients had higher baseline LDL-C levels. These results are consistent with phase 3 studies of LDL-C lowering among patients receiving low-dose or no statin therapy at all [26,27]. Pooled data in patients not taking statins from four phase 3 bempedoic acid studies [26] has shown evidence to support the effectiveness of BA and BA + EZE in patients not taking statin therapy. The percent reduction in LDL-C levels in this subgroup is also consistent with the 21% reduction with BA in the CLEAR Outcomes clinical trial in patients with statin intolerance [17].
Our analysis spans the period shortly after FDA approval of BA and BA + EZE (in February 2020), and it remains to be seen whether the observed results will be maintained with increasing use in clinical practice where high variability exists with patient- and prescriber-related factors. In clinical trial settings, post hoc exploratory analyses have identified several characteristics associated with a hyper-response to BA (≥30% or 50% LDL-C reduction), including absence of statin therapy use or presence of statin intolerance, female sex, and history of diabetes [25,28]. Future analyses could be undertaken to understand the impact of these characteristics on the LDL-C reduction in this real-world cohort. Additionally, future analyses should be undertaken to evaluate the proportion of patients achieving treatment goals across categories of total CV risk. As our objective was to evaluate LDL-C lowering in a real-world setting, where attainment of <70 mg/dL is a challenge, we did not assess attainment of LDL-C in patients who may be at very high CV risk (treatment goal of <55 mg/dL), such as the approximately one-third of patients with documented ASCVD.
4.1. Study strengths and limitations
This observational study provided insights into the effectiveness of BA and BA + EZE in real-world clinical practice. The major limitation of the analysis is the inability to make causal inference based on these observational results due to the lack of a control cohort of alternative LLT initiators. As a retrospective analysis, this study used routinely collected healthcare claims and EHR data and is subject to the typical limitations of all retrospective studies using data not gathered for specific research purposes. This includes data entry errors, missing data, and coding specificity limitations which can lead to the misclassification of baseline patient characteristics and outcomes of interest. As open healthcare claims data were used in the primary study analysis, the data are also subject to a common limitation of open claims data: the potential for incompleteness as these claims are not all fully adjudicated. To ensure the robustness of our linked study results, a sensitivity analysis using closed healthcare claims was conducted, in which similar results to the overall cohorts that used open claims data were seen.
In this study, patients were not excluded based on LDL-C levels at baseline. As such, patients who were already at their goal LDL-C levels of <70 mg/dL who may have switched to BA or BA + EZE may have been included, which may dilute the observed LDL-C lowering effects of BA or BA + EZE. As the BA + EZE cohort only included patients taking the fixed-dose combination therapy, to account for those taking BA and ezetimibe separately, these patients indexed on BA and were included in such cohort. Patients taking ezetimibe in the prior 6 weeks to their index medication were excluded from the study to better understand the efficacy of BA and BA + EZE as non-statin LLTs. Patients were required to have ≥2 LDL-C labs after the index event within discrete time periods, including 1 of the labs at the 12-month ±60-day time point to ensure the LDL-C values that were captured reflected accurate changes over the reported follow-up period. However, this resulted in a loss of ∼75% of the sample population, potentially biasing towards patients who receive more comprehensive care. In addition, while the Veradigm Integrated Database EHRs are used in all 50 US states, this database should not be considered a random sample of US patients with dyslipidemia. The characteristics of the database reflect the needs of the contributing practitioners who tend to work in small to mid-sized practices. The contributing practitioners are not a random sample of US healthcare providers. Furthermore, this database only included insured individuals and thus may not be generalizable to individuals without healthcare insurance coverage.
It should be noted that the primary analysis of the overall cohorts included patients who may have discontinued BA or BA + EZE early or had gaps in treatment, thus providing a real-world picture of the LDL-C lowering effectiveness. Stratification of these results was conducted to evaluate the potential impact of early discontinuation, but these patients were not excluded from the analysis. Discontinuation or gaps in treatment could have been influenced by factors other than the therapy itself, including insurance benefit design changes and high patient out-of-pocket costs, and COVID-19 isolation protocols as BA and BA + EZE were approved for use in late February 2020, right before the declaration of the COVID-19 pandemic. Future studies that incorporate clinical notes may provide more insight into the treatment pattern variations seen amongst the study cohorts and reasons for non-continuous therapy treatment. Lastly, evidence of LLT use was only determined in the 12 months prior to index claim and did not account for statin dose. In a similar manner, the inclusion of clinical notes may underscore the contributing factors to non-statin LLT use in the prior 12 months as this was not captured in the current study.
5. Conclusions
In this US real-world study, despite background LLT use, patients initiating BA or BA + EZE had elevated LDL-C values. Our results indicate that BA and BA + EZE was associated with LDL-C-lowering in a real-world patient cohort consistent with findings reported in the phase 3 CLEAR clinical studies [12,13,29]. The observed results reinforce the importance of long-term treatment adherence and an effective LLT option for patients not taking statin therapy.
Data availability statement
The data that support the findings of this study were used under license from Veradigm and Komodo Healthcare Map. Due to data use agreements and its proprietary nature, restrictions apply regarding the availability of the data. Further information is available from the corresponding author, Evelyn Sarnes.
Author contribution statement
Muthiah Vaduganathan: Conceptualization, Writing- Reviewing and Editing, Visualization. James Nelson: Conceptualization, Methodology, Investigation, Visualization, Writing- Reviewing and Editing. Mac Bonafede: Conceptualization, Methodology, Supervision, Writing- Reviewing and Editing, Visualization. LeAnne Bloedon: Conceptualization, Methodology, Writing- Reviewing and Editing, Visualization. Evelyn Sarnes: Conceptualization, Methodology, Supervision, Visualization, Writing- Reviewing and Editing. Dave Lewandowski: Data Curation, Software, Formal analysis, Methodology, Writing- Reviewing and Editing. Maryam Ajose: Writing- Original Draft, Writing- Reviewing and Editing, Visualization.
Ethics approval and consent to participate
The linked dataset only contains de-identified data as per the de-identification standard defined in Section §164.514(a) of the Health Insurance Portability and Accountability Act of 1996 (HIPAA) Privacy Rule. The process by which the data is de-identified is attested to through a formal determination by a qualified expert as defined in Section §164.514(b)(1) of the HIPAA Privacy Rule. Because this study used only de-identified patient records, it is therefore no longer subject to the HIPAA Privacy Rule and is therefore exempt from Institutional Review Board approval and for obtaining informed consent according to US law. This study was conducted in compliance with the Declaration of Helsinki and used only de-identified data.
Use of AI and AI-assisted technologies statement
The use of generative AI and AI-assisted technologies were not used in the writing of the manuscript.
Funding
This study was funded by Esperion Therapeutics, Inc.
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Evelyn Sarnes reports financial support was provided by Esperion Therapeutics Inc. LeAnne Bloedon reports financial support was provided by Esperion Therapeutics Inc. Muthiah Vaduganathan reports financial support was provided by Esperion Therapeutics Inc. James Nelson reports financial support was provided by Esperion Therapeutics Inc. Dave Lewandowski reports financial support was provided by Esperion Therapeutics Inc. Mac Bonafede reports financial support was provided by Esperion Therapeutics Inc. Maryam Ajose reports financial support was provided by Esperion Therapeutics Inc. James Nelson reports financial support was provided by Veradigm LLC. Dave Lewandowski reports financial support was provided by Veradigm LLC. Mac Bonafede reports financial support was provided by Veradigm LLC. Maryam Ajose reports financial support was provided by Veradigm LLC. Muthiah Vaduganathan reports a relationship with Alnylam Pharmaceuticals, Inc. that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with American Regent Inc that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Amgen Inc that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with AstraZeneca that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Bayer AG that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Baxter Healthcare that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Boehringer Ingelheim Ltd that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Chiesi Pharmaceuticals Inc that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Cytokinetics Inc that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Fresenius Medical Care that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Idorsia Pharmaceuticals Ltd that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Lexicon Pharmaceuticals, Inc. that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Merck & Co Inc that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Milestone Pharmaceuticals that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Novartis that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Novo Nordisk that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Pharmacosmos, Inc. that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Recordati Rare Diseases that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Relypsa that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Roche Diagnostics that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Sanofi that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan reports a relationship with Tricog Health that includes: consulting or advisory, funding grants, and speaking and lecture fees. Muthiah Vaduganathan participates on clinical trial committees for studies sponsored by Amgen, AstraZeneca, Boehringer Ingelheim, Galmed, Novartis, Bayer AG, Occlutech, Pharmacosmos, and Impulse Dynamics. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
Portions of this study were presented in a poster at the: Academy of Managed Care Pharmacy 2024 Nexus Meeting, Las Vegas, Nevada, October 14-17, 2024; American Heart Association 2024 Scientific Sessions, Chicago, Illinois, November 16-18, 2024; Academy of Managed Care Pharmacy 2025 Annual Meeting, Houston, Texas, March 31-April 3, 2025; National Lipid Association 2025 Scientific Sessions, Miami, Florida, May 29-June 1, 2025.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.athplu.2026.01.007.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study were used under license from Veradigm and Komodo Healthcare Map. Due to data use agreements and its proprietary nature, restrictions apply regarding the availability of the data. Further information is available from the corresponding author, Evelyn Sarnes.