2025 Volume 32 Issue 2 Pages 163-175
Aim: To investigate medication adherence and treatment persistence in patients receiving proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) in Japan.
Methods: Using an anonymized claims database from January 2015 to December 2021, data on adult patients at high risk for atherosclerotic cardiovascular disease or with a history of coronary artery disease (CAD) who had at least 1 prescription for PCSK9-mAbs were retrieved.
Results: In total, 276 patients were analyzed. The cumulative treatment persistence rate after 1 year was 67.0%. A multivariate analysis revealed that better adherence to oral low-density lipoprotein cholesterol (LDL-C)-lowering therapy in the year before starting PCSK9-mAbs (adjusted odds ratio [OR] 2.16) and a history of CAD for secondary prevention (adjusted OR 2.44) were associated with better adherence to PCSK9-mAbs in the first year. Better adherence to oral LDL-C-lowering therapy in the year before starting PCSK9-mAbs (adjusted OR 2.32) and a history of CAD for secondary prevention (adjusted OR 3.03) were also associated with a lower rate of discontinuation of PCSK9-mAbs. Age, sex, comorbidity, number of tablets taken daily (all medications), and number of hospital or clinic visits in the year prior to starting PCSK9-mAbs did not affect the persistence rate or adherence to PCSK9-mAbs in the multivariate analyses.
Conclusion: Better adherence to oral LDL-C-lowering therapy and secondary prevention were identified as factors associated with better medication adherence and treatment persistence in patients receiving PCSK9-mAbs within the first year.
Abbreviations: CAD: coronary artery disease, CI: confidence interval, CKD: chronic kidney disease, DM: diabetes mellitus, FH: familial hypercholesterolemia, ICD-10: International Statistical Classification of Diseases and Related Health Problems, 10th Revision, LDL-C: low-density lipoprotein cholesterol, mAb: monoclonal antibody, OR: odds ratio, PAD: peripheral artery disease, PCSK9: proprotein convertase subtilisin/kexin type 9, PDC: proportion of days covered, SD: standard deviation
Cardiovascular disease is among the leading causes of mortality in Japan1), and it was the leading cause of death worldwide in 2021 2). Elevated levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides and low levels of high-density lipoprotein cholesterol have been associated with a higher risk of atherosclerotic cardiovascular disease3-5). LDL-C-lowering therapy has proven to be effective in both the primary and secondary prevention of cardiovascular events6).
In 2017, the Japan Atherosclerosis Society guidelines for the prevention of atherosclerotic cardiovascular disease set the following LDL-C targets for the prevention of cardiovascular events7): ＜120 mg/dL for primary prevention in high-risk patients, ＜100 mg/dL for secondary prevention in patients with a history of coronary artery disease (CAD), and ＜70 mg/dL for secondary prevention in patients with a history of CAD and acute coronary syndrome, familial hypercholesterolemia (FH), or diabetes mellitus (DM) complicated by other high-risk conditions. Various LDL-C-lowering therapies are available, including statins, ezetimibe, anion exchange resins, fibrates, probucol, nicotinic acid derivatives, and PCSK9-mAbs7). Statins are primarily recommended for patients with secondary prevention of CAD or FH in combination therapy if LDL-C targets are not achieved7-10). Previous studies have shown the efficacy of these medications, including PCSK9-mAbs, in lowering LDL-C levels and improving cardiovascular outcomes11-16). However, despite the potential of these medications, the rate of LDL-C target attainment remains low in Japan17, 18).
Medication adherence and persistence are crucial for the management of cardiovascular diseases19). Evaluating these aspects can help identify barriers to successful treatment and optimize treatment plans, potentially improving patient outcomes. Studies conducted in the US and Netherlands have shown that medication adherence is associated with improved LDL-C levels20, 21), and a systematic review has demonstrated that adherence and persistence are linked to a reduction in cardiovascular events and mortality22). Although data on treatment adherence and persistence have been reported for statin monotherapy and statin therapy combined with ezetimibe in Japan23, 24), no studies have examined medication adherence and treatment persistence specifically for PCSK9-mAbs.
We investigated the medication adherence and treatment persistence of Japanese patients undergoing LDL-C-lowering therapy with PCSK9-mAbs. Additionally, we explored factors associated with medication adherence and treatment persistence in this patient population.
We conducted a non-interventional retrospective cohort study using an anonymized medical fee claims database maintained by JMDC Inc.25). The JMDC database provides data on inpatient, outpatient, and pharmacy claims, representing approximately 13 million insured patients (as of April 2022) from more than 200 health insurance associations in Japan since 2005, accounting for approximately 10% of the Japanese population. In the medical fee claims, disease names were based on International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) codes26).
We obtained JMDC claims data from January 2015 to December 2021 (Fig.1), with the index date defined as the date of the first use of PCSK9-mAbs between January 2016 and December 2019. The baseline was set at 12 months prior to the index date. The follow-up period for each patient was either 1 or 2 years. The study complied with the latest version of the Declaration of Helsinki and adhered to Good Clinical Practice guidelines. The requirement for informed consent was waived because an anonymized commercial database was used.
LDL-C, low-density lipoprotein cholesterol; M, months; PCSK9, proprotein convertase subtilisin/kexin type 9 monoclonal antibodies; PDC, proportion of days covered.
The inclusion criteria were as follows: adult patients (age ≥ 18 years between January 2015 and December 2020) at high risk for atherosclerotic cardiovascular disease (patients with dyslipidemia, DM, chronic kidney disease [CKD], peripheral artery disease [PAD], or non-cardiogenic cerebral infarction; for primary prevention) or those with a history of CAD for secondary prevention based on the Japan Atherosclerosis Society guideline 2017; at least 1 prescription of PCSK9-mAbs, presence of at least 12 months of data before the index date (baseline period), presence of at least 12 months of data after the index date, and no recorded history of treatment with PCSK9-mAbs in the 6 months before the index date. Patients for whom the prescription dates or number of prescription days were unknown were excluded from the study.
OutcomesThe primary outcome was to identify medication adherence and persistence at 1 year in patients receiving PCSK9-mAb treatment. Medication adherence was calculated as the proportion of days covered (PDC) by dividing the actual number of prescription days by the follow-up period of 1 or 2 years. In this study, adherence was defined as PDC ≥ 80%.
Statistical MethodsDescriptive statistics were used to summarize patients’ demographic and clinical characteristics. The cumulative rate of treatment persistence in patients receiving PCSK9-mAbs was assessed using the Kaplan–Meier method and compared using the log-rank test. If the target drug was not prescribed for 90 days after exhausting the drug supply of the previous prescription or if the patient switched to another therapy, the treatment was discontinued, and the last prescription date was set as the end date of treatment persistence. We also estimated the adherence rate (PDC ≥ 80%) at 1 and 2 years. These estimates were separately explored in the subgroups of interest (LDL-C-lowering therapy adherence, prevention category, and sex).
Logistic regression models were used to evaluate the factors affecting adherence to PCSK9-mAbs (PDC ＜80% vs. PDC ≥ 80% in the first year for adherence) and persistence (persistent vs. non-persistent by end of year 1), with odds ratios (ORs) and 95% confidence intervals (CIs) calculated for each factor. The following factors affecting medication adherence and persistence were evaluated: age (＜60, ≥ 60 years), sex, prevention category (primary or secondary), medication adherence to oral LDL-C-lowering therapy 1 year before the index date (PDC ＜80%, ≥ 80%), comorbidities (DM, hypertension, respiratory disease, anxiety disorder/depression), the physical number of tablets taken daily (including all medications: ＜4 or ≥ 4), and the number of hospital/clinic visits (＜12, ≥ 12 times within 1 year) during the baseline period. All reported P values were 2-tailed, and statistical significance was set at 5%. All statistical analyses were performed using SAS (version 9.4; SAS Institute Inc., Cary, NC, US).
Fig.2 illustrates a flowchart of the patients included in the study. Between January 2015 and December 2021, 13,366,845 patients were included in the JMDC population. Among them, 2,001,742 patients were diagnosed with at least 1 of the following conditions: dyslipidemia, DM, CKD, PAD, non-cardiogenic cerebral infarction, and CAD. Among the 529 patients who had at least 1 prescription of PCSK9-mAbs, 276 met the inclusion criteria and were included in the analysis (Fig.2).
＊Continuous registration was defined as follows: before index date, registered for at least 360 days; after index date, registered for at least 450 days.
CAD, coronary artery disease; CKD, chronic kidney disease; DM, diabetes mellitus; PAD, peripheral artery disease; PCSK9, proprotein convertase subtilisin/kexin type 9 monoclonal antibody.
The baseline demographic and clinical characteristics of the patients (n=276) are summarized in Table 1. The mean±SD age of the patients was 53.6±9.7 years, and the majority were male (78.3%). Most patients received PCSK9-mAbs for secondary prevention of atherosclerotic cardiovascular disease (71.0%). The most common comorbidities at baseline were dyslipidemia (94.6%), CAD (71.0%), hypertension (69.2%), respiratory disease (58.0%), DM (46.4%), FH (33.3%), and PAD (31.5%). The most frequently prescribed LDL-C-lowering drugs at the baseline were statins (88.8%) and ezetimibe (62.0%). The mean medication adherence (PDC) to oral LDL-C-lowering therapy at baseline was 61.8%±34.2%.
| Characteristics | N = 276 |
|---|---|
| Male, n (%) | 216 (78.3) |
| Age, years, mean±SD | 53.6±9.7 |
| Prevention category, n (%) | |
| Primary prevention | 80 (29.0) |
| Secondary prevention | 196 (71.0) |
| Complications at baseline, n (%) | |
| Dyslipidemia | 261 (94.6) |
| Coronary artery disease | 196 (71.0) |
| Hypertension | 191 (69.2) |
| Respiratory disease | 160 (58.0) |
| Diabetes mellitus | 128 (46.4) |
| Familial hypercholesterolemia | 92 (33.3) |
| Peripheral artery disease | 87 (31.5) |
| Non-cardiogenic cerebral infarction | 19 (6.9) |
| Anxiety disorder/depression | 18 (6.5) |
| Depression | 16 (5.8) |
| Chronic kidney disease | 11 (4.0) |
| Anxiety disorder | 7 (2.5) |
| Number of drugs prescribed on the index date, median (range) | 4 (0–6) |
| Number of tablets taken on the index date, median (range) | 6 (0–10) |
| Number of hospital/clinic visits per year in baseline period, median (range) | 13 (7–22) |
| Lipid-lowering drugs at baseline, n (%) | |
| Statin | 245 (88.8) |
| Rosuvastatin | 165 (59.8) |
| Atorvastatin | 61 (22.1) |
| Pitavastatin | 56 (20.3) |
| Pravastatin | 11 (4.0) |
| Simvastatin | 1 (0.4) |
| Fluvastatin | 1 (0.4) |
| Ezetimibe | 171 (62.0) |
| Anion exchange resin | 24 (8.7) |
| Fibrate | 16 (5.8) |
| Probucol | 16 (5.8) |
| Nicotinic acid derivatives (nicomol and niceritrol) | 3 (1.1) |
| Medication adherence to LDL-C-lowering therapy at baseline, PDC, mean±SD | 61.8±34.2 |
| PDC ＜80%, n (%) | 150 (54.3) |
| PDC ≥ 80%, n (%) | 126 (45.7) |
LDL-C, low-density lipoprotein cholesterol; PDC, proportion of days covered; SD, standard deviation.
The mean±SD PDC was 67.0%±34.5% (n=185) after 1 year of PCSK9-mAbs therapy and was 61.1%±36.4% after 2 years (n=114) (Fig.3A). The adherence rates (PDC ≥ 80%) were 55.1% and 48.9% at 1 and 2 years, respectively. The cumulative treatment persistence rates after 1 and 2 years were 67.0% and 61.4%, respectively.
Data are presented as n (%) or mean±SD ＊Treatment was considered to be discontinued if the next prescription was ≥ 90 days after completion of the theoretical prescription period. CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin/kexin type 9 monoclonal antibodies; PDC, proportion of days covered; SD, standard deviation.
Patients with FH and CAD had significantly higher adherence rates (PDC ≥ 80%) to PCSK9-mAbs than non-FH and non-CAD patients (65.2% vs. 50.0%; P=0.0166 and 61.2% vs. 40.0%; P=0.0013, respectively). FH and CAD patients also had significantly higher persistence rates (persistence ≥ 1 year) for PCSK9-mAbs than non-FH and non-CAD patients (77.2% vs. 62.0%; P=0.0112 and 73.5% vs. 51.3%; P=0.0004, respectively) (Supplementary Tables 1 and 2).
| Complications at baseline | Adherence rate (1 year) | |||||
|---|---|---|---|---|---|---|
| PDC ≥ 80% | PDC ＜80% | P value Chi-square test | ||||
| n | (%) | n | (%) | |||
| Dyslipidemia | Yes | 148 | (56.7) | 113 | (43.3) | 0.0229 |
| No | 4 | (26.7) | 11 | (73.3) | ||
| Diabetes mellitus | Yes | 71 | (55.5) | 57 | (44.5) | 0.9020 |
| No | 81 | (54.7) | 67 | (45.3) | ||
| Chronic kidney disease | Yes | 5 | (45.5) | 6 | (54.5) | 0.5500＊ |
| No | 147 | (55.5) | 118 | (44.5) | ||
| Peripheral artery disease | Yes | 50 | (57.5) | 37 | (42.5) | 0.5867 |
| No | 102 | (54.0) | 87 | (46.0) | ||
| Noncardiogenic cerebral infarction | Yes | 10 | (52.6) | 9 | (47.4) | 0.8246 |
| No | 142 | (55.3) | 115 | (44.7) | ||
| Coronary artery disease | Yes | 120 | (61.2) | 76 | (38.8) | 0.0013 |
| No | 32 | (40.0) | 48 | (60.0) | ||
| Hypertension | Yes | 106 | (55.5) | 85 | (44.5) | 0.8315 |
| No | 46 | (54.1) | 39 | (45.9) | ||
| Respiratory disease | Yes | 92 | (57.5) | 68 | (42.5) | 0.3410 |
| No | 60 | (51.7) | 56 | (48.3) | ||
| Dementia | Yes | - | - | - | - | - |
| No | 152 | (55.1) | 124 | (44.9) | ||
| Depression | Yes | 10 | (62.5) | 6 | (37.5) | 0.5383 |
| No | 142 | (54.6) | 118 | (45.4) | ||
| Anxiety | Yes | 4 | (57.1) | 3 | (42.9) | 1.0000＊ |
| No | 148 | (55.0) | 121 | (45.0) | ||
| Depression/anxiety | Yes | 12 | (66.7) | 6 | (33.3) | 0.3064 |
| No | 140 | (54.3) | 118 | (45.7) | ||
| Familial hypercholesterolemia | Yes | 60 | (65.2) | 32 | (34.8) | 0.0166 |
| No | 92 | (50.0) | 92 | (50.0) | ||
＊Fisher's exact test
mAbs, monoclonal antibodies; PCSK9, proprotein convertase subtilisin/kexin type 9; PDC, proportion of days covered.
| Complications at baseline | Persistence rate | |||||
|---|---|---|---|---|---|---|
| ≥ 1 year | ＜1 year | P value Chi-square test | ||||
| n | (%) | n | (%) | |||
| Dyslipidemia | Yes | 180 | (69.0) | 81 | (31.0) | 0.0084＊ |
| No | 5 | (33.3) | 10 | (66.7) | ||
| Diabetes mellitus | Yes | 91 | (71.1) | 37 | (28.9) | 0.1816 |
| No | 94 | (63.5) | 54 | (36.5) | ||
| Chronic kidney disease | Yes | 6 | (54.5) | 5 | (45.5) | 0.5134＊ |
| No | 179 | (67.5) | 86 | (32.5) | ||
| Peripheral artery disease | Yes | 60 | (69.0) | 27 | (31.0) | 0.6424 |
| No | 125 | (66.1) | 64 | (33.9) | ||
| Noncardiogenic cerebral infarction | Yes | 13 | (68.4) | 6 | (31.6) | 0.8936 |
| No | 172 | (66.9) | 85 | (33.1) | ||
| Coronary artery disease | Yes | 144 | (73.5) | 52 | (26.5) | 0.0004 |
| No | 41 | (51.3) | 39 | (48.8) | ||
| Hypertension | Yes | 129 | (67.5) | 62 | (32.5) | 0.7869 |
| No | 56 | (65.9) | 29 | (34.1) | ||
| Respiratory disease | Yes | 108 | (67.5) | 52 | (32.5) | 0.8450 |
| No | 77 | (66.4) | 39 | (33.6) | ||
| Dementia | Yes | - | - | - | - | - |
| No | 185 | (67.0) | 91 | (33.0) | ||
| Depression | Yes | 13 | (81.3) | 3 | (18.8) | 0.2125 |
| No | 172 | (66.2) | 88 | (33.8) | ||
| Anxiety | Yes | 7 | (100.0) | 0 | (0.0) | 0.0997＊ |
| No | 178 | (66.2) | 91 | (33.8) | ||
| Depression/anxiety | Yes | 15 | (83.3) | 3 | (16.7) | 0.1280 |
| No | 170 | (65.9) | 88 | (34.1) | ||
| Familial hypercholesterolemia | Yes | 71 | (77.2) | 21 | (22.8) | 0.0112 |
| No | 114 | (62.0) | 70 | (38.0) | ||
＊Fisher's exact test
mAbs, monoclonal antibodies; PCSK9, proprotein convertase subtilisin/kexin type 9.
The cumulative rates of treatment persistence in patients receiving PCSK9-mAbs inhibitors according to medication adherence, prevention category, and sex are shown in Fig.3B–D. The group that adhered to oral LDL-C-lowering therapy (PDC ≥ 80%) in the year before starting PCSK9-mAbs had a significantly higher treatment persistence rate than the non-adherent group (77.8% vs. 58.0%; P=0.0001) (Fig.3B). The secondary prevention group had a significantly higher treatment persistence rate than the primary prevention group (73.5% vs. 51.3%; P＜0.0001) (Fig.3C). There was no significant difference in the treatment persistence rate according to sex (Fig.3D).
Factors Associated with Medication Adherence After 1 Year in Patients Receiving PCSK9-mAbsUnivariate analyses showed that better adherence to oral LDL-C-lowering therapy in the year before starting PCSK9-mAbs (PDC ≥ 80%), taking ≥ 4 tablets per day, and secondary prevention were associated with better adherence to PCSK9-mAbs (Table 2). A multivariate analysis revealed that better adherence to oral LDL-C-lowering therapy in the year before starting PCSK9-mAbs (adjusted OR 2.16 [95% CI 1.24, 3.78]) and secondary prevention (adjusted OR 2.44 [95% CI 1.30, 4.55]) were associated with better adherence to PCSK9-mAbs (Table 2).
| Medication adherence (PDC ≥ 80%) |
Univariate analysis Odds ratio (95% CI) |
Multivariate analysis Odds ratio (95% CI) |
|---|---|---|
| Sex | ||
| Female | 1.09 (0.61, 1.93) | 1.31 (0.70, 2.46) |
| Age, years | ||
| ≥ 60 | 1.03 (0.61, 1.73) | 0.97 (0.54, 1.72) |
| Prevention category | ||
| Secondary prevention | 2.38 (1.39, 4.00) | 2.44 (1.30, 4.55) |
| Medication adherence to oral LDL-C-lowering therapy in 1 year before the index date, % | ||
| ≥ 80% | 2.13 (1.31, 3.47) | 2.16 (1.24, 3.78) |
| Complications on the index date | ||
| Diabetes mellitus | ||
| Yes | 1.03 (0.64, 1.66) | 0.68 (0.39, 1.20) |
| Hypertension | ||
| Yes | 1.06 (0.63, 1.77) | 0.65 (0.35, 1.20) |
| Respiratory disease | ||
| Yes | 1.26 (0.78, 2.04) | 1.18 (0.69, 2.01) |
| Anxiety disorder/depression | ||
| Yes | 1.69 (0.61, 4.63) | 1.73 (0.58, 5.10) |
| Number of tablets taken daily (including all medication) | ||
| ≥ 4 | 1.73 (1.06, 2.83) | 1.61 (0.95, 2.73) |
| Number of hospital/clinic visits | ||
| ≥ 12 | 1.10 (0.68, 1.78) | 0.94 (0.53, 1.65) |
CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; mAbs, monoclonal antibodies; PCSK9, proprotein convertase subtilisin/kexin type 9; PDC, proportion of days covered.
Univariate analyses showed that better adherence to oral LDL-C-lowering therapy in the year before starting treatment with PCSK9-mAbs (PDC ≥ 80%) and secondary prevention were associated with a lower risk of discontinuation of PCSK9-mAbs (Table 3). A multivariate analysis confirmed that adherence to oral LDL-C-lowering therapy in the year before starting PCSK9-mAbs (adjusted OR 2.32 [95% CI 1.28, 4.20]) and secondary prevention (adjusted OR 3.03 [95% CI 1.56, 5.88]) were associated with a lower risk of discontinuation of PCSK9-mAbs (Table 3).
| Treatment persistence rate (at 1 year) | Univariate analysis Odds ratio (95% CI) | Multivariate analysis Odds ratio (95% CI) |
|---|---|---|
| Sex | ||
| Female | 1.19 (0.64, 2.21) | 1.50 (0.76, 2.95) |
| Age, years | ||
| ≥ 60 | 1.35 (0.77, 2.38) | 1.04 (0.56, 1.95) |
| Prevention category | ||
| Secondary prevention | 2.63 (1.54, 4.55) | 3.03 (1.56, 5.88) |
| Medication adherence to oral LDL-C-lowering therapy in 1 year before the index date, % | ||
| ≥ 80% | 2.53 (1.49, 4.31) | 2.32 (1.28, 4.20) |
| Complications on the index date | ||
| Diabetes mellitus | ||
| Yes | 1.41 (0.85, 2.35) | 0.96 (0.53, 1.76) |
| Hypertension | ||
| Yes | 1.08 (0.63, 1.85) | 0.62 (0.33, 1.19) |
| Respiratory disease | ||
| Yes | 1.05 (0.63, 1.75) | 1.03 (0.58, 1.82) |
| Anxiety disorder/depression | ||
| Yes | 2.59 (0.73, 9.18) | 2.31 (0.60, 8.84) |
| Number of tablets taken daily (including all medication) | ||
| ≥ 4 | 0.81 (0.48, 1.37) | 0.68 (0.38, 1.20) |
| Number of hospital/clinic visits | ||
| ≥ 12 | 1.08 (0.65, 1.78) | 0.83 (0.46, 1.52) |
CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; mAbs, monoclonal antibodies; PCSK9, proprotein convertase subtilisin/kexin type 9.
To our knowledge, this study is the first to investigate medication adherence to PCSK9-mAbs and treatment persistence, and the factors influencing them, among patients in Japan.
We found that medication adherence to oral LDL-C-lowering therapy (PDC ≥ 80%) in the year before starting PCSK9-mAbs and the prevention category had an impact on both medication adherence to PCSK9-mAbs during the first year and treatment persistence at 1 year in patients receiving PCSK9-mAbs. The mean PDC rates were 67.0% and 61.1% at 1 and 2 years, respectively. The percentages of adherent patients (PDC ≥ 80%) 1 and 2 years after starting treatment with PCSK9-mAbs were 55.1% and 48.9%, respectively. The cumulative treatment persistence rates 1 and 2 years after starting treatment with PCSK9-mAbs were 67.0% and 61.4%, respectively. The subgroup with adherence (PDC ≥ 80%) to oral LDL-C-lowering therapy in the year prior to the index date had significantly higher treatment persistence rates than the nonadherent subgroup (PDC ＜80%) (P=0.0001). Similarly, the secondary prevention subgroup had higher treatment persistence rates than the primary prevention subgroup (P＜0.0001). The decrease in adherence to PCSK9-mAbs and treatment persistence over time observed in this study is consistent with previous reports of oral LDL-C-lowering therapy globally27-31) and in reports from Japan24, 32, 33).
In this study, a history of cardiovascular disease (secondary prevention) was associated with better adherence to PCSK9-mAbs and better treatment persistence, supporting previous findings. Previous studies have shown that medication adherence and treatment persistence in patients receiving statins is higher in patients treated for secondary prevention and a history of CAD in comparison to patients treated for primary prevention27, 34). The reasons for this difference are unclear, but it is speculated that patients treated for secondary prevention, who have already experienced an event that statin use aims to prevent, may have an increased motivation to adhere to medication35). Additionally, the benefits of statin therapy increase with higher cardiovascular risk, whereas the risk of side effects remain relatively constant36, 37), which may contribute to better medication adherence in patients treated for secondary prevention.
Furthermore, we revealed that good adherence to oral LDL-C-lowering therapy was associated with better adherence to PCSK9-mAbs and treatment persistence. The complexity of drug regimens and cost of medication have also been suggested to increase patients’ dyslipidemia-related burden and affect medication adherence38). The concomitant use of multiple oral medications leads to poor medication adherence38). However, few studies have investigated the effect of combining injectable and oral medications on adherence. The reasons for discontinuing glucagon-like peptide-1 receptor agonists were explored in a real-world cross-sectional survey of physicians and patients with type 2 diabetes39). Preference for oral medication over injections was noted as one of the most common problems. Therefore, we speculate that patients with poor adherence to oral medications may also have poor adherence to injectable medications. Strategies such as patient education, medication reminders, cost reduction, closer follow-up and monitoring by healthcare providers (e.g., physicians, nurses, and pharmacists), simplified dosing regimens, and regular lipid testing have been recommended to improve medication adherence and treatment persistence27, 40, 41). It is essential to assess the adherence status of oral LDL-C-lowering medications before initiating PCSK9-mAbs. Medication adherence to PCSK9-mAbs may also improve if patients understand the necessity of initiating such therapy. The occurrence of adverse events (in 54% of patients) was reported as the main reason for non-persistence of PCSK9-mAb therapy at 24 months in a previous study, highlighting the importance of monitoring by a medical team for patients requiring continuous administration31). The sustained LDL-C-lowering effect of PCSK9-mAbs has been shown to emphasize the need for patient education regarding the efficacy and safety of treatment and the importance of medication adherence and persistence42).
The findings of this study suggest that patients with a history of CAD who are receiving treatment for secondary prevention and who show good adherence to oral LDL-C-lowering therapy may benefit more from treatment with PCSK9-mAbs. Factors such as age, sex, income, treatment for comorbidities, frequency of lipid testing, and medical costs have been shown to influence statin adherence27) and may also influence adherence to PCSK9-mAbs. Reducing the burden of these influencing factors may improve adherence and should be investigated further. This information can assist physicians in decision-making when prescribing PCSK9-mAb treatment to patients.
The present study was associated with several limitations. LDL-C data were not captured at 1 or 2 years. The reasons for discontinuation of PCSK9-mAbs were not obtained, and no distinction was made between the end of treatment and discontinuation. Good adherence to general oral medications, including antihypertensive and antiplatelet drugs, was likely associated with better adherence to injectable medications, such as PCSK9-mAbs. The accuracy of the patients’ health status based on the ICD-10 diagnosis registered for reimbursement may be limited. Information about treatment adherence was based on prescription data, and there was no information on whether the patient actually took the medication. The study population may also be younger than the general population with atherosclerotic cardiovascular disease owing to limitations in data availability for older age groups. Furthermore, the generalizability of the study’s findings to non-Japanese patients is limited.
This study, which was based on the analysis of an anonymized claims database, demonstrated that medication adherence and treatment persistence decreased over time with the long-term administration of PCSK9-mAbs for 2 years. Better adherence to oral LDL-C-lowering therapy and a history of cardiovascular disease were associated with better adherence to PCSK9-mAbs and treatment persistence over the first year. Further research is needed to investigate strategies to reduce patient burden and improve adherence. The findings of this study can help guide physicians in prescribing PCSK9-mAb treatment to patients.
The authors are grateful to Takumi Tajima for data management and statistical analysis. We thank Michelle Belanger, MD, of Edanz, Japan, for providing medical writing support, which was funded by Novartis Pharma K.K., Japan, through EMC K.K., Japan, in accordance with the Good Publication Practice 2022 guidelines (https://www.ismpp.org/gpp-2022).
Takeshi Morimoto received honoraria from the Bristol-Myers Squibb Company and Daiichi Sankyo Co., Ltd. Hidenori Arai received honoraria from Kowa Company, Ltd.; Daiichi Sankyo Company, Limited; Tsumura & Co.; and Astellas Pharma Inc. The authors declare no competing interests.
This study was funded by Novartis Pharma K.K.
The datasets used in the current analysis are available from the corresponding author upon request.
Y.T. contributed to the conception and design of the study; acquisition, analysis, and interpretation of data; and drafting and critical revision of the manuscript. T.M., K.I., and H.A. contributed to the conception and design of the study, interpretation of data, and drafting and critical revision of the manuscript. All authors are accountable for the accuracy and integrity of the manuscript and approved the final version.
