Addressing adherence challenges in long-term statin treatment among Asian populations: Current gaps and proposed solutions

Abstract

Statin therapy, known for its lipid-lowering properties, substantially lowers the risk of cardiovascular events in patients vulnerable to atherosclerotic cardiovascular disease (ASCVD) across diverse demographic groups. Despite evidence supporting their benefits, statins are often underutilized or even discontinued. Disparities in statin utilization exist across Asian countries due to healthcare system policies and economic circumstances. Addressing these disparities is essential, especially in the context of global initiatives designed to enhance affordability and raise awareness. Healthcare practitioners (HCPs) must assess ASCVD risks and take proactive measures aimed at lowering these risks, particularly through the management of low-density lipoprotein cholesterol (LDL-C) levels. It is imperative for HCPs and patients to collaborate for effective management of ASCVD risk, prioritizing improved adherence, treatment continuity, and better health outcomes. This review focuses on statin utilization and adherence in six Asian countries—Thailand, Malaysia, Philippines, Vietnam, Singapore, and Indonesia. It aims to explore the common factors that influence long-term adherence to statin treatment and also offers practical recommendations to improve adherence, ultimately leading to better cardiovascular outcomes in the Asian population.

1. Introduction

Statins are widely recommended for both primary and secondary prevention and treatment of atherosclerotic cardiovascular disease (ASCVD) [1,2]. Treatment with statins significantly reduces the risk of cardiovascular (CV) events in patients at high risk of ASCVD and has been shown to bring about 23 % reduction in major coronary events, 22 % reduction in vascular events, and 10 % lower all-cause mortality over 5 years [3,4].

Long-term statin therapy plays a pivotal role in preventing ASCVD and all-cause deaths through reduction in low-density lipoprotein cholesterol (LDL-C) levels and stabilization or regression of atherosclerotic plaque [[5], [6], [7]]. However, despite the significance of long-term statin therapy in achieving clinical benefits, many patients do not meet their treatment goals, thereby increasing the risk of CV events and mortality [8]. Discontinuation of statin therapy has been shown to result in a 32 % increase in major cardiovascular events (MACE) in primary prevention patients and a 28 % increase in secondary prevention patients [9].

Compared to their Caucasian counterparts, individuals of South Asian descent exhibit lower adherence to statin therapy, and it is imperative to address this issue to optimize the effectiveness of statin therapy in the management of ASCVD [10]. This review highlights the significant burden of dyslipidemia and the inadequate adherence to statin treatment in six Asian countries—Thailand, Malaysia, Philippines, Vietnam, Singapore, and Indonesia—while also providing practical recommendations to overcome these challenges and improve adherence to statin therapy in the region.

2. Epidemiology of dyslipidemia

In the last three decades, there has been a notable increase in the global prevalence of dyslipidemia, with elevated LDL-C levels advancing from being the 15^th leading cause of death in 1990 to the 8^th by 2019, thus having a major impact on public health outcomes [11]. According to the World Health Organization’s last published report, the prevalence of hypercholesterolemia among adults worldwide is 39 %, with the highest prevalence in Europe (53.7 %) and America (47.7 %). In contrast, Southeast Asia and Africa showed lower prevalence of 30.3 % and 23.1 %, respectively [12,13]. Notably, within the Southeast Asian region marked differences in hypercholesterolemia prevalence have been reported, with Thailand having the highest prevalence (56.8 %) and Singapore the lowest (17.4 %). Fig. 1 shows the prevalence of dyslipidemia across the six Asian countries, highlighting regional disparities and emphasizing the urgent need for effective management strategies [[14], [15], [16], [17], [18]]. It is important to highlight that the lipid cut-off for all the countries was set at ≥200 mg/dL.

Fig. 1.

The prevalence of dyslipidemia in Thailand, Malaysia, Philippines, Vietnam, Singapore and Indonesia have been collated from various sources; Lipid cut-off used: Total Cholesterol ≥200 mg/dL; Thailand [14]; Malaysia [15]; Philippines [16]; Vietnam [17]; Singapore [18]; Indonesia [18].

A comprehensive analysis of 1,127 population-based studies from 200 countries reports a geographical shift in the lipid-related risk between 1980 and 2018. The findings showed a decline in prevalence of dyslipidemia in high-income countries in Western Europe, North America, and Australasia which were earlier facing significant challenges in dyslipidemia management. On the contrary, dyslipidemia is becoming increasingly prominent in the Eastern and South-eastern Asian countries [19]. This increase in dyslipidemia prevalence in Asian countries can be attributed to rapid urbanization, dietary shifts, and lifestyle modifications [11].

The rise in cholesterol levels linked to elevated non–high-density lipoprotein cholesterol (non–HDL-C) levels in Asia has led to significant increase in CV mortality in countries like Thailand, Indonesia, Malaysia, Cambodia, and China [20,21]. A recent analysis of regional trends in LDL-C-related burden revealed that South Asia and East Asia are among the top three regions globally for the highest disability-adjusted life years attributable to high LDL-C and the highest number of deaths [22].

3. Statins in dyslipidemia management: Benefits and challenges

Therapeutic strategies focused on decreasing LDL-C levels have been shown to lower the risk of major coronary events [9,23]. Evidence suggests that for every 1 mmol/L decrease in LDL-C, there is roughly a 25 % relative risk reduction in CV events over a five-year timeframe [24]. Statins are the frequently prescribed medications to lower the serum levels of LDL-C, thereby playing a crucial role in secondary prevention of CVD. Table 1 outlines the LDL-C targets for secondary prevention of CVD, along with recommended treatments based on the local guidelines from the six Asian countries that are the focus of this study. High-intensity statins lower the risk of ASCVD by an additional one-third compared to moderate-intensity statins [25]. Furthermore, advantages of statin use accumulate gradually over an individual’s lifetime, with a greater proportion accruing at an older age. In addition, delaying statin therapy initiation by five years for individuals under the age of 45 results in a slight reduction in its therapeutic advantages, which is more pronounced in those at higher CV risk [26].

Table 1.

LDL-C goals for secondary cardiovascular disease prevention and suggested treatments according to local guidelines from Thailand, Malaysia, the Philippines, Vietnam, Singapore, and Indonesia.

Guidelines	LDL-C Goal	Lipid Management
Thailand[67]	•<100 mg/dL (or a 30 % reduction) for those with 10-year risk ≥10 % •<70 mg/dL for primary prevention in DM or FH •<55 mg/dL (or a 50 % reduction for clinical ASCVD)	Statins (moderate to high intensity depending on ASCVD) Non-statin intervention if LDL-C target is not reached
Malaysia[68]	•Low and intermediate CV risk: <3.0 mmol/L (116 mg/dL) •High CV risk: ≤2.6 mmol/L (100 mg/dL) or a reduction of >50 % from baseline •Very high CV risk: <1.8 mmol/L (70 mg/dL) or a reduction of >50 % from baseline	High-intensity statins for all patients with CHD or ACS and prior to PCI and CABG
Philippines[69]	•With target organ damage <70 mg/dL •With established ASCVD <55 mg/dL	High-intensity statins (based on LDL-C reduction)
Vietnam[70]	•LDL-C <1.4 mmol/L (55 mg/dL)	Statins for patients with atherosclerosis, ACS, history of MI, stable/unstable angina
Singapore[71]	•Aim for LDL-C <1.4 mmol/L (<55 mg/dL) in patients with history of ACS •Aim for LDL-C <1.8 mmol/L (<70 mg/dL) in other patients, consider lower based on clinical need and tolerability	Treat with maximally tolerated statins ± ezetimibe Consider PCSK9 monoclonal antibody or Inclisiran if LDL-C ≥1.8 mmol/L despite maximally tolerated statin and ezetimibe, especially for post-ACS, recurrent ASCVD, polyvascular disease, or FH
Indonesia[72]	•Very high risk: LDL-C <70 mg/dL and/or 50 % reduction if baseline 70–135 mg/dL	Statins for all patients unless statin intolerant
	•High risk: LDL-C <100 mg/dL or 50 % reduction if baseline 100–200 mg/dL •Moderate risk: LDL-C <115 mg/dL	Additional non-statin therapy with ezetimibe or PCSK9 inhibitors if LDL-C goals are not achieved with the highest tolerated dose of statins

ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CABG, coronary artery bypass grafting; CHD, coronary heart disease; CV, cardiovascular; CVD, cardiovascular disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; FH, familial hypercholesterolemia; HbA1c, glycated hemoglobin; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; PCI, percutaneous coronary intervention; PCSK9, Proprotein convertase subtilisin/kexin type 9; TLC, therapeutic lifestyle changes.

Despite substantial evidence supporting the benefits of statins, several barriers contribute to their under prescription by physicians and suboptimal adherence by patients, ultimately hindering attainment of treatment goals [27]. Additional factors include patients’ general preference towards lifestyle changes over medications, fear of side effects, insufficient information on treatment benefits, lack of resources in clinics (e.g., no provision of treatment tracking system or access to patient health records), and lack of continuity in patient relationships [28].

4. Statin utilization and adherence in the Asian population

4.1. Statin utilization

According to a recent study conducted across 91 countries, global statin utilization has increased by 24.7 % between 2015 and 2020. In this study, the statin sale data was converted into defined daily doses (DDD), and statin utilization was measured as DDDs per 1000 population ≥40 years per day (TPD) (2015: 54.7 DDDs/TPD; 2020: 68.3 DDDs/TPD [29]. In comparison to the global average, the statin utilization rate for Asian countries was markedly low despite having the highest age-adjusted CV mortality (East Asia: 29.3 DDDs/TPD; South Asia: 16.1 DDDs/TPD) [29]. Fig. 2 presents the statin utilization data for the Asian countries, including the 6 countries that are the focus of this review, i.e., Thailand, Malaysia, Philippines, Vietnam, Singapore, and Indonesia, relative to the global average. Both Thailand and Singapore demonstrated relatively high rates of statin utilization, which could be owing to the robust healthcare infrastructure and effective awareness campaigns. However, this should be interpreted with caution as sales data from many low income countries were not available which may underestimate the true difference in statin utilization between high and low-middle income countries.

Fig. 2.

Statin utilization in 2020 (Plot recreated from data presented in [29]).

4.2. Statin adherence

Non-adherence to statin therapy is one of the major barriers to attainment of target LDL-C levels. A pan-Asian survey-based study conducted in eight Asian countries reported that 44.1 % of participants occasionally forgot to take their statin medication, 22.7 % admitted to forgetting once every two weeks, and 15.6 % acknowledged missing their medication at least once a week [30]. This data highlights that a considerable segment of Asian population with hypercholesterolemia does not comply with the prescribed dosage of statins, thereby increasing their risk of experiencing CV events. Furthermore, findings from a recent interview-based study on patients with coronary heart disease (CHD) from 14 countries, including Indonesia, Malaysia, Philippines, and Singapore, demonstrate that only 1 % patients adhered to the recommended guidelines for secondary prevention (such as, adequate adherence to lipid-lowering drugs and LDL-C levels <1.8 mmol/L) within one year post-hospitalization [31]. Fig. 3 and the following sections present some key facts on dyslipidemia management and the available statin adherence data from six Asian countries.

Fig. 3.

Dyslipidemia management and Statin Adherence in Thailand, Malaysia, Philippines, Vietnam, Singapore, and Indonesia: An overview.

4.2.1. Thailand

The Thai National Health Examination Survey (NHES-VI) conducted in 2019 reports a marked increase in the mean plasma total cholesterol level from 199.5 to 213.2 mg/dL in women and from 192.7 to 206.8 mg/dL in men compared to that reported by NHES-V in 2014 [14]. The prevalence of dyslipidemia among the Thai population, according to the NHES-IV survey, was 66.5 % for any form of dyslipidemia with 29.6 % exhibiting elevated levels of plasma LDL-C. The NHES-IV survey adopted the classifications for high, moderate, and low HDL-C levels as outlined by the Adult Treatment Panel III of the National Cholesterol Education Program [NCEP 2002]. Notably, only 17.8 % of individuals with high LDL-C levels were aware of their condition, and merely 11.7 % received treatment [32]. However, a decade later, the NHES-VI survey reported dyslipidemia prevalence of 56.8 % and improvements in dyslipidemia screening, with a significant increase in awareness from 17.8 % to 37.5 % and treatment rates from 11.7 % to 31.9 % [14].

In 2016, Thailand implemented an institutional policy change that extended the duration of medication prescription to 90 days instead of 30 days. Subsequently, a study was conducted at Phramongkutklao Hospital to examine the effects of this policy change on medication adherence among patients with dyslipidemia and type-2 diabetes mellitus (T2DM). The study findings revealed a 4 % increase in medication possession ratios (MPRs) for dyslipidemia patients and a 5 % increase for diabetes patients in the intervention group, indicating the positive association with extended prescription lengths [33].

4.2.2. Malaysia

A cross-sectional interview and questionnaire-based study conducted in Malaysia on patients with T2DM and dyslipidemia who received statin therapy showed that majority had a high rate of adherence (98.3 %) to statin therapy (Medication Compliance Questionnaire [MCQ] scores of ≥75), with 20.5 % achieving full adherence (MCQ score of 100) [34]. A recent prospective cohort study involving 233 patients who attended a primary care clinic in Malaysia and for whom statin use was recommended found that 52.4 % of participants did not adhere to statin therapy, with low adherence linked to the behavior of seeking health information online [35].

4.2.3. Philippines

Though CVDs have been the leading cause of death in the Philippines for more than three decades, there is limited country-level statin adherence data in those at risk of CV events [36]. A semi-systematic review that examines the patient journey stages to identify any gaps that may impact decision-making and improve patient outcomes showed that the prevalence of dyslipidemia in the Philippines was 38.8 %, with 59 % of the patients undergoing treatment and 44.2 % achieving control [36]. However, there is a lack of data on patient journey touchpoints such as awareness, screening, and diagnosis for dyslipidemia [37].

In the Philippines, the national health insurance program excludes coverage for preventive services and outpatient medications. As a result, patients are responsible for 55.3 % of health expenditures through out-of-pocket costs. Additionally, unavailability of low-priced generic statins in most of the government-operated pharmacy stores and logistical challenges of maintaining medication supplies across the Philippine archipelago are other barriers to statin accessibility [36].

The limited availability of statins at grassroots levels and local government units presents a significant challenge. In rural barangay (or community) health centers, simvastatin, and occasionally atorvastatin, are the only affordable options, whereas urban barangay health centers also offer rosuvastatin. The rural barangay health centers, especially those in remote locations, face storage and staffing limitations, which contribute to the inadequate supply of these statins. However, the Universal Health Care program aims to address this by prioritizing cost-effective drugs for ASCVD prevention. Another factor that has been shown to affect medication adherence is polypharmacy, especially among elderly individuals. In addition, primary care physicians sometimes deviate from the guidelines, discontinuing statins once LDL-C goal is achieved, often due to concerns related to potential long-term side effects.

4.2.4. Vietnam

A recent semi-systematic review that aimed at identifying challenges in the management of dyslipidemia and hypertension in Vietnam did not find relevant data on medication adherence. However, based on their knowledge and current practices, the authors suggest that only around one-third of the patient population adheres to treatment for both dyslipidemia and hypertension [38]. A prospective cohort study conducted in two public hospitals in Vietnam investigated the association between prescribing guideline-recommended medications (including antiplatelet agents, beta-blockers, ACE inhibitors or angiotensin II receptor blockers and statins) to patients with acute coronary syndrome and the occurrence of major adverse events 6 months after discharge. Although the study does not provide adherence data for statins, it shows that the patients who received the recommended medications had a lower risk of experiencing major adverse events [39].

4.2.5. Singapore

A retrospective cohort study from the National Healthcare Group and Singapore Stroke Registry examined adherence to secondary stroke preventive medications and its impact on stroke recurrence and mortality post-ischemic stroke. Among 1160 patients who were prescribed statins at discharge, adherence levels were high in 28.8 %, intermediate in 17.9 %, low in 23.1 %, and very low in 30.2 % patients. Younger patients in private wards without hypertension or chronic kidney disease were less likely to adhere to statins after discharge [40].

A single-center, cross-sectional study from Singapore showed that of the 400 participants with at least one chronic disease (age ≥60 years), 60 % were non-adherent to their treatment regimen. Smokers were 2.9 times more likely to be non-adherent, while older individuals who perceived their medication regimen as complicated were 2.5 times more likely to be non-adherent. Expressing dissatisfaction with the regimen increased the likelihood of non-adherence by 2.5 times, incomplete knowledge about the purpose of the medication increased it by 2.6 times, and experiencing side effects increased it by 3.3 times [41].

4.2.6. Indonesia

In the 2013 CEPHEUS Indonesian Survey, conducted prior to the implementation of universal health coverage as part of the Pan-Asian CEPHEUS (CEntralized Pan-Asian survey on tHE Under-treatment of hypercholeSterolemia) study, patients with hypercholesterolemia aged ≥18 years, who had been on lipid-lowering therapy (LLT) for ≥3 months, were included. The survey revealed a general lack of compliance with treatment, with 50.4 % of patients ceasing medication when cholesterol levels returned to normal and 56.3 % of patients occasionally forgetting to take their tablets (22.2 % forgetting at least once a week). Furthermore, 65.1 % of the patients believed that they could miss a dose without affecting their blood cholesterol levels [42].

There have been significant developments in the lipid management landscape within the Indonesian healthcare system as of 2023. Universal health coverage in 2014 included LLT, making statins such as simvastatin 20 mg and atorvastatin 20 mg more accessible to 75 % of patients. However, there are noteworthy limitations and gaps in lipid management, such as low affordability of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and inconsistent usage of high intensity statins in the country.

4.3. Comparison with global adherence data

A comparison of adherence rates in Asian populations with the global adherence data provides valuable insights into the complex interplay of cultural and contextual influences on adherence behaviors worldwide. In real-world clinical practice, adherence to statins has been found to be inadequate. Publications from Northern America have reported statin adherence rates of 25 % after initiation of primary prevention, 36 % in patients with ASCVD, and 40 % in those with acute coronary syndromes [43].

An observational study conducted in Stockholm, Sweden, evaluated the usage trends, persistence, and adherence to LLT in patients with CHD and their correlation with achieving the LDL-C goal [44]. The findings indicated that overall, 52 % of the patients achieved the LDL-C targets. The percentage of patients who achieved the LDL-C goal was higher (56 %) among those who received high-intensity statin treatment and who exhibited good adherence. A Spanish study on 15,332 new statin users revealed that only 30.8 % had continuous medication availability, and 37.2 % showed high adherence. High adherence predictors included older age (>44 years), being a pensioner, and having comorbidities like hypertension and diabetes. Poor adherence (35.6 %) was more common in younger individuals (16-44 years) with fewer comorbidities. Occasional use was seen in 14.9 %, mostly in women and those switching statin intensity. Additionally, 12.3 % showed a gradual decline in use despite initial adherence, with no clear underlying factors [45].

Countries including Canada, the United Kingdom, Italy, Finland, and Taiwan report that between 40.8 % and 74 % of users have a mean proportion of days covered (PDC) or MPR ≥0.80. Conversely, data from China shows a mean PDC of 0.20, with only 5.9 % users achieving a PDC ≥0.50, and <1 % reaching a PDC ≥0.80, indicating a concerningly low level of adherence [46].

4.4. Impact of statin medication adherence on treatment outcomes

Despite the widespread usage of statins, the recommended LDL-C targets are often not achieved due to multiple factors, with poor adherence significantly impacting their efficacy and increasing the risk of CV events and overall mortality [47,48].

The Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study highlighted the increased CV risk associated with poor adherence to atorvastatin. The sub-analysis revealed a notable 6 % decrease in CV risk among patients with adherence rates of 80 % [47]. In China, a population-based study found a link between statin adherence and a reduced risk of MACE in patients initiating statins for primary prevention of ASCVD. These findings are consistent with those of previous studies. However, the expected correlation between statin use and a reduced incidence of MACE was not evident in patients treated for the secondary prevention of ASCVD. This could be due to the variability in disease severity within this patient population or the use of lower PDC cut-off of 0.5, which may not have effectively captured the benefits of statin adherence. Notably, there remains a scarcity of studies on statin utilization and adherence with a focus on Asian populations [46].

5. Factors influencing adherence in Asian populations

Several factors are known to contribute to poor adherence to and discontinuation of statins, and these can be categorized into patient-related, physician-related, therapy-related, disease-related, and healthcare system-related factors [8,33,49,50].

5.1. Patient-related factors

Patient-related factors, such as age and sex, play a significant role in medication adherence. Findings from a Thai study demonstrated a lower likelihood of medication adherence by patients in the age range of 26-50 years compared to those aged 18 to 25 years [33]. Data indicated that patients aged 51 to 75 years had higher adherence rates, but this trend was not statistically significant. Further, women and individuals with history of hospitalization demonstrated a lower likelihood of adhering to their prescribed medication compared to men [33].

Affordability of lipid-lowering drugs also significantly influences adherence, particularly in low- and middle-income countries, where a 10 % rise in out-of-pocket health expenses has been associated with 11 % drop in utilization [29,51]. The expenses associated with conventional medicines have also contributed to preference for complementary and alternative medicine (CAM), particularly in the Asian population. A study from the Philippines reveals that 43 % of the population chose CAMs over conventional medicines, while only 15 % sought formal medical consultation [52].

Concerns regarding possible side effects, or previous experiences of adverse effects with the same medication, represent another significant patient-related factor that has been linked to non-adherence or the cessation of treatment [28]. Numerous studies, predominantly observational, non-randomized, and unblinded, have suggested that statin therapy is linked to an increased incidence of adverse events. However, findings from double-blinded randomized clinical trials indicate that the only adverse events with substantial evidence attributable to long-term statin therapy are myopathy, new-onset diabetes mellitus, and transaminitis [53,54]. Furthermore, the ASCOT trial, which involved patients with hypertension from the UK and Nordic countries receiving atorvastatin 10 mg, noted that an increase in reported adverse events occurred only when both patients and their physicians were aware of the statin therapy, i.e., during the non-blinded phase, compared to the blinded phase [53]. These findings are consistent with the nocebo effect, which has also been demonstrated by a retrospective cohort study that used the Food and Drug Administration Adverse Event Reporting System. The analysis indicated that the rates of nocebo-related subjective adverse events linked to statin use, such as fatigue and weakness, were greater than those of objective adverse events [55].

The nocebo effect for adverse events may further be amplified if the information on these subjective adverse events is easily accessible online. A recent study investigated whether there is a link between the behavior of searching for health-related information on the internet and statin adherence. The results indicated that individuals who proactively searched for information online are more likely to come across misinformation regarding statins. This exposure to health information from unverified sources may result in increased concerns about statin use and impact medication adherence [56].

Another notable patient-related factor that affects adherence is statin intolerance. The National Lipid Association’s scientific statement from 2022 defines statin intolerance as a condition in which a patient experiences adverse effects after trying at least two statins, including one administered at the lowest daily dosage. These adverse effects typically arise within 12 weeks of starting treatment and tend to improve on dose reduction or discontinuation [57]. Statin intolerance may present as either complete intolerance to a statin or partial inability to tolerate a specific dose. A retrospective study conducted in Japan revealed that 10 % of patients within the ASCVD cohort exhibited possible statin intolerance after 12 months of initiating treatment [58]. Furthermore, a meta-analysis with data from 176 studies involving over 4 million patients estimated the global prevalence of statin intolerance to be 9.1 % (8.1 %-10 %) [59]. The diagnosis of statin intolerance is often challenging due to various factors such as presence of other health issues, concomitant medication use, and demographic characteristics. A meta-analysis of large, long-term, randomized clinical trials revealed that over 90 % of muscle-related symptoms experienced by statin users were not attributable to statins themselves. This highlights the importance of accurate diagnosis of statin intolerance and the need for thorough evaluation of potential indicators and symptoms of statin intolerance [60]. Addressing these in a timely manner is essential to prevent treatment discontinuation due to statin intolerance and to mitigate the heightened risk of ASCVD.

Patient’s insufficient knowledge and understanding of the disease, refusal to acknowledge the seriousness of the disease, uncertainty towards the effectiveness and safety of the prescribed regimen, lack of trust in HCPs, low socioeconomic status, and poor health literacy are some of the other patient-related factors that act as barriers to statin adherence [33,37,50].

5.2. Physician-related factors

The absence of a strong rapport and mutual understanding between the HCPs and the patients, coupled with non-compliance with clinical guidelines, and a lack of insight into the patient’s adherence-behavior are the key physician-related factors that lead to poor adherence. It has also been observed that the involvement of multiple physicians in managing a single patient can result in inconsistencies in the treatment regimen [50].

Moreover, many physicians are often hesitant to prescribe statins to patients with multiple comorbidities, including diabetes, kidney or liver disease, HIV infection, due to concerns about potential side effects and drug interactions. Consequently, patients at high-risk for CV events may not receive adequate statin therapy or necessary treatment intensification, which is critical for lowering LDL-C levels and preventing significant CV events [27].

The role of physicians is essential in ensuring patients adhere to long-term statin therapy, as they can help alleviate many patient-related factors by providing accurate information and enhancing patient education.

5.3. Therapy-related factors

Therapy-related factors (e.g., quantity and type of medication, medication prescription length) also affect adherence rates. Findings from a study conducted in dyslipidemia and diabetes patients from Thailand demonstrated that individuals prescribed a single medication demonstrated a 3.2-times higher likelihood of adherence compared to those with multiple prescriptions (polypharmacy), with the frequency of drug administration also playing a role. Further, an increase in the duration of prescription to 90 days instead of 30 days was associated with an improved adherence, which could be due to continuity of care at the same hospital. This would also allow HCPs to dedicate more time to their patients’ needs [33,50].

5.4. Disease-related factors

The presence of other comorbidities also affected adherence levels. Patients with concomitant comorbidities such as cerebrovascular disease, congestive heart failure, cancer, and cognitive impairments showed lower adherence rates, while those with other diseases demonstrated higher adherence. Over time, adherence to therapy regimens tends to decrease, particularly during management of long-term chronic diseases [33,50].

5.5. Healthcare system-related factors

Healthcare system-related factors, such as access to medications, cost of medications and healthcare amenities, and limited access to healthcare facilities and medical care can significantly impact adherence to statin treatment. The challenges in maintaining adherence to statin therapy may have been exacerbated due to the COVID-19 pandemic by causing disruptions in continuity of care and access to medications [45].

The lack of adherence to recommended treatment protocols and clinical practice guidelines by HCPs is another healthcare system-related factor that may affect patients’ adherence to statins. It is essential to establish systems that monitor adherence to these protocols across various levels of care, ensuring consistency and quality in treatment delivery.

Moreover, constraints in the logistical set-up may restrict adequate consultation time which in turn can limit the amount of time available for the HCPs to educate the patient, assess patients' concerns related to adherence. Other factors include inadequate clinical supervision of patients and reimbursement challenges [37,50].

6. Practical recommendations for improving adherence

It is crucial to educate patients on treatment goals and ASCVD risks and document their ASCVD risk scores. HCPs should emphasize lipid-related CV risk assessment and the aggressive management of LDL-C levels. Furthermore, the HCPs should be aware of the known predictors and factors associated with statin intolerance to ensure early recognition and management through dose adjustments or alternative therapies. Ensuring that statins can be prescribed and managed effectively at lower levels of the healthcare system (like in primary care) is crucial for improving accessibility and reducing barriers for those who need treatment. Innovative treatment strategies should be embraced to overcome existing barriers, with a focus on multifactorial interventions tailored to individual patient needs and considering the use of combination therapies when necessary for optimal LDL-C reduction in high or very high CV-risk patients [61]. The 23^rd WHO Model List of Essential Medicines includes polypills for CVD prevention [62]. The widespread adoption of polypills could result in considerable public health benefits, particularly by increasing access in the low- and middle-income countries. However, a larger-scale implementation would require training of HCPs on clinical algorithms related to polypills and inclusion in clinical guidelines.

HCPs and patients can collaborate to optimize ASCVD risk management, focusing on improved adherence, treatment continuity, and health outcomes. Behavioral nudges can be an effective tool to address some of the common barriers to treatment adherence through setting of achievable health goals and engagement of patients in shared decision-making. The ENCOURAGE trial that used artificial intelligence-driven behavioral nudges in cardiology patients highlighted the potential of behavioral nudges in the form of personalized reminders and goal setting to improve statin adherence [63]. The findings demonstrated significantly higher statin adherence in the nudge group compared to the controls after 12 months, demonstrating the potential of this strategy in promoting better health outcomes. A systematic literature review focusing on the impact of non-pharmacological interventions showed that health education approaches, phone reminders, and digital self-management applications positively impact medication adherence [64]. Another systematic review of studies used electronic health record (EHR) systems to identify patients who were non-adherent to statins. Apart from strategies such as in-person counselling and phone/text reminders, simplification of treatment regimens, use of combination medicines, alternate dosing, and medication refill reminders to the pharmacies have also been shown to improve statin adherence [65].

Policymakers should consider revising existing public hospital policies and guidelines to address the lack of national policy direction, while public hospitals can set an example by prioritizing medication adherence with patient-centered policies [33]. The HEARTS technical package, which is a component of the broader Global Hearts Initiative of WHO, serves as an effective resource for policymakers and influence CVD primary care delivery [66]. Further research and customized educational programs are required to comprehend and enhance patient adherence in real-world contexts [47]. Table 2 outlines actionable recommendations for HCPs, allied professionals, policymakers, and patients to improve treatment outcomes and improve adherence rates by implementing evidence-based strategies that are customized to address barriers to adherence.

Table 2.

Practical recommendations to improve statin adherence.

Healthcare practitioners	Inform patients about the significance of total CVD risk prevention Emphasize the importance of consistent statin therapy adherence [33,43,73] Educate and empower patients to be actively involved in their treatment [43,50,73] Encourage open communication and address concerns regarding adverse outcomes [73,74] Inform patients about potential adverse drug interactions between statins and other prescription drugs [74] Maintain patient engagement through regular check-ins [43] Schedule follow-up appointments to monitor effectiveness and make any adjustments as needed [43,50,75] Intervene early if signs of non-adherence are noted [33] Customize treatment strategies to overcome barriers to adherence [43,50] Pay attention to symptoms of and factors associated with statin intolerance for timely intervention [58] Consider statin rechallenge with a washout period for patients with previously documented occurrence of statin intolerance [73] Use behavioral nudges to engage patients in shared decision-making with a focus on achievement of their health goals [63]
Policy makers	Develop patient education programs to increase awareness of the benefits of following prescribed regimens and risks of non-adherence [73] Enhance patient care through better collaboration between healthcare practitioners and pharmacists, who can monitor adherence, offer counselling, and address concerns [43,73] Address disparities between high-income and low/middle-income countries and emphasize on the need for global initiatives, improved medication access, and reduced ASCVD burden in low- and middle-income countries [29] Consider extension of prescription lengths from 30 to 90 days (where applicable) to improve long-term medication adherence [33] Prioritize initiatives for improved affordability of statins Encourage and develop common understanding between policy makers, national health insurances, and healthcare practitioners on the importance of accessibility of statins, especially high intensity statins for the high-risk and very high-risk patients, for better health outcomes and reduced burden on the healthcare system
Patients	Understand the importance of adherence to their prescribed medication [43] Maintain consistent adherence as directed by their healthcare practitioner [43] Employ medication schedules specifying the time to take medications, drug cards, medication pill boxes, ‘unit-of-use’ packaging, and special containers indicating the time of dose [76] Use electronic reminders like SMS alerts or mobile apps to refill prescriptions in a timely manner [43,50]
Pharmacists	Consider use of single-dose packaging or prefilled blister packs when dispensing medication [43,50] Provide counselling, monitor side effects, and offer solutions for adherence issues, where needed [37,50] Review medication refill details with patients [43] Utilize automated reminders to prompt timely refills and prevent treatment interruptions [43]
Other recommendations	Incorporate patient-centered education tools like videos or apps to emphasize the significance of statin treatment [43,50] Implement pharmaceutical care programs to encourage collaboration between pharmacists and HCPs to address patients’ specific needs [73] Address risk perception and symptom awareness as dyslipidemia is often asymptomatic [37] Explore cost-effective options like generic medications and patient assistance programs for financial constraints [37,75]

7. Conclusion

Statins play a crucial role in reducing ASCVD risk. However, suboptimal adherence remains a significant challenge, especially in the Asian populations. This necessitates tailored interventions to overcome barriers related to patients, physicians, therapy, disease, and healthcare systems. The global adherence data underscore the importance of improving medication adherence to enhance treatment outcomes and reduce CV risks. Implementing evidence-based strategies, enhancing patient education, revising existing policies, and establishing longitudinal adherence monitoring systems in Asia are essential steps toward providing robust data for informed decision-making, improving statin adherence and alleviating the burden of ASCVD in Asia. Furthermore, additional research and customized educational programs are warranted to effectively address adherence challenges. This review also highlights a critical need for multi-country collaborative studies to explore regional factors affecting statin adherence.

Funding

Medical writing support was funded by Viatris.

Author declaration

We wish to draw the attention of the Editor to the following facts which may be considered as potential conflicts of interest and to significant financial contributions to this work.

Elmer Jasper B Llanes declares speaker honoraria from Servier, Orient EuroPharma, Organon, Menarini, and AstraZeneca. Nuntakorn Thongtang declares speaker honoraria from Amgen, Novartis, Merck Sharp & Dohme, AstraZeneca and Daiiji Sankyo. Zhen-Vin Lee declares speaker honoraria from Abbott Vascular, Amgen, Aspen, AstraZeneca, Bayer, BIOTRONIK, Boehringer Ingelheim, Medtronic, Merck Sharp & Dohme, Novartis, Novugen, Pfizer, Sanofi, Servier, and Viatris. Tran Hoa declares speaker honoraria from Novartis, Viatris, and AstraZeneca. Ong Hean Yee and Renan Sukmawan have no conflicts of interest to declare.

We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.

We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.

We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). He is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author.

CRediT authorship contribution statement

Elmer Jasper B Llanes: Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Conceptualization. Nuntakorn Thongtang: Writing – review & editing, Writing – original draft, Visualization, Validation, Conceptualization. Zhen-Vin Lee: Writing – review & editing, Writing – original draft, Visualization, Validation, Conceptualization. Tran Hoa: Writing – review & editing, Writing – original draft, Visualization, Validation, Conceptualization. Ong Hean Yee: Writing – review & editing, Writing – original draft, Visualization, Validation, Conceptualization. Renan Sukmawan: Writing – review & editing, Writing – original draft, Visualization, Validation.

Declaration of competing interest

Elmer Jasper B Llanes declares speaker honoraria from Servier, Orient EuroPharma, Organon, Menarini, and AstraZeneca. Nuntakorn Thongtang declares speaker honoraria from Amgen, Novartis, Merck Sharp & Dohme, AstraZeneca and Daiiji Sankyo. Zhen-Vin Lee declares speaker honoraria from Abbott Vascular, Amgen, Aspen, AstraZeneca, Bayer, BIOTRONIK, Boehringer Ingelheim, Medtronic, Merck Sharp & Dohme, Novartis, Novugen, Pfizer, Sanofi, Servier, and Viatris. Tran Hoa declares speaker honoraria from Novartis, Viatris, and AstraZeneca. Ong Hean Yee and Renan Sukmawan have no conflicts of interest to declare.