Abstract
Aims: Patients with familial hypercholesterolemia (FH) are known to have higher exposure to coronary risk than those without FH with similar low-density lipoprotein cholesterol (LDL-C) level. Lipid-lowering medications (LLMs) are the mainstay treatments to lower the risk of premature coronary artery disease in patients with hypercholesterolemia. However, the LLM prescription pattern and its effectiveness among Malaysian patients with FH are not yet reported. The aim of this study was to report the LLM prescribing pattern and its effectiveness in lowering LDL-C level among Malaysian patients with FH treated in specialist hospitals.
Methods: Subjects were recruited from lipid and cardiac specialist hospitals. FH was clinically diagnosed using the Dutch Lipid Clinic Network Criteria. Patients’ medical history was recorded using a standardized questionnaire. LLM prescription history and baseline LDL-C were acquired from the hospitals’ database. Blood samples were acquired for the latest lipid profile assay.
Results: A total of 206 patients with FH were recruited. Almost all of them were on LLMs (97.6%). Only 2.9% and 7.8% of the patients achieved the target LDL-C of ＜1.4 and ＜1.8 mmol/L, respectively. The majority of patients who achieved the target LDL-C were prescribed with statin–ezetimibe combination medications and high-intensity or moderate-intensity statins. All patients who were prescribed with ezetimibe monotherapy did not achieve the target LDL-C.
Conclusion: The majority of Malaysian patients with FH received LLMs, but only a small fraction achieved the therapeutic target LDL-C level. Further investigation has to be conducted to identify the cause of the suboptimal treatment target attainment, be it the factors of patients or the prescription practice.
See editorial vol. 30: 1303-1304
Introduction
Familial hypercholesterolemia (FH) is the most commonly inherited dyslipidemia in humans, which is caused by a number of lipid metabolism-regulating genes, including LDLR, APOB, and PCSK9 1). The global prevalence of FH is estimated to be approximately 1:250 2). In Malaysia, a national epidemiological study on FH had estimated the FH prevalence as twice as high at approximately 1:100 3). The genetic mutations lead to severe elevation of blood low-density lipoprotein cholesterol (LDL-C) level even in very young age, causing increased risk of premature coronary artery disease (CAD). Without appropriate treatment, patients with FH will suffer a 20-fold lifetime increase risk of CAD compared to those without FH4).
Statin has been utilized for almost three decades as first-line medication in treating various hyperlipidemia, including FH5). Even with the emergence of novel and potent lipid-lowering medications (LLMs) such as PCSK9 inhibitors, statin remains as the mainstay medication for FH due to its lower cost. Depending on the intensity of the statin, consistent administration of statin may reduce the LDL-C level to ≥ 50%6). Other non-statin LLMs such as bile acid sequestrant or ezetimibe are prescribed in conjunction with a statin to further increase the LDL-C reduction by an additional 15%–19%7). Prescription of moderate- to high-intensity statin monotherapy to patients with FH may reduce the CAD mortality by up to 44%8). Early initiation of statin therapy as early as 10 years in patients with FH has been demonstrated to extend CAD risk-free life for almost up to 20 years compared to untreated patients with FH9), which is just as good as individuals without FH10). Second-line non-statin LLM such as ezetimibe monotherapy is also prescribed to patients who do not tolerate the side effects of statin. Although the LDL-C reduction of ezetimibe monotherapy is not as great as statin, approximately 19% reduction of LDL-C was expected when 10 mg of ezetimibe was prescribed to patients with hypercholesterolemia11).
Despite the documented benefits of LLMs in treating FH, patients with FH are often under-diagnosed and under-treated among the general population, where many non-European countries only managed to identify ＜1% of their estimated nationwide patients with FH12). Currently, Malaysia is still lacking of standardized national clinical practice guidelines for diagnosis and management of FH, with the Dutch Lipid Clinic Network (DLCN) and Simon Broome Register Criteria being the most popular diagnostic criteria utilized by the clinicians to screen for FH13). Nevertheless, only approximately a quarter of Malaysian primary care physicians were aware of the FH diagnostic criteria, and only 19.1% correctly stratified patients with FH as patients with high coronary risk14). Even if the patients with FH were treated with LLMs, not all of them achieved the therapeutic target LDL-C level. In many Western Pacific and Southeast Asian countries, ＜10% of patients with FH achieved the desired LDL-C level of ＜1.8 mmol/L15).
Thus far, the largest multinational Asian study on the pattern and effect of LLMs was conducted under the Centralized Pan-European Survey on The Under-treatment of Hypercholesterolemia (CEPHEUS) Pan-Asia study, where eight countries, including Malaysia, had participated16). The study had enrolled 8,064 patients with hypercholesterolemia on LLMs and found that approximately half of the patients achieved their target LDC-C level after ≥ 6 weeks of stable medication, whereas 36.6% (n=112) of patients with FH within the study cohort managed to achieve the target LDL-C level. However, the study did not report the composition and coronary risk stratification of the patients with FH. Recently, a new guideline on coronary risk stratification for patients with FH has been outlined by the European Society of Cardiology and European Atherosclerosis Society (ESC/EAS)17). Therefore, there is a need to review the epidemiological information on the LLMs among patients with FH using the new guidelines. Here, we aimed to study the prescribing pattern of LLMs among Malaysian hospital-based patients with FH and how many of them achieved the target LDL-C level according to their DLCN categories and coronary risk stratification.
Methods
Subject Recruitment
Candidate subjects were screened among Malaysian patients with hypercholesterolemia registered in the National Heart Institute (IJN), Universiti Teknologi MARA (UiTM) Cardiology Clinic and UiTM Specialist Lipid Clinic database. All subjects were clinically diagnosed using the DLCN criteria. Patients with baseline LDL-C ＜4.0 mmol/L were excluded due to the low possibility of those patients being FH18). Patients with a DLCN score of ＜3 (unlikely FH) were also excluded. Patients with secondary hypercholesterolemia (hypothyroidism, chronic kidney disease, nephrotic syndrome, and cholelithiasis) or pregnant patients were also excluded. Subjects who were clinically diagnosed as definite, probable, and possible FH after considering the exclusion criteria were considered as patients with FH and contacted for an appointment for study enrollment. Written informed consents were obtained from all patients with FH prior to participation in the study.
Demographic, Anthropometric, and Clinical Data Collection
Demographic data, lifestyle, and personal and family history were acquired using a standardized questionnaire. Detailed clinical data such as baseline LDL-C level and history of LLMs were acquired from the hospitals’ database. If baseline LDL-C level was not available, the estimated level was calculated using the pre-treatment LDL-C correction factor19). To preserve data confidentiality, only one graduate research assistant was assigned to collect the primary data from the hospitals’ database, whereas the patients in secondary data were deidentified and assigned with new subject numbers. Post-treatment LDL-C was defined as LDL-C with at least 3 months of stable LLM administration. Target LDL-C level attainment was evaluated based on the 2019 ESC/EAS Guidelines for the Management of Dyslipidaemia17) and Malaysian Clinical Practice Guidelines for Dyslipidaemia20). The intensity of statin therapy was classified according to the American College of Cardiology/American Heart Association Guidelines on the Management of Blood Cholesterol6). Patients with poor adherence (self-reported of frequent failed, reduced, or alternate intake of medications in the past 1 month or failure to attend previous medication resupply appointment at the pharmacy counter) to LLM prescription for more than 1 month were considered as not on LLMs. Anthropometric measurements such as height, weight, and waist circumference were measured on site. Blood pressure was measured twice, 2 min apart on the right arm in a sitting position, where blood pressure ≥ 140/90 mmHg or current use of antihypertensive medication was considered as hypertension.
Premature CAD was defined as subjects with abnormal coronary angiogram with stenosis of ＞50% in at least one major epicardial artery segment, who had undergone percutaneous coronary intervention, and/or who had a history of coronary artery bypass graft surgery. Those criteria must be first diagnosed at the age of ＜55 years old in men and ＜60 years old in women12). Coronary risk was assessed according to the Framingham Coronary Risk Scoring21) and EAS/ESC Guidelines for the Management of Dyslipidemias17). All patients with FH were at least considered as high-risk patients, whereas those FH patients with atherosclerotic cardiovascular disease or with at least one major coronary risk factor were further classified as very high-risk patients. Physical examination for premature corneal arcus (at age ＜45 years) and tendon xanthomata was conducted by physicians at the clinics.
Blood Sampling and Laboratory Analysis
Nine milliliter of venous blood from patients with FH was collected into plain and sodium fluoride/potassium oxalate tubes for lipid profile and glucose assays, respectively. Serum and plasma were obtained after the tubes were centrifuged at 4,000 rpm for 15 min and stored at −20℃ until analysis. Lipid profile (total cholesterol, triglycerides, and high-density lipoprotein cholesterol) and glucose assays were performed using an automated analyzer (COBAS Integra® 400; Roche, Germany). LDL-C level was calculated using the Friedewald equation. Diabetes was defined as having a fasting plasma glucose ＞7.0 mmol/L, random plasma glucose ＞11.1 mmol/L, or on antidiabetic medication.
Statistical Analysis
Data were analyzed using the IBM SPSS Statistics version 22 (IBM, Armonk, NY, USA).
Ethical Approval
Ethical approval was obtained from the related Institutional Research Ethics Committee [Ref: UiTM 600-IRMI [5/1/6] and IJNEC/03/2012 (6)] in accordance with the Declaration of Helsinki.
Results
Out of 815 patients screened in this study, a total of 206 patients with FH were recruited, where the majority was male patients (68.0%). All patients were with LDL-C ≥ 4.0 mmol/L and clinically diagnosed as definite, probable, or possible by the DLCN criteria, with the majority classified as possible FH (40.8%) (Fig.1). Except for four individuals, the rest of the recruited patients with FH have a history of premature CAD or at least one major coronary risk factor (n=202, 98.1%) (Table 1), where they were classified under the very high coronary risk category.
Table 1.
Baseline characteristics of recruited patients (
n = 206)
| Variables |
Values |
| Age (years) |
52.3 (±12.07) |
| Gender (n, % male)
|
140 (68.0%) |
| Untreated LDL-C (mmol/L) |
6.0 (±1.7) |
| Treated LDL-C (mmol/L) |
3.2 (±1.3) |
| TC (mmol/L) |
6.2 (±2.3) |
| TG (mmol/L) |
1.5 (IQR 1.1) |
| HDL-C (mmol/L) |
|
| - Male |
1.2 (±0.3) |
| - Female |
1.5 (±0.3) |
| BMI (kg/m2)
|
27.7 (±5.5) |
| Waist circumference (cm) |
|
| - Male |
96.2 (±10.8) |
| - Female |
88.1 (±12.0) |
| Diabetes (n, % yes)
|
62 (32.5%) |
| Hypertension (n, % yes)
|
104 (51.5%) |
| Smoking (n, %)＊
|
Current smoker: 47 (23.2%) |
|
Ex-smoker: 49 (24.1%) |
|
Non-smoker: 107 (52.7%) |
| Personal history of premature CAD |
116 (56.3%) |
| Family history of CAD |
99 (49.3%) |
| Corneal arcus (age ＜45 years old) |
42 (20.4%) |
| Tendon xanthomata |
44 (21.4%) |
| On LLM (n, % yes)
|
201 (97.6%) |
| Presence of ≥ 1 coronary risk factors |
202 (98.1%) |
LDL-C = Low-density lipoprotein cholesterol; TC = Total cholesterol; TG = Triglycerides; HDL- C = High-density lipoprotein cholesterol; CAD = Coronary artery disease; BMI = Body mass index; LLM = Lipid-lowering medication.
Normally distributed continuous data are presented as mean with±standard deviation (SD);
Non-normally distributed continuous data are presented as median with interquartile range (IQR); Nominal data are presented as percentage of individuals who have the condition.
＊Individuals without data were removed.
With respect to target LDL-C level achievement, only 2.9% of patients with FH in this study achieved the ＜1.4 mmol/L target, but the percentage was almost triple (7.8%) if the LDL-C target was set at 1.8 mol/L (Fig.2a). The percentage of patients who achieved 50% LDL-C level reduction was gradually decreased from possible and probable to definite FH (from 52.4% and 43.6% to 29.9%) (Fig.2b-d). Generally, patients with less severe FH, which is possible FH, were more prone to achieve the therapeutic target LDL-C levels than those with probable and definite FH. When excluding the patients with high coronary risk, the percentages of patients with very high coronary risk (n=202) who achieved the LDL-C target attainment of ＜1.4, ＜1.8, ＜2.6, ＜3.0, and ＜3.4 mmol/L and ＞50% reduction were 3.0%, 7.9%, 34.2%, 50.0%, and 62.9%, respectively. Out of the four remaining patients with FH who were categorized as high coronary risk, three did not achieve any targeted LDL-C levels, whereas one achieved ＜3.0 mmol/L and ＞50% reduction of LDL-C.
The majority of the recruited patients were on LLMs (97.6%) (Table 1), where almost half of the recruited patients (42.2%) were on high-intensity statins. Moderate-intensity and low-intensity statins were the next most frequently prescribed LLMs at 28.6% and 13.6%, respectively. Statin–ezetimibe combination was prescribed to 12.1% of the patients. Of the 206 patients, 1.0% received monotherapy ezetimibe 10 mg instead of statin (Fig.3). High-intensity statins were the most frequently prescribed LLMs. Five out of 206 (2.4%) recruited patients were categorized as not on LLMs, where three of them were in the very high coronary risk group.
As expected, the LDL-C level of patients without LLMs or who only received monotherapy ezetimibe was at the higher end of the LDL-C level categories, where their post-treatment LDL-C was ≥ 3.0 mmol/L. The majority of very high-risk patients (＞90%) who reached an LDL-C of ＜1.8 mmol/L (target LDL-C level for high-risk patient) were treated with statin–ezetimibe combination LLM and high-intensity or moderate-intensity statin, whereas only one received moderate-intensity statin (Fig.4).
Discussion
To the best of our knowledge, this is the first study to report the LLM pattern and the therapeutic target attainment of patients with FH while stratifying their coronary risk based on the latest ESC/EAS guidelines. Identifying high and very high-risk patients with FH is important because the presence of FH mutation increases the odds of CAD for 3.8 fold compared to those without FH mutation22), thus making patients with FH require more aggressive LLMs, which was not being sufficiently addressed in the preceding guidelines.
As outlined by the NCEP ATP III guidelines for coronary risk stratification, all patients with FH were generally categorized as high-risk patients with therapeutic target for LDL-C set at ＜1.8 mmol/L16). In the 2016 ESC/EAS guidelines for the management of dyslipidemia, patients with FH with and without major coronary risk factors were further stratified into very high and high risk, respectively, where both of the risk categories have different therapeutic target LDL-C levels of ＜1.8 and ＜2.6 mmol/L, respectively23). However, the guidelines were updated in 2019 where target LDL-C levels in very high-risk and high-risk categories were further lowered to ＜1.4 and ＜1.8 mmol/L respectively, making the therapeutic target even more stringent17). In Malaysia, the general practice for treating patients with FH at very high and high risk is in accordance with the 2019 ESC/EAS guidelines20). In the present study, owing to guidelines change, the therapeutic target LDL-C level attainment for patients with FH appears to be low compared to what has been reported in the 2012 CEPHEUS Pan-Asia study, which used the NCEP ATP III guidelines for target LDL-C attainment (2.9% vs. 49.4% achieved LDL-C level for very high-risk patients), although not all of the participants in the CEPHEUS Pan-Asia study were patients with FH16).
The Spain-based SAFEHEART study had reported its national target LDL-C attainment in a cohort of ＞4,000 patients with FH, following the earlier version of the ESC/EAS guidelines that set the target LDL-C level for very high and high-risk patients with FH as ＜1.8 and ＜2.6 mmol/L, respectively24). The study reported that 1.1% of their very high-risk patients with FH reached an LDL-C of ＜1.8 mmol/L, whereas 3.3% of high-risk patients with FH reached ＜2.6 mmol/L. For comparison purpose, if the present study uses the similar guidelines instead of the updated 2019 ESC/EAS guidelines, the LDL-C target attainment could be significantly high at 7.8% for ＜1.8 mmol/L (if set for very high risk) and 33.5% for ＜2.6 mmol/L (if set for high risk). However, a sub-cohort report of the CEPHEUS Pan-Asia study from Hong Kong had reported an even higher target LDL-C level attainment of ＞80% at 1.8 mmol/L among their participants with hypercholesterolemia (n=561)25). The exceptionally high target LDL-C attainment was reported as due to their very efficient and aggressive national treatment protocol for patients with CAD. Nevertheless, the Hong Kong study was not an FH-specific observational study, where only one of their recruited patients had FH, who did not achieve the target LDL-C level anyway. This could be the reason behind the high target LDL-C attainment of the study, suggesting that FH genetic mutations may play a role in determining the efficacy of LLMs.
A large Japanese retrospective observational study on LLMs and target LDL-C level attainment among patients with cardiovascular disease (n=33,000), which followed the Japan Atherosclerosis Society (JAS) guidelines for cardiovascular risk stratification, had recorded a target LDL-C level attainment of 68%26), which is also almost as high as in the Hong Kong cohort CEPHEUS Pan-Asia study. Two years later, the same study group reported an FH-exclusive LLM and target LDL-C level attainment study, with a total sample size of ＞3,000 patients with FH27). With the JAS guidelines that set the target LDL-C level for FH as 2.6 mmol/L, 16.5% of their patients with FH had achieved the target LDL-C level (compared to this study at 43.4%). However, their LDL-C level attainment for ＜1.8 mmol/L was only 2.8%, which was lower than the present study (7.8%). The Japanese study achieved the lower rate of target attainment probably due to the inclusion of large portion of patients with FH who were not treated with any LLM (35%), compared to this study that only included 2.4% of patients with FH who were without any LLM. The relatively lower percentage of LLM prescription in Japan than in Malaysia may be due to the difference in prescription of high-intensity LLMs between these two countries (Japan: 2.9% vs. Malaysia: 42.2%). The source of disparity also lies within the medical bill coverage in both countries, where the LLMs for Japanese patients with FH have to be covered by medical insurance28), whereas in Malaysia, the LLMs are fully subsidized by government hospitals29).
With the oddly superior percentages of LLM prescription and target LDL-C level attainment when compared with other previous studies, Malaysian hospital-based patients with FH can be considered as relatively well-treated and controlled. However, if taking the updated 2019 ESC/EAS guidelines as a standard treatment rule, the target LDL-C attainment for very high-risk patients in the present study is still significantly low, where only 2.9% of definite patients with FH achieved the target LDL-C level of ＜1.4 mmol/L. Nationwide, the estimated detection rate of patients with FH in Malaysia is very low at ＜0.5%3). Even if the patients with FH are detected by the primary care physicians among the community, only approximately half of them will be referred to the specialist lipid clinics, whereas those who are not referred to the specialist lipid clinics will continue to receive suboptimal LLMs from the primary care clinics30).
All patients with FH should have been treated with maximally tolerated moderate- to high-intensity statin or co-administered with other non-statin LLMs if statin monotherapy is ineffective. Initiation of LLMs in younger age may also improve the target LDL-C level attainment in later life16). PCSK9 inhibitors have been documented to further reduce the LDL-C for additional ＞50% among heterozygous patients with FH when combined with statins31, 32) and should be considered if none of the LLM modality stated above is effective. However, PCSK9 inhibitors are still not commonly prescribed in Malaysian hospitals due to the unsubsidized high cost of the medication, where not many routine patients with FH can afford this treatment option15).
The present study had some limitations, including limited sample size and small number of participating hospitals. Owing to financial constraint, FH was also only clinically diagnosed without being molecularly confirmed. Other cited studies may have not been fairly compared to the present study due to the difference in inclusion criteria, the way of defining FH, and the classification of LLMs. A high percentage of patients with diabetes in the present study at 32.5% compared to the Malaysian normal population, which is approximately 10%33), may also influence the accuracy of mean LDL-C level of this study, as insulin resistance is known to cause diabetic dyslipidemia34). Further study with multicenter participants across the nation, supported by molecular confirmation of FH using streamlined genetic test such as next-generation sequencing, is warranted.
Conclusion
Therapeutic target LDL-C levels are generally harder to achieve by patients with severe FH than by patients with less severe FH. Both high and very high coronary risk groups have low percentage of LDL-C target achievement. The reinforcement of target LDL-C levels for very high and high-risk patients with FH by current guidelines has set the FH treatment into a stricter regime, where only a very small percentage of Malaysian patients with FH had successfully achieved the target LDL-C level. While the majority of Malaysian patients with FH had been already treated with high-intensity statin or statin–ezetimibe combination, only a small percentage of very high-risk patients with FH achieved the target LDL-C level of 1.4 mmol/L as outlined by the updated ESC/EAS guidelines. Nevertheless, the LDL-C target attainment of Malaysian patients with FH was still comparable or better than other countries if the target LDL-C levels are set at 1.8 and 2.6 mmol/L. Specialist doctors should be more proactive in initiating high-intensity LLMs to patients with FH from the time of diagnosis and strive to adjust the prescription until the therapeutic target is achieved, whether by monotherapy or combination therapies, without compromising the patients’ tolerance to the medication.
Acknowledgement
This study was funded by Malaysia Ministry of Higher Education Long Term Research Grant Scheme [600-RMI/LRGS 5/3 (2/2011)-2] and UiTM MITRA Grant [600-IRMI/MYRA 5/3/MITRA (003/2017)-1], which had been awarded to the Corresponding Author. We would also like to acknowledge IJN, UiTM Cardiology Clinic and UiTM Specialist Lipid Clinic staff who assisted the patient recruitment.
Conflict of Interest
All authors declared no financial conflict of interest to disclose concerning this study.
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