Abstract
Aim: We aimed to clarify the degree and factors associated with low-density lipoprotein (LDL)-cholesterol treatment target attainment among patients with heterozygous familial hypercholesterolemia (HeFH) using the Hokuriku-plus FH registry.
Methods: The Hokuriku-plus FH registry (UMIN000038210) was a prospective, observational, multicenter cohort study that enrolled consecutive patients with FH who fulfilled the clinical criteria for FH in Japan from 37 participating hospitals, mostly in the Hokuriku region, from April 2020 to March 2024. This registry collects data on clinical parameters, including lipid levels, physical findings, genetic background, and clinical events. In total, 431 patients were enrolled, and the median followup period was 3.1 years. We assessed the degree and factors associated with LDL-cholesterol treatment target attainment among patients with HeFH using the Hokuriku-plus FH registry.
Results: Among the 431 patients, sufficient data were collected from 386 patients. Logistic regression analysis revealed that male sex (odds ratio [OR] = 2.16, 95% confidence interval [CI]: 1.14–3.18, p＜0.001) and genetic testing (OR = 1.68, 95% CI: 1.10–2.26, p＜0.001) were significantly associated with LDL-cholesterol treatment target attainment. In fact, female patients were less likely to attain LDL-cholesterol treatment target than male patients (24.0% vs. 38.1%, p＜0.001), and patients who did not undergo genetic testing were less likely to attain LDL-cholesterol treatment target than those who underwent genetic testing (24.5% vs. 37.1%, p＜0.001).
Conclusion: Sex bias and masked genetic status are significant barriers to the clinical management of patients with HeFH.
†The Hokuriku-plus Familial Hypercholesterolemia Registry Study Group: Hayato Tada (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences), Hirofumi Okada (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences), Shohei Yoshida (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences), Masaya Shimojima (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences), Akihiro Nomura (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences), Toyonobu Tsuda (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences), Mika Mori (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences), Shin-ichiro Takashima (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences), Takeshi Kato (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences), Soichiro Usui (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences), Kenji Sakata (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences), Kenshi Hayashi (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences), Noboru Fujino (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences), Akihiro Inazu (Department of Laboratory Science, Molecular Biochemistry and Molecular Biology, Graduate School of Medical Science), Katsuhiko Nagase (Innovative Clinical Research Center, Kanazawa University (iCREK)), Eishiro Mizukoshi (Innovative Clinical Research Center, Kanazawa University (iCREK)), Toshihiko Yasuda (Department of Cardiology, Ishikawa Prefectural Central Hospital), Atsushi Nohara (Department of Cardiology, Ishikawa Prefectural Central Hospital), Kenji Miwa (Department of Cardiology, Ishikawa Prefectural Central Hospital), Masanobu Namura (Department of Cardiology, Kanazawa Cardiovascular Hospital), Hidenobu Terai (Department of Cardiology, Kanazawa Cardiovascular Hospital), Taiji Yoshida (Department of Cardiology, Kanazawa Cardiovascular Hospital), Tsutomu Araki (Division of Internal Medicine, Saiseikai Kanazawa Hospital), Masahiro Minamoto (Department of Internal Medicine, JCHO Kanazawa Hospital), Toru Aburao (Department of Internal Medicine, JCHO Kanazawa Hospital), Yuji Ito (Department of Internal Medicine, KKR Hokuriku Hospital), Chiaki Nakanishi (Department of Internal Medicine, KKR Hokuriku Hospital), Suguru Kawasaki (Department of Internal Medicine, Kanazawa-Nishi Hospital), Yasuhiro Todo (Department of Internal Medicine, Hokuriku Central Hospital of Japan Mutual Aid Association of Public School Teachers), Junji Koizumi (Department of Internal Medicine, Suzu City General Hospital), Yoshihito Kita (Department of Internal Medicine, Wajima City Hospital), Hiroshi Matsumoto (Department of Internal Medicine, Wajima City Hospital), Hiroaki Shintaku (Department of Internal Medicine, Wajima City Hospital), Akihiko Hodatsu (Department of Cardiology, Keiju General Hospital), Hidekazu Ino (Department of Cardiology, Hoju Memorial Hospital), Toshinori Higashikata (Department of Internal Medicine, Komatsu Municipal Hospital), Mutsuko Takata (Department of Internal Medicine, Komatsu Municipal Hospital), Katsushi Misawa (Department of Internal Medicine, Kaga Medical Center), Masato Yamaguchi (Department of Cardiology, Fukui Prefectural Hospital), Yoshihiro Noji (Department of Cardiology, Fukui Prefectural Hospital), Kazuo Osato (Department of Cardiology, Fukui Cardiovascular Center), Tomohito Mabuchi (Department of Cardiology, Fukui Cardiovascular Center), Taro Ichise (Department of Cardiology, Fukui Cardiovascular Center), Bunji Kaku (Division of Cardiovascular Medicine, Toyama Red Cross Hospital), Shoji Katsuda (Division of Cardiovascular Medicine, Toyama Red Cross Hospital), Manabu Fujimoto (Department of Cardiology, Koseiren Takaoka Hospital), Katsuharu Uchiyama (Department of Cardiology, Koseiren Takaoka Hospital), Kensuke Fujioka (Department of Cardiology, Koseiren Takaoka Hospital), Takuya Nakahashi (Department of Cardiology, Takaoka City Hospital), Tsuyoshi Nozue (Division of Cardiology, Department of Internal Medicine, Yokohama Sakae Kyosai Hospital), Ichiro Michishita (Division of Cardiology, Department of Internal Medicine, Yokohama Sakae Kyosai Hospital), Kazuo Usuda (Division of Cardiology, Department of Internal Medicine, Toyama Prefectural Central Hospital), Kanichi Otowa (Division of Cardiology, Department of Internal Medicine, Toyama Prefectural Central Hospital), Kazuyasu Okeie (Division of Cardiology, Toyama City Hospital), Satoshi Hirota (Department of Cardiology, Kurobe City Hospital), Isao Aburadani (Department of Cardiology, Kurobe City Hospital), Keisuke Kurokawa (Department of Cardiology, Tonami General Hospital), Osamu Takatori (Department of Cardiology, Tonami General Hospital), Shunichiro Hondo (Department of Cardiology, Public Central Hospital of Matto Ishikawa), Hiroyuki Oda (Department of Cardiology, Public Central Hospital of Matto Ishikawa), Shigeo Takata (Department of Cardiology, Kanazawa City Hospital), Hisayoshi Murai (Department of Cardiology, Kanazawa City Hospital), Masaki Kinoshita (Department of Cardiology, Kanazawa-Arimatsu Hospital), Hideo Nagai (Department of Cardiology, Kanazawa Red Cross Hospital), Yoshiteru Sekiguchi (Department of Cardiology, Kanazawa Red Cross Hospital), Satoru Sakagami (Department of Cardiology, National Hospital Organization Kanazawa Medical Center), Wataru Omi (Department of Cardiology, National Hospital Organization Kanazawa Medical Center), Chikara Fujita (Yawata Medical Center), Tatsuo Katsuki (Yawata Medical Center), Hiroshi Ootsuji (Department of Internal Medicine, Hakui Public Hospital), Atsushi Igarashi (Department of Internal Medicine, Hakui Public Hospital), Manabu Nakano (Department of Internal Medicine, Noto General Hospital,), Seiichiro Okura (Department of Internal Medicine, Fukui-ken Saiseikai Hospital), Koji Maeno (Department of Internal Medicine, Fukui-ken Saiseikai Hospital), Yasuhito Mitamura (Department of Cardiology, Municipal Tsuruga Hospital), Naoki Sugimoto (Department of Internal Medicine, Tsurugi Hospital), Masakazu Yamamoto (Department of Cardiology, Kouseiren Namerikawa Hospital), Hironobu Akao (Division of Cardiology, Kanazawa Medical University Hospital), Kouji Kajinami (Division of Cardiology, Kanazawa Medical University Hospital), Masa-aki Kawashiri (Department of Internal Medicine, Kaga Medical Center), Masayuki Takamura (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences)
1.Introduction
Familial hypercholesterolemia (FH), which has been shown as one of the most common Mendelian disorders, is significantly associated with a high risk of atherosclerotic cardiovascular disease (ASCVD) based on life-long exposure to high low-density lipoprotein (LDL)-cholesterol levels1, 2). Lowering LDL-cholesterol levels should be the primary goal of their treatment. Accordingly, clinical guidelines stipulate the LDL-cholesterol treatment target goals3-6). In Japan, according to the Japan Atherosclerosis Society (JAS) FH guideline 2022, the LDL-cholesterol treatment targets are ＜100 mg/dL for primary prevention and ＜70 mg/dL for secondary prevention among patients with heterozygous FH (HeFH) aged ≥ 15 years and ＜140 mg/dL among patients aged ＜15 years5, 6). However, data regarding the degree and factors associated with LDL-cholesterol treatment target attainment among high-risk patients in Japan are limited.
Therefore, we aimed to clarify the degree and factors associated with LDL-cholesterol treatment target attainment among patients with HeFH using the Hokuriku-plus FH registry (UMIN ID: UMIN000038210). The Hokuriku-plus FH registry is a prospective, observational, multicenter cohort study that enrolled consecutive patients with FH who fulfilled the clinical criteria for FH in Japan from 37 participating hospitals, mostly in the Hokuriku region, from April 2020 to March 2024. This registry collected data on clinical parameters, including lipid levels, physical findings, genetic background, and clinical events7).
2.Methods
2.1. Study Population
The details of the Hokuriku-plus FH registry are described elsewhere7). In brief, patients who fulfilled the clinical diagnostic criteria for FH according to the JAS 2017 at 37 participating hospitals, mostly located in the Hokuriku region, were enrolled in this study from April 2020 to March 2024. In total, 431 patients with FH were enrolled. Among them, 45 patients were excluded due to the presence of homozygous FH or lack of data (Supplemental Fig.1). Therefore, 386 patients were ultimately enrolled in this study.
2.2. Clinical Data
Baseline clinical variables, including age; sex; hypertension at baseline (defined as a systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg or the use of antihypertensive medications); diabetes mellitus (diagnosed using the Japanese clinical diagnostic criteria for diabetes mellitus); smoking (defined as current smoking habit); and total cholesterol, triglyceride, high-density lipoprotein (HDL)-cholesterol, and LDL-cholesterol levels (determined either using the Friedewald formula or enzymatically). Cardiovascular disease (CVD) was defined as severe stenosis [≥ 75%] at any coronary artery either as chronic coronary syndrome or acute coronary syndrome. We classified atherosclerotic CVD (ASCVD) events as fatal or nonfatal myocardial infarction; angina pectoris; ischemic diseases, including carotid atherosclerosis (≥ 75% stenotic lesion), coronary atherosclerosis (≥ 75% stenotic lesion), peripheral artery disease (≥ 75% stenotic lesion), or aortic valve stenosis (max velocity ≥ 3 m/s); and ischemic or hemorrhagic stroke. LDL-cholesterol treatment targets are ＜100 mg/dL for primary prevention and ＜70 mg/dL for secondary prevention among patients with HeFH aged ≥ 15 years and ＜140 mg/dL among patients aged ＜15 years5, 6). Clinical data were obtained from the electronic health records of each institution. Data were recorded through electronic data capture (EDC) using the browser-based, metadata-driven EDC software REDCap.
2.3. Genetic Testing
The findings of genetic testing on the so-called FH genes, including LDL receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein B (APOB), and LDL receptor adaptor protein 1 (LDLRAP1), were collected via EDC. Most genetic tests in this registry were performed at Kanazawa University8).
2.4. Ethical Considerations
This study was conducted according to the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and other applicable laws and guidelines in Japan. The Institutional Review Board of Kanazawa University approved the study protocol [2019-114 (3154)]. Informed consent was obtained from all patients enrolled in this study.
2.5. Statistical Analysis
Continuous variables with normal distribution are expressed as means±standard deviations. Continuous variables with non-normal distribution are presented as medians with interquartile ranges. Categorical variables are expressed as percentages and were compared using Fisher’s exact test or the chi-square test. The mean values of continuous variables were compared using Student’s t-test for independent variables. The median values were compared using the nonparametric Wilcoxon Mann–Whitney rank-sum test. Logistic regression analysis was performed to identify factors associated with LDL-cholesterol treatment target attainment. Cochran-Armitage trend test was performed to see if there was any trend of the rate of genetic testing for FH before and after the insurance coverage of genetic testing for FH (at April 2022). All statistical analyses were performed using R statistics (https://www.r-project.org). P-values ＜0.05 were used to denote statistical significance.
3.Results
3.1. Clinical Characteristics at Baseline according to Sex
Table 1 shows the clinical characteristics of the patients at baseline. The mean age of the patients was 47 years, and 194 (50.3%) of them were men. The median LDL-cholesterol level at enrollment was 120 mg/dL. Furthermore, 202 (52.3%) patients underwent genetic testing, among whom 112 (29.0%) had a pathogenic mutation in the FH gene. In total, 108 (28.0%) patients had a history of prior CVD events. When the patients were divided according to sex, significant differences in age; smoking; total cholesterol, triglyceride, HDL-cholesterol, and LDL-cholesterol levels; and history of prior CVD events were observed.
Table 1.Characteristics of the study subjects
|
All |
Male |
Female |
P-value
|
| (N = 386) |
(N = 194) |
(N = 192) |
| Age (years) |
47±16 |
44±18 |
51±19 |
＜0.001 |
| Hypertension (%) |
94 (24.3 %) |
48 (24.7 %) |
46 (24.0 %) |
0.95 |
| Diabetes (%) |
38 (9.8 %) |
16 (8.2 %) |
22 (11.5 %) |
0.37 |
| Smoking (%) |
49 (12.5 %) |
40 (20.6 %) |
9 (4.7 %) |
＜0.001 |
| Total cholesterol (mg/dL) |
194 [172–214] |
183 [168–208] |
201 [181–220] |
＜0.001 |
| Triglyceride (mg/dL) |
121 [80–172] |
136 [101–188] |
109 [75–159] |
＜0.001 |
| HDL-cholesterol (mg/dL) |
48 [40–58] |
44 [38–56] |
53 [44–64] |
＜0.001 |
| LDL-cholesterol (mg/dL) |
120 [89–140] |
114 [88–132] |
125 [91–148] |
＜0.001 |
| Genetic testing (%) |
202 (52.3 %) |
104 (53.6 %) |
98 (51.0 %) |
0.69 |
| FH pathogenic mutation (%) |
112 (29.0 %) |
59 (30.4 %) |
53 (27.6 %) |
0.62 |
| History of prior CVD (%) |
108 (28.0 %) |
78 (40.2 %) |
30 (15.6 %) |
＜0.001 |
CVD, cardiovascular disease; FH, familial hypercholesterolemia; LDL, low-density lipoprotein; HDL, high-density lipoprotein.
As shown in Table 2, patients with HeFH were treated with statins, ezetimibe, colestimide, PCSK9 inhibitor, fibrate, and n-3 polyunsaturated fatty acids. Significant differences in the use of ezetimibe and PCSK9 inhibitor were observed between male and female patients. When we divided the patients according to the prior history of CVD, we found that LDL-lowering therapies were more frequently prescribed in patients with prior history of CVD as expected (Supplemental Table 1).
Table 2.LDL-cholesterol-lowering therapies
| Lipid-lowering therapies |
All (N = 386) |
Male (N = 194) |
Female (N = 192) |
P-value
|
| Statins/maximum dose (%) |
379 (98.2 %) /226 (58.5 %) |
192 (99.0 %) /122 (62.9 %) |
187 (97.4 %) /104 (54.2 %) |
0.44 /0.10 |
| Ezetimibe (%) |
101 (26.2 %) |
68 (35.1 %) |
33 (17.2 %) |
＜0.001 |
| Colestimide (%) |
45 (11.7 %) |
24 (12.3 %) |
21 (10.9 %) |
0.78 |
| PCSK9 inhibitor (%) |
56 (14.5 %) |
41 (21.1 %) |
15 (7.8 %) |
＜0.001 |
| Fibrates (%) |
34 (8.8 %) |
20 (10.3 %) |
14 (7.3 %) |
0.39 |
| n-3 PUFAs (%) |
31 (8.0 %) |
18 (9.3 %) |
13 (6.8 %) |
0.47 |
PCSK9, proprotein convertase subtilisin/kexin type 9; PUFA, polyunsaturated fatty acid; LDL, low-density lipoprotein.
Supplemental Table 1.LDL-cholesterol-lowering therapies according to prior history of CVD
| Lipid‐lowering therapies |
All (N = 386) |
History of prior CVD (+) (N = 108) |
History of prior CVD (–) (N = 278) |
P‐value
|
| Statins/maximun dose (%) |
379 (98.2 %) /226 (58.5 %) |
108 (100 %) /76 (70.4 %) |
271 (97.4 %) /150 (54.0 %) |
0.22 / 0.005 |
| Ezetimibe (%) |
101 (26.2 %) |
73 (67.6 %) |
28 (10.1 %) |
＜0.001 |
| Colestimide (%) |
45 (11.7 %) |
25 (23.1 %) |
20 (7.2 %) |
0.001 |
| PCSK9 inhibitor (%) |
56 (14.5 %) |
41 (38.0 %) |
15 (5.4 %) |
＜0.001 |
| Fibrates (%) |
34 (8.8 %) |
18 (16.7 %) |
16 (5.8 %) |
0.001 |
| n‐3 PUFAs (%) |
31 (8.0 %) |
19 (17.6 %) |
12 (4.3 %) |
＜0.001 |
We found no significant difference between the genetic testing and CVD; however, we found a significant positive association between a pathogenic variant and CVD (Supplemental Table 2).
Supplemental Table 2.Relationship between genetic testing and CVD, a pathogenic variant and CVD
| Lipid‐lowering therapies |
All (N = 386) |
History of prior CVD (+) (N = 108) |
History of prior CVD (–) (N = 278) |
P‐value
|
| Genetic testing (%) |
202 (52.3 %) |
61 (56.5 %) |
141 (50.7 %) |
0.37 |
| Pathogenic variant (%) |
134 (34.7 %) |
58 (53.7 %) |
76 (27.3 %) |
＜0.001 |
Multiple logistic regression analysis revealed that age (odds ratio [OR] = 1.16, 95% confidence interval [CI] = 0.78–1.44, p = 0.33), hypertension (OR = 1.21, 95% CI = 0.56–1.86, p = 0.58), diabetes mellitus (OR = 1.14, 95% CI = 0.38–1.90, p = 0.67), smoking (OR = 0.88, 95% CI = 0.28–1.68, p = 0.88), and history of CVD events (OR = 1.45, 95% CI = 0.68–2.22, p = 0.18) were not associated with LDL-cholesterol treatment target attainment, whereas male sex (OR = 2.16, 95% CI = 1.14–3.18, p＜0.001) and genetic testing (OR = 1.68, 95% CI = 1.10–2.26, p＜0.001) were significantly associated with LDL-cholesterol treatment target attainment (Table 3).
Table 3.Factors associated with LDL-cholesterol treatment target attainment
| Variable |
OR |
95% CI |
P-value
|
| Age (per year) |
1.11 |
0.78–1.44 |
0.33 |
| Male (yes vs. no) |
2.16 |
1.14–3.18 |
＜0.001 |
| Hypertension (yes vs. no) |
1.21 |
0.56–1.86 |
0.58 |
| Diabetes mellitus (yes vs. no) |
1.14 |
0.38–1.90 |
0.67 |
| Smoking (yes vs. no) |
0.88 |
0.28–1.68 |
0.88 |
| History of prior CVD events (yes vs. no) |
1.45 |
0.68–2.22 |
0.18 |
| Genetic testing (yes vs. no) |
1.68 |
1.10–2.26 |
＜0.001 |
OR, odds ratio; CI, confidence interval; CVD, cardiovascular disease; LDL, low-density lipoprotein.
Overall, the LDL-cholesterol treatment target attainment rate was 31.1% (120 of 386 patients). When we assessed this issue according to sex and genetic testing, we found that female patients were less likely to attain the LDL-cholesterol treatment target goal than male patients (24.0% vs. 38.1%, p＜0.001) (Fig.1), and patients who did not undergo genetic testing were less likely to attain the LDL-cholesterol treatment target goal than those who underwent genetic testing (24.5% vs. 37.1%, p＜0.001) (Fig.2).
3.6. Trend for FH Genetic Testing
Interestingly, we found a significant trend (p = 0.036) when we compared the rate of genetic testing before and after the insurance coverage in Japan (Supplemental Table 3).
Supplemental Table 3.Trend of genetic testing for FH
|
Apr 2020 ～ Mar 2022 |
Apr 2022 ～ Mar 2023 |
Apr 2023 ～ Mar 2024 |
| Number of registered patients (All) |
277 |
65 |
44 |
| Number of registered patients (who performed genetic testing) |
123 |
35 |
26 |
We observed 18 ASCVD events (3 cases of nonfatal myocardial infarction, 9 cases of angina pectoris, 2 cases of peripheral artery disease, and 3 cases of aortic valve stenosis) during a median followup duration of 3.1 years.
4.Discussion
We aimed to clarify the degree and factors associated with LDL-cholesterol treatment target attainment among patients with HeFH using the Hokuriku-plus FH registry. The following results were obtained: first, 31.1 % of the patients with HeFH attained the LDL-cholesterol treatment target. Second, female patients were less likely to achieve the LDL-cholesterol treatment target than male patients. Third, patients who did not undergo genetic testing were less likely to achieve the LDL-cholesterol treatment target than those who did.
FH is a common cause of premature ASCVD. The risk of FH can be significantly mitigated through early diagnosis and appropriate treatment. However, the diagnostic rate of this disease was slightly low. A recent study showed that the diagnostic rate of FH in Japan was only 2.6%9). Therefore, the JAS revised the clinical guidelines for diagnosing FH in 2022, which included the adoption of genetic testing and relaxation of the definition of Achilles tendon xanthoma. Hence, more patients with FH will be appropriately diagnosed. Moreover, it clearly stipulates the LDL-cholesterol treatment target according to age and prevention setting. However, data regarding the degree and factors associated with LDL-cholesterol treatment target attainment in Japan are limited. We found that the target attainment rate was significantly improved from approximately 10% to 31.1% during the past decade, although it remains insufficient10, 11). Furthermore, we found that male sex and genetic testing were significantly associated with better LDL-cholesterol treatment target attainment. Regarding sex-related differences, other FH registries worldwide have reported similar results12-17). Although male sex is one of the most important risk factors for ASCVD and thus intensifying LDL-lowering therapy in male patients is reasonable, the attainment rate in female patients is too low to adequately mitigate the risk among female patients with HeFH. In this study, we found that female patients have been less likely prescribed ezetimibe and PCSK9 inhibitor compared with male patients. In fact, it is difficult to clarify the potential reasons for this situation; however, it has been shown that females FH patients had a 49% lower chance of being prescribed a PCSK9 inhibitor than males in the Spanish registry as well18), female FH patients received less often ezetimibe in a study of Netherlands and Norway19). We anticipate that most of the physicians and patients have some hesitations to intensify LDL-lowering therapies on top of statins among female due to the fact that female FH patients in general exhibit less risk for CAD compared with male. We believe that female FH patients still have extremely high risk for CAD, although it may be lower than male, and thus more proactive introduction of concomitant therapy using ezetimibe and/or PCSK9 inhibitor for female FH patients appear to be the challenge to be solved. Regarding genetic testing, we assume that our results reflect several important aspects of this disorder. First, physicians tended to perform genetic testing to optimize the LDL-cholesterol-lowering therapy for patients with HeFH. In fact, in an randomized controlled trial, we showed that genetic testing and genetic counseling can help lower LDL-cholesterol levels20). Second, patients who undergo genetic testing are better aware of elevated LDL-cholesterol levels; thus, they are more likely to accept more intensive medical therapies. Third, physicians and patients are not fully motivated to implement more intensive medical therapies, such as PCSK9 inhibitor therapy, without knowledge regarding genetic background. Based on these results, we recommend making the best use of genetic testing for FH to achieve better LDL-cholesterol control. Furthermore, we must bridge the gap between male and female patients regarding LDL-cholesterol treatment.
This study has several limitations. First, the study cohort comprised patients mostly from the Hokuriku region of Japan. Thus, our results may not be applicable to other populations. Second, selection bias may have existed, and only data from patients with HeFH who were referred to our affiliated institutions were used. Third, changes in medications during followup could not be assessed in this study, which may have affected our results. Fourth, the indication for genetic testing was based on the discretion of the attending physicians, which may have been associated with the intensiveness of LDL-cholesterol treatment.
In conclusion, sex bias and masked genetic status are significant barriers to the clinical management of patients with HeFH.
Acknowledgements:
We are thankful to Ms. Kazuko Honda and Mr. Sachio Yamamoto for their outstanding technical assistance.
Sources of Funding:
This work received support from the scientific research grants from the Ministry of Health, Labor and Welfare of Japan (Sciences Research Grant for Research on Rare and Intractable Diseases) and the Japanese Circulation Society (project for genome analysis in cardiovascular diseases) to Dr. Hayato Tada.
Declaration of Generative AI in Scientific Writing:
AI or AI-assisted technologies were not used in the writing process of this manuscript.
Data Availability Statement:
The data in this study are available from the corresponding author upon reasonable request.
Ethical Approval:
This study was conducted according to the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and other applicable laws and guidelines in Japan. The Institutional Review Board of Kanazawa University (Kanazawa, Japan) approved the study protocol [2019-114 (3154)]. Informed consent was obtained from all participants.
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