Characterizing Hypercholesterolemia Patients Initiated in PCSK9 Inhibitor Treatment in Denmark from 2017 to 2022 – a National Registry-Based Study

Characterizing Hypercholesterolemia Patients Initiated in PCSK9 Inhibitor Treatment in Denmark from 2017 to 2022 – a National Registry-Based Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Characterizing Hypercholesterolemia Patients Initiated in PCSK9 Inhibitor Treatment in Denmark from 2017 to 2022 – a National Registry-Based Study Elena Klitgaard, Marius Mølsted Flege, Ramune Jacobsen, Kristoffer Jarlov Jensen, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5259548/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: Statins are the first-line treatment for high cholesterol, but 10 to 20% of patients discontinue due to intolerance. Proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) have a favorable safety profile. Despite this, PCSK9is represent the last-line treatment option, primarily due to their high cost. This study aims to examine changes in PCSK9i initiation frequency and patient characteristics in Denmark from 2017 to 2022, investigate previous lipid-lowering treatments before PCSK9i initiation, and describe the medical specialties prescribing PCSK9i. Methods: National registry study including all patients initiated on a PCSK9i in the period from 2017 to 2022. Patients were identified by the first PCKS9 prescription in the Danish National Patient Register and/or the National Hospital Medication Register. Results: The final study population consisted of 959 patients. In 2017 to 2018, 225 patients were initiated on a PCSK9i, which increased to 494 patients in 2021 to 2022. Most PCSK9i initiations originated from cardiology departments (76.0%). Overall, 56.4% of patients had very high LDL-C (≥2.6 mmol/L) before being initiated on a PCSK9i, while 16.9% of patients had an LDL-C already lower than the treatment goal (<1.4 mmol/L). The majority of patients had tried a statin prior to PCSK9i initiation (96.6%), whereas 86,2% patients had used ezetimibe – 85.1% of patients had used both a statin and ezetimibe. The number of hospitals initiating PCSK9is was four in 2017 and rose to 19 in 2022. Conclusion: PCSK9i initiations in Denmark increased between the years 2017 to 2022, but the number of PCSK9i users is still low in Denmark. Almost all patients had used a statin before being initiated on PCSK9i treatment, and prior ezetimibe use was also very common, although 14% did not try ezetimibe before PCSK9i; thus, most patients were initiated in accordance with national guidelines. When, over time, a larger number of patients have been initiated in PCSK9i further real-world evidence studies should be performed. hypercholesterolemia PCSK9i lipid-lowering treatment drug utilization register study Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Dyslipidemia is a widespread metabolic condition characterized by elevated lipid levels in the bloodstream, specifically low-density lipoprotein cholesterol (LDL-C) and triglycerides [ 1 ]. Excessive cholesterol levels increase the likelihood of developing cardiovascular disease (CVD), which stands as the leading cause of death and disability worldwide, with more than 60 million people each year developing CVD worldwide [ 2 – 4 ]. It is estimated that high cholesterol causes 2.6 million deaths yearly, equivalent to 4.5% of all deaths globally [ 5 ]. In Denmark, approximately, 2 million people live with high cholesterol [ 6 ]. Due to its extensive impact on public health, monitoring and treating high cholesterol levels is of paramount importance. Statins represent the first-line treatment for high cholesterol, with ezetimibe being the second-line treatment option [ 7 – 9 ]. Between 10 and 20% of patients discontinue statin treatment due to intolerance, with skeletal muscle-related events being the most common cause of treatment discontinuation [10 − 12]. Proprotein Convertase Subtilisin-Kexin type 9 inhibitors (PCSK9i) are a relatively recent addition to the assortment of lipid-lowering treatment [ 13 , 14 ]. PCSK9is are expensive biological drugs that are highly effective and have displayed a favorable safety profile compared to statins, both overall and regarding skeletal muscle-related events [ 15 – 18 ]. The first PCSK9i was granted marketing authorization by European Medical Association (EMA) in 2015 [ 19 , 20 ]. Although PCSK9i have advantages over statins, they are the last-line option for the treatment of dyslipidemia, mainly due to their high cost [ 21 ]. In 2023, it cost approximately 25,000 DKK annually to treat a single patient with a PCSK9i in Denmark without accounting for healthcare staff costs, whereas treatment with a statin cost approximately 200 DKK per year [ 22 ]. Therefore, to improve the balance between healthcare spending and public health, it is valuable to determine whether cheaper lipid-lowering treatment have been employed before a PCSK9i, and to examine PCKS9i initiation and adherence to guidelines in Denmark, which is relatively unexplored. The aim of this cohort study is to investigate how the frequency of PCSK9i initiations, as well as the characteristics of initiated patients, including sociodemographics, morbidity and LDL-C, have changed between the year 2017 to 2022 in Denmark. Additionally, this study will examine which other lipid-lowering treatment strategies were employed prior to the initiation of PCSK9i. Finally, this study will explore which specialties of hospital department were responsible for these initiations. Methods Setting and treatment criteria PCSK9i is approved for adults with hypercholesterolemia or combined hyperlipidemia where the combination of a statin at its maximum tolerated dose, a cholesterol absorption inhibitor, and possibly a bile acid sequestrant are unable to produce an LDL-C level of < 2.6 mmol/L, or in patients with an LDL-C level of ≥ 2.6 mmol/L who are statin intolerant or where statin is contraindicated [ 22 , 23 ]. In Denmark, only specialists in cardiology, endocrinology or neurology are authorized to prescribe PCSK9i. The medicine is handed out free of charge from the hospital to the patients [ 6 , 22 ]. Study population All registered patients initiated on PCSK9i treatment in the period from 2017 to 2022 in Denmark were included, with the date of first prescription serving as the index date. Patients were identified in the Danish National Patient Register (DNPR) and the National Hospital Medication Register. To identify all patients in PCSK9i treatment, searches included Anatomical Therapeutic Chemical codes (ATC: C10AX13, C10AX14, C10AX16), procedure codes (MC10AX13, MC10AX14, MC10AX16), active ingredients (evolocumab, alirocumab, inclisiran), and brand names (Repatha, Praluent, Leqvio). To secure full information on treatment history, patients were excluded if they had migrated to or from Denmark five years prior to their first PCSK9i administration (index date), as to avoid missing data issues. The first year 2017 was selected as this was when PCSK9i was beginning to be prescribed in Denmark in larger scale [ 23 ] Data sources This nationwide register-based cohort study was approved by Statistics Denmark (DST), the Danish Data Protection Agency and the Danish Health Data Authority. According to Danish law, register-based studies do not require informed patient consent or approval from ethical committees. We used data from seven Danish nationwide registers, which all were made available by DST [ 24 ]. The source population was linked through the Danish Civil Registration System (CRS) by CPR numbers, which are unique numbers used for identification purposes. The register was established in 1968 and contains basic information on all Danish citizens, including sex, date of birth, date of death, immigration, or emigration [ 25 ]. DNPR contains information on diagnoses, dates of admission and discharge, some treatments, and examinations from public hospitals in Denmark since 1977 [ 26 ]. The National Hospital Medication Register is a newer register, introduced in 2018 and made available for research in 2022. This register contains information on the administrations and diagnoses related to medication at public hospitals [ 27 ]. The Danish National Prescription Register (NPR) holds information on all prescriptions dispensed at community pharmacies in Denmark since 1994 [ 28 ]. The Danish Education Register contains information on the education levels of individuals who have received education in Denmark, as well as those who have immigrated to Denmark, since 1910 [ 29 ]. The Income Statistics Register has been available since 1970 and contains data on salaries, taxes, capital income, pensions, and benefits of all Danish citizens [ 30 ]. The Clinical Laboratory Information Register contains information on biomarker results from all laboratories in Denmark since 2015 with partial coverage since 2011[ 31 ]. Variables Information on sex, age and cohabitation was identified using the register CRS. Ages were divided into the following intervals: 18–55, 55–65, 65–75 and ≥ 75 years. Information on education was retrieved from the Danish Education Register, and patients were classified according to the following three categories: Low (primary, lower secondary or missing), intermediate (higher secondary) and high (tertiary). Income was extracted from the Income Statistics Register and within each combination of sex, five-year interval age-groups, and calendar year of index date the income was assigned a quartile defined by the same stratification in the general population. As data in the Danish Education Register and Income Statistics Register is updated December each year, data on education and income were extracted from the year prior to index year; if data was missing, a look-back period of up to three years was employed. Morbidities were identified using DNPR. Patients were considered to have a morbidity if the relevant International Classification of Diseases 10th revision (ICD-10) diagnostic code was registered as a diagnosis up to ten years prior to index date. The following morbidities were included as they are either associated with a risk of getting hypercholesterolemia or a possible outcome of hypercholesterolemia: atrial fibrillation (ICD-10: I48), chronic kidney disease (ICD-10: N18), cerebrovascular disease (ICD-10: I630, I631, I632, I633, I634, I635, I638, I639, I66, I672, G458, G459), diabetes mellitus (ICD-10: E10, E11, N083), familial hypercholesterolemia (ICD-10: E780B, E780B1, E780B2), heart failure (ICD-10: I500, I501, I502, I503, I508, I509, I110, I130, I132, I420, I426, I427, I428, I429), hypertension (ICD-10: I10, I11, I12, I13, I15) and peripheral arterial disease (ICD-10: I739, DI702). Patients were divided into following year groups: 2017 to 2018, 2019 to 2020, and 2021 to 2022 to avoid groups with < 5 due to rules of data protection. LDL-C measurements were obtained from the Clinical Laboratory Information Register with a two-year look-back period. If several LDL-C values existed in the period, the measurement closest to index date was chosen. If LDL-C values were missing, but total cholesterol, triglyceride, and high-density lipoprotein cholesterol (HDL-C) values were available, LDL-C was calculated using Friedewald’s formula: $$\:LDLC=Total\:Cholesterol-HDLC-\frac{Triglycerides}{5}$$ , with triglyceride/5 being a surrogate measure for very low-density lipoprotein cholesterol (VLDL-C). LDL-C measurements were categorized into four groups based on the Danish guidelines for LDL-C levels: <1.4 mmol/L, 1.4 to 1.8 mmol/L, 1.8 to 2.6 mmol/L, and ≥ 2.6 mmol/L [ 7 ]. Information about the medical specialties of the departments responsible for PCSK9i initiation, as well as the number of hospitals initiating PCSK9is, was gathered using cross linkage between DNPR and the National Hospital Medication Register. Medical specialties of the department that administrated the initiation of PCSK9i were divided into the following groups: Cardiology, internal medicine and other; where internal medicine included endocrinology, infectious disease, pulmonary disease, gastroenterology, acute medicine, geriatric medicine, nephrology, rheumatology, and hematology. Information on prior lipid-lowering treatment strategies was identified using NPR with a look-back period ten years prior to a patient’s treatment initiation. Statistical analysis LDL-C measurements, fraction of patients fulfilling treatment criteria, and medical specialties responsible for PCSK9i initiations were constructed as stacked percentage histograms for each year group of the study, with χ 2 -tests comparing the year groups. Prior lipid-lowering treatment was illustrated as an upset plot for each year group of the study, with χ 2 -tests comparing the year groups[ 34 ]. As new medication is registered in different ways during the implementation period, it is expected that some patients will be included after PCSK9i treatment initiation, for example if they received PCSK9i as a part of a phase 3 trial. A sensitivity analysis of LDL-C value 28 days before initiation was included to secure an LDL-C value before treatment initiation. Data management, statistical analyses, and graphics were conducted using SAS Enterprise Guide 8.3, except for the upset plot, which was generated in R version 4.3.2. Results The total number of patients initiating PCSK9i was 966 from 2017 to 2022. Out of these, seven patients were excluded due to migration within five years prior to index date. The final study population consisted of 959 patients corresponding to 0.016% of the Danish population, 846 were identified in DNPR and 455 were identified in the National Hospital Medication Register, with 171 patients identified in both registers. In 2017 to 2018, 225 patients were initiated, whereas 240 patients were initiated in 2019 to 2020. In 2021 to 2022, the number of patients initiating PCSK9i increased to 494 (see Table 1 ). Table 1 Baseline characteristics for patients initiated on a PCSK9i from 2017 to 2022. p -values are calculated by χ 2 -tests. Baseline characteristic Total (N = 959) 2017–2018 (N = 225) 2019–2020 (N = 240) 2021–2022 (N = 494) Sex, N (%) p = 0.199 Male 493 (51%) 106 (47%) 120 (50%) 267 (54%) Female 466 (49%) 119 (53%) 120 (50%) 227 (46%) Age group (year), N (%) p = 0.018 18–55 224 (24%) 63 (28%) 58 (24%) 103 (21%) 55–65 310 (32%) 79 (35%) 84 (35%) 147 (30%) 65–75 347 (36%) 74 (33%) 78 (33%) 195 (39%) ≥75 78 (8%) 9 (4%) 20 (8%) 49 (10%) Cohabitation, N (%) p = 0.293 Yes 694 (72%) 172 (76%) 170 (71%) 352 (71%) No 265 (28%) 53 (24%) 70 (29%) 142 (29%) Education, N (%) p = 0.603 Low 278 (29%) 63 (28%) 65 (27%) 150 (30%) Intermediate 374 (39%) 89 (40%) 89 (37%) 196 (40%) High 307 (32%) 73 (32%) 86 (36%) 148 (30%) Income, N (%) p = 0.176 Q3 233 (24%) 65 (29%) 56 (23%) 112 (23%) Morbidity, N (%) Atrial fibrillation 117 (12%) 26 (12%) 26 (11%) 65 (13%) p = 0.6285 Chronic Kidney Disease 39 (4%) 6 (3%) 8 (3%) 25 (5%) p = 0.2576 Cerebrovascular Disease 116 (12%) 29 (13%) 30 (12%) 57 (12%) p = 0.8546 Diabetes Mellitus 185 (19%) 31 (14%) 41 (17%) 113 (23%) p = 0.0100 Familial hypercholesterolemia 262 (27%) 71 (32%) 61 (25%) 130 (26%) p = 0.2565 Heart failure 105 (11%) 26 (12%) 29 (12%) 50 (10%) p = 0.6878 Hypertension 433 (45%) 98 (44%) 109 (45%) 226 (46%) p = 0.8576 Ischemic Heart Disease 606 (63%) 143 (64%) 153 (64%) 310 (63%) p = 0.9580 Peripheral Arterial Disease 110 (11%) 24 (11%) 35 (15%) 51 (10%) p = 0.2151 The largest age group was 65–75 years with 36.2%, followed by age 55–65 years with 32.2%. There was a change over the calendar years, as more patients aged ≥ 65 years were initiated as time passed ( p = 0.0182). Overall, 40% of patients belonged to the group with secondary education as their highest achieved education, which mirrors the Danish population well. Out of all initiated patients, over half suffered from ischemic heart disease (63.2%), almost half suffered from hypertension (45.2%), whereas about a quarter of patients suffered from familial hypercholesterolemia (27.3%). A change was seen over the period for diabetes mellitus, as more patients initiated on PCSK9i had diabetes mellitus at the end of period ( p = 0.0100). PCSK9i treatment was estimated to be mostly used for secondary prevention of CVD, since over half of the initiated patients already suffered from CVD (n = 677, 70.6%). Overall, 56.4% of patients who were initiated on a PCSK9i between 2017 to 2022 had very high LDL-C (≥ 2.6 mmol/L) measured as their last LDL-C measurement prior to initiation (see Fig. 1). Meanwhile, 16.3% of patients had LDL-C levels in the 1.8–2.6 mmol/L range. Interestingly, 16.9% of patients had an LDL-C level in the healthy range (< 1.4 mmol/L) prior to initiation. The median LDL-C level of initiated patients was 2.9 mmol/L (IQR of 1.7 to 4.1). The sensitivity analysis only including LDL-values 28 days before treatment initiation resulted in a median LDL-C of 3.2 (IQR of 1.8 to 4.2, n = 944). There was no clear change over time from 2017 to 2022 when examining the patient’s LDL-C levels prior to PCSK9i initiation ( p = 0.1394) (see Fig. 1). The vast majority of patients who were initiated on a PCSK9i from 2017 to 2022 had used a statin at some point during ten years prior to the initiation of a PCSK9i (n = 926, 96.6%), whereas slightly fewer had used ezetimibe (n = 827, 86.2%). Overall, most patients had used a statin and ezetimibe prior to PCSK9i initiation (n = 816, 85.1%), which is in accordance with treatment guidelines (see Fig. 2). Many had used a statin and ezetimibe and nothing else prior to the initiation of a PCSK9i (n = 628, 65.5%). Prior fibrate and bile acid sequestrant treatment were less common (n = 116, 12.1% and n = 85, 8.9%, respectively). Use of nicotine acid was least common (n = 53, 5.5%). The largest percentage of patients that had used a statin and ezetimibe was found in the year group 2021 to 2022 (87.5%), while the lowest percentage had used a statin and ezetimibe in the year group 2019 to 2020 (79.6%); this difference was significant ( p = 0.0184). Some patients had only used a statin before being initiated on a PCSK9i (n = 90, 9.4%). Surprisingly, a small but substantial number of patients were completely treatment naïve ten years prior to being initiated on a PCSK9i (n = 20, 2.1%). Additionally, patients were divided according to LDL-C (</≥ 1.4 mmol/L) and treatment (did or did not try statins and ezetimibe as a minimum) prior to PCSK9i initiation. In all year groups, most patients belonged to the group with high LDL-C and previous statin and ezetimibe treatment (Fig. 3). Thus, most patients were initiated on a PCSK9i in accordance with treatment guidelines, with 671 (70.0%) patients having tried both statin and ezetimibe treatment and having an LDL-C ≥ 1.4 mmol/L. In contrast, the smallest group across all year groups was the low LDL-C and, no treatment group. The majority of the first PCSK9i prescriptions initiating treatment were issued from cardiology departments (76.0%), as shown in Fig. 4. Overall, internal medicine departments accounted for 17.5% of prescriptions, and other departments accounted for 6.5%. No significant change was observed over the period ( p = 0.0925). The number of hospitals prescribing PCSK9is was four in 2017, 12 in 2018, 16 in 2019, 17 in 2020, 12 in 2021, and 19 in 2022. Discussion In this nationwide cohort register study investigating initiation of PCSK9i in the years 2017 to 2022 in Denmark we found relatively few, but increasing, number of patients initiating PCSK9i treatment with 225 patients in 2017 to 2018, to 494 patients in 2021 to 2022. The majority of PCSK9i initiations originated from cardiology departments (76.0%). The number of hospitals initiating PCSK9is was four in 2017 and grew to 19 in 2022. Overall, 56.4% of patients had very high LDL-C (≥ 2.6 mmol/L) prior to PCSK9i initiation, whereas 16.9% of patients had an LDL-C already lower than the treatment goal (< 1.4 mmol/L). Also, 85.1% of the patients were in accordance with the treatment guidelines and tried both statin and ezetimibe prior to PCSK9i initiation, and in addition to having tried these treatments 70% also had an LDL-C ≥ 1.4 mmol/L. Nearly all patients had used a statin prior to the initiation of a PCSK9i (96.6%). The number of PCSK9i initiations appears to be low in Denmark compared to the US. In total, 959 patients were initiated on a PCSK9i from 2017 to 2022 in Denmark, corresponding to 0.016% of the Danish population. For comparison, 470,018 patients were initiated from 2019 to 2021 in the US [ 32 ], which corresponds to 0.14% of the US population. The US study had a study period that spanned only three years, compared to six years in the present study; even so, the percentage of the US population initiated on a PCSK9i was nearly tenfold higher compared to the Danish population. To our knowledge, there are no studies that report the number of PCSK9i initiations by years in any European country besides Denmark. One study found that between 0.1–1.7% of the Spanish population was eligible for PCSK9i treatment, following the same treatment criteria as in Denmark [ 33 ]. Assuming the percentage of ? is similar for Denmark, as both countries have very similar age distributions of their populations, there are many Danish patients who could benefit from PCSK9i treatment that are not currently on it. This may be attributed to a lack of knowledge about the long-term safety and effectiveness of PCSK9i, as they represent a relatively new lipid-lowering treatment, but it also may be due to their high cost; it has been claimed that it would be unrealistic for any country to finance the utilization of PCSK9i treatment in all eligible patients [ 34 , 35 ]. Still, it is apparent that more and more patients are being initiated on PCSK9i in Denmark. The most recent year group, 2021 to 2022, saw the highest number of initiations by a wide margin. The number of hospitals responsible for PCSK9i initiations also rose during the study period, indicating PCSK9 slowly becoming more widespread in Denmark during the timeframe. Some patients had an LDL-C level lower than the treatment goal (< 1.4 mmol/L) prior to being initiated on a PCSK9i (16.9%). Danish guidelines state that PCSK9i treatment should not be initiated at such low LDL-C levels [ 23 ]. The median LDL-C level of initiated patients was 2.9 mmol/L; this median is low compared to what has been found in other studies. Mulder et al. (Netherlands) found a median LDL level of 4.2 mmol/L for initiated patients [ 36 ]. Lehrke et al. (Germany) found a median of 3.7 mmol/L [ 37 ]. Sudano et al. (Switzerland) observed a median of 3.6 mmol/L [ 38 ]. Thus, as far as we are aware, the median found in the present study is the lowest to date in any PCSK9i utilization study, although when restricting LDL-C to 28 before or earlier a slightly higher median of 3.2 mmol/L was found. Almost all patients had used a statin at some point prior to PCSK9i initiation (96.6%). Fewer patients had used ezetimibe prior to initiation, although the number was still high (86.2%). In Denmark, it is a requirement that patients have tried, at the very least, a statin and ezetimibe before being initiated on a PCSK9i [ 6 , 23 ]. Thus, in the present study, most patients (85.1%) fulfilled this treatment requirement, and many also had an LDL-C ≥ 1.4 mmol/L (70%). Surprisingly, a few patients were completely treatment naïve prior to being initiated on a PCSK9i (2.1%), which is strongly contradictory to the national guidelines, although it could be explained by previous statin intolerance over 10 years prior to index date. This study does not contain any data on statin intolerance, as this is not registered, which can be viewed as a limitation. It would have been interesting to explore, whether the patients having only used a statin prior to being initiated on a PCSK9i were statin intolerant; perhaps some physicians skip ezetimibe monotherapy and go straight to PCSK9i treatment. However, it is not possible to draw any conclusions on this from the obtained data. Other studies have also found that most patients had used a statin and/or ezetimibe prior to PCSK9i initiation. Jensen et al. (Denmark) found that 100% of patients who were initiated from 2016 to 2017 had used a statin prior to initiation, whereas 94.9% had used ezetimibe [ 35 ]. However, this study had a small study population of only 137 patients, and the study period was only 15 months. Similarly, Derington et al. (US) found that 94.5% of patients had used a statin prior to being initiated in the period 2018 to 2019 [ 39 ]. Upon review of existing literature, it appears that most PCSK9i utilization studies focus on which lipid-lowering treatments were used shortly before PCSK9i initiation rather than which were used at any point in patients’ lives [ 36 – 38 , 40 ]. A strength of this study is that data was retrieved from nationwide registers with high validity and completeness, which are not affected by selection bias, except for the National Hospital Medication Register, which is a newer register whose validation cannot be ensured. To identify all patients, we used two registers and searched for ATC codes, procedure codes, active ingredients, and brand names. A few limitations should be taken into consideration when evaluating this study. There can be misclassification in the DNPR regarding procedure codes, resulting in patients registered with an incorrect code for treatment. Thus, we cannot be sure that all patients initiated on a PCSK9i are included in this study, which is indicated by the only 271 patients out of 959 appearing in both registers. Errors regarding patients’ LDL-C levels prior to treatment initiation could also exist; it is possible that some patients’ LDL-C values were measured after treatment initiation instead of prior to it if there was a lack of registration of PCSK9i initiations. This would explain why a substantial number of patients appeared to have an LDL-C level already lower than the treatment goal before being initiated, however the median LDL-C level did not change greatly in the sensitivity analysis where LDL-C levels were examined 28 days or earlier before treatment initiation. It is also a limitation that we only know the medical specialties of departments initiating PCSK9is rather than those of individual doctors, since doctors may work for a department, whose medical specialty is different than their own. Conclusion The findings of this nationwide cohort register study suggest that PCSK9i initiations increased between the years 2017 to 2022, but the number of PCSK9i users is still low in Denmark. Most PCSK9i initiations originated from cardiology departments. Prior to initiation, more than half of patients had very high LDL-C, while a smaller percentage of patients had an LDL-C already lower than the treatment goal. The number of hospitals initiating patients on PCSK9is increased almost five-fold in the period. Almost all patients had used a statin prior to PCSK9i initiation, and most had used ezetimibe – prior use of other lipid-lowering treatments was not as common, with 85% of patients having tried both ezetimibe and statins, and 70% having LDL-C ≥ 1.4 mmol/L in addition to having tried these treatments. A few patients were treatment naïve prior to PCSK9i initiation. In the present study, most patients were initiated in accordance with national guidelines. Declarations Competing Interests No funding has been received for the conduct of this study and/or preparation of the manuscript. However, Flege, Jensen, and Petersen are all associated with the Copenhagen Phase IV Unit. The Copenhagen Phase IV Unit conduct research regarding cardiovascular disease funded by Novartis and Amgen, all funds were given to the institution. Klitgaard was a part-time student assistant at Pfizer during the conduction of the study. Jacobsen has no conflicts of interest to disclose. Author Contribution EK and MF contributed equally to the study. MF and JP conceptualized ideas. EK and MF conducted data management and performed analyses. MF, RJ, and JP provided surpervision and help with interpretation. EK wrote the manuscript in consultation with all other authors. All authors have read and approved the manuscript. 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J Pharm Pharm Sci Publ Can Soc Pharm Sci Soc Can Sci Pharm 19:137–146. https://doi.org/10.18433/J3J02P Chatzizisis YS, Koskinas KC, Misirli G, Vaklavas C, Hatzitolios A, Giannoglou GD (2010) Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment. Drug Saf 33:171–187. https://doi.org/10.2165/11319380-000000000-00000 Armitage J (2007) The safety of statins in clinical practice. Lancet Lond Engl 370:1781–1790. https://doi.org/10.1016/S0140-6736(07)60716-8 Kosmas CE, Skavdis A, Sourlas A, Papakonstantinou EJ, Peña Genao E, Echavarria Uceta R et al (2020) Safety and Tolerability of PCSK9 Inhibitors: Current Insights. Clin Pharmacol Adv Appl 12:191–202. https://doi.org/10.2147/CPAA.S288831 Feng Z, Li X, Tong WK, He Q, Zhu X, Xiang X et al (2022) Real-world safety of PCSK9 inhibitors: A pharmacovigilance study based on spontaneous reports in FAERS. Front Pharmacol 13:894685. https://doi.org/10.3389/fphar.2022.894685 Repatha | European Medicines Agency (2024) n.d. https://www.ema.europa.eu/en/medicines/human/EPAR/repatha Praluent | European Medicines Agency (2024) n.d. https://www.ema.europa.eu/en/medicines/human/EPAR/praluent Weintraub WS, Gidding SS (2016) Paying For? PharmacoEconomics 34:217–220. https://doi.org/10.1007/s40273-015-0355-y . PCSK9 Inhibitors: A Technology Worth Diskussion blandt hjertelæger (2024) Skal alle patienter have mere effektiv, men dyrere medicin? n.d. https://sundhedspolitisktidsskrift.dk/nyheder/2677-diskussion-blandt-hjertelaeger-skal-alle-patienter-have-mere-effektiv-men-dyrere-medicin.html Jensen JS, Weeke PE, Bang LE, Høfsten DE, Ripa MS, Schjerning A-M et al (2019) Clinical characteristics and lipid lowering treatment of patients initiated on proprotein convertase subtilisin-kexin type 9 inhibitors: a nationwide cohort study. BMJ Open 9:e022702. https://doi.org/10.1136/bmjopen-2018-022702 Midler med virkning på PCSK9 - information til (2024) sundhedsfaglige - Medicin.dk n.d. https://pro.medicin.dk/Laegemiddelgrupper/grupper/318678 Medicinrådets lægemiddelrekommandation og behandlingsvejledning vedrørende PCSK9- hæmmere til hyperlipidæmi 2023 Grunddataoversigt (2024) accessed April 29, n.d. https://www.dst.dk/extranet/forskningvariabellister/Oversigt%20over%20registre.html Schmidt M, Pedersen L, Sørensen HT (2014) The Danish Civil Registration System as a tool in epidemiology. Eur J Epidemiol 29:541–549. https://doi.org/10.1007/s10654-014-9930-3 The Danish National Patient Registry (2024) a review of content, data quality, and research potential - PMC n.d. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655913/ Sygehusmedicinregisteret (2024) accessed February 23, - Sundhedsdatastyrelsen n.d. https://sundhedsdatastyrelsen.dk/da/registre-og-services/om-de-nationale-sundhedsregistre/sygdomme-laegemidler-og-behandlinger/sygehusmedicinregisteret Kildemoes HW, Sørensen HT, Hallas J (2011) The Danish National Prescription Registry. Scand J Public Health 39:38–41. https://doi.org/10.1177/1403494810394717 Jensen VM, Rasmussen AW (2011) Danish Education Registers. Scand J Public Health 39:91–94. https://doi.org/10.1177/1403494810394715 Baadsgaard M, Quitzau J (2011) Danish registers on personal income and transfer payments. Scand J Public Health 39:103–105. https://doi.org/10.1177/1403494811405098 Arendt JFH, Hansen AT, Ladefoged SA, Sørensen HT, Pedersen L, Adelborg K (2020) Existing Data Sources in Clinical Epidemiology: Laboratory Information System Databases in Denmark. Clin Epidemiol 12:469–475. https://doi.org/10.2147/CLEP.S245060 Conway JR, Lex A, Gehlenborg N (2017) UpSetR: an R package for the visualization of intersecting sets and their properties. Bioinformatics 33:2938–2940. https://doi.org/10.1093/bioinformatics/btx364 Trends in Patient Access to and Utilization of Prescribed PCSK 9 Inhibitors in a Large US Claims Database From 2015 to 2021 n.d. https://doi.org/10.1161/CIRCOUTCOMES.123.009988 Zamora A, Masana L, Comas-Cufi M, Plana N, Vila À, García-Gil M et al (2018) Number of Patients Eligible for PCSK9 Inhibitors Based on Real-world Data From 2.5 Million Patients. Rev Esp Cardiol Engl Ed 71:1010–1017. https://doi.org/10.1016/j.rec.2018.03.003 Hess GP, Natarajan P, Faridi KF, Fievitz A, Valsdottir L, Yeh RW (2017) Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Therapy. Circulation 136:2210–2219. https://doi.org/10.1161/CIRCULATIONAHA.117.028430 Mulder JWCM, Galema-Boers AMH, Roeters van Lennep JE (2023) First clinical experiences with inclisiran in a real-world setting. J Clin Lipidol 17:818–827. https://doi.org/10.1016/j.jacl.2023.09.005 Lehrke M, Vogt A, Schettler V, Girndt M, Fraass U, Tabbert-Zitzler A et al (2024) Evolocumab-Based LDL-C Management in High and Very High Cardiovascular Risk Patients in German Clinical Practice: The HEYMANS Study. Adv Ther 41:1184–1200. https://doi.org/10.1007/s12325-023-02757-x Sudano I, Krähenbühl S, Mach F, Anstett A, Dhalwani N, Bridges I et al (2024) Evolocumab use in clinical practice in Switzerland: final data of the observational HEYMANS cohort study. Ther Adv Cardiovasc Dis 18:17539447231213288. https://doi.org/10.1177/17539447231213288 Derington CG, Colantonio LD, Herrick JS, Cook J, King JB, Rosenson RS et al (2021) Factors Associated With PCSK9 Inhibitor Initiation Among US Veterans. J Am Heart Assoc 10:e019254. https://doi.org/10.1161/JAHA.120.019254 Kaufman TM, Warden BA, Minnier J, Miles JR, Duell PB, Purnell JQ et al (2019) Application of PCSK9 Inhibitors in Practice. Circ Res 124:32–37. https://doi.org/10.1161/CIRCRESAHA.118.314191 Additional Declarations Competing interest reported. No funding has been received for the conduct of this study and/or preparation of the manuscript. However, Flege, Jensen, and Petersen are all associated with the Copenhagen Phase IV Unit. The Copenhagen Phase IV Unit conduct research regarding cardiovascular disease funded by Novartis and Amgen, all funds were given to the institution. Klitgaard was a part-time student assistant at Pfizer during the conduction of the study. Jacobsen has no conflicts of interest to disclose. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5259548","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":369977682,"identity":"7da259fc-1b99-48af-9851-34afd69c3d3f","order_by":0,"name":"Elena Klitgaard","email":"","orcid":"","institution":"Copenhagen Phase IV unit (Phase4CPH), Department of Clinical Pharmacology and Center of Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital","correspondingAuthor":false,"prefix":"","firstName":"Elena","middleName":"","lastName":"Klitgaard","suffix":""},{"id":369977683,"identity":"60a49cf9-5277-4bb8-bdaa-8e0cffc7ae20","order_by":1,"name":"Marius Mølsted Flege","email":"data:image/png;base64,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","orcid":"","institution":"Copenhagen Phase IV unit (Phase4CPH), Department of Clinical Pharmacology and Center of Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital","correspondingAuthor":true,"prefix":"","firstName":"Marius","middleName":"Mølsted","lastName":"Flege","suffix":""},{"id":369977684,"identity":"2c0db9b3-4e49-49f1-97bd-7f356dbc1722","order_by":2,"name":"Ramune Jacobsen","email":"","orcid":"","institution":"Department of Social and Clinical Pharmacy, University of Copenhagen, Copenhagen, Denmark","correspondingAuthor":false,"prefix":"","firstName":"Ramune","middleName":"","lastName":"Jacobsen","suffix":""},{"id":369977685,"identity":"a9e8e8d9-8293-47b3-8de3-fc96a08f9fb7","order_by":3,"name":"Kristoffer Jarlov Jensen","email":"","orcid":"","institution":"Copenhagen Phase IV unit (Phase4CPH), Department of Clinical Pharmacology and Center of Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kristoffer","middleName":"Jarlov","lastName":"Jensen","suffix":""},{"id":369977686,"identity":"a8d68d76-1c59-4174-84c8-1ca8c6b2a6dd","order_by":4,"name":"Janne Petersen","email":"","orcid":"","institution":"Copenhagen Phase IV unit (Phase4CPH), Department of Clinical Pharmacology and Center of Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital","correspondingAuthor":false,"prefix":"","firstName":"Janne","middleName":"","lastName":"Petersen","suffix":""}],"badges":[],"createdAt":"2024-10-14 08:53:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5259548/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5259548/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":67652152,"identity":"59e54ccf-2aac-41a1-a111-9a2127496205","added_by":"auto","created_at":"2024-10-28 11:51:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":43722,"visible":true,"origin":"","legend":"\u003cp\u003ePatients’ LDL-C levels before being initiated on a PCSK9i, including the year groups of the initiations. The year group 2017 to 2018 included 216 patients, 2019 to 2020 included 233 patients, and 2021 to 2022 included 494 patients.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5259548/v1/70a6645e80c9ccb730e19583.png"},{"id":67652153,"identity":"bbc4634f-3bd0-49fa-865d-581f7e7feb66","added_by":"auto","created_at":"2024-10-28 11:51:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":26262,"visible":true,"origin":"","legend":"\u003cp\u003eMost frequently used lipid-lowering treatment by patients ten years prior to being initiated on a PCSK9i. On the left, the number of patients who had used a given treatment prior to PCSK9i initiation is displayed. On the right, patients are grouped according to the most frequently treatment combinations that were tried prior to PCSK9i initiation. Intersects with \u0026lt;5 patients were removed due to data sensitivity restrictions, removing 10 very small intersects.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5259548/v1/2ff3cfa4537dc2c0ad2ce62e.png"},{"id":67651200,"identity":"a4b32560-dfe3-42cb-88f1-ed71a802ad7e","added_by":"auto","created_at":"2024-10-28 11:43:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":40190,"visible":true,"origin":"","legend":"\u003cp\u003ePatients divided according to LDL-C and treatment prior to PCSK9i initiation, per year group. Low LDL-C was defined as \u0026lt;1.4 mmol/L, whereas high LDL-C was defined as ≥1.4 mmol/L. \u003cem\u003eTreat\u003c/em\u003e was defined as having used a statin and ezetimibe prior to PCSK9i initiation, while \u003cem\u003eNo Treat\u003c/em\u003e was defined as not having used a statin and ezetimibe.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5259548/v1/241c47cce90f326dda097d79.png"},{"id":67651203,"identity":"b84130fe-7f7e-4418-8231-f0870b6f8065","added_by":"auto","created_at":"2024-10-28 11:43:48","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":37130,"visible":true,"origin":"","legend":"\u003cp\u003eHealthcare professionals responsible for PCSK9i initiations, including the year groups of the initiations.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5259548/v1/96170eb6bcbb9263a4949b0e.png"},{"id":67690096,"identity":"66ee47b3-c518-455f-8117-e91c7cf0b8cf","added_by":"auto","created_at":"2024-10-28 17:31:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":686256,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5259548/v1/51401819-029d-4b91-bb7f-1271cca91171.pdf"}],"financialInterests":"Competing interest reported. No funding has been received for the conduct of this study and/or preparation of the manuscript. However, Flege, Jensen, and Petersen are all associated with the Copenhagen Phase IV Unit. The Copenhagen Phase IV Unit conduct research regarding cardiovascular disease funded by Novartis and Amgen, all funds were given to the institution. Klitgaard was a part-time student assistant at Pfizer during the conduction of the study. Jacobsen has no conflicts of interest to disclose.","formattedTitle":"Characterizing Hypercholesterolemia Patients Initiated in PCSK9 Inhibitor Treatment in Denmark from 2017 to 2022 – a National Registry-Based Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDyslipidemia is a widespread metabolic condition characterized by elevated lipid levels in the bloodstream, specifically low-density lipoprotein cholesterol (LDL-C) and triglycerides [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Excessive cholesterol levels increase the likelihood of developing cardiovascular disease (CVD), which stands as the leading cause of death and disability worldwide, with more than 60\u0026nbsp;million people each year developing CVD worldwide [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. It is estimated that high cholesterol causes 2.6\u0026nbsp;million deaths yearly, equivalent to 4.5% of all deaths globally [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In Denmark, approximately, 2\u0026nbsp;million people live with high cholesterol [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Due to its extensive impact on public health, monitoring and treating high cholesterol levels is of paramount importance.\u003c/p\u003e \u003cp\u003eStatins represent the first-line treatment for high cholesterol, with ezetimibe being the second-line treatment option [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Between 10 and 20% of patients discontinue statin treatment due to intolerance, with skeletal muscle-related events being the most common cause of treatment discontinuation [10 \u0026minus;\u0026thinsp;12]. Proprotein Convertase Subtilisin-Kexin type 9 inhibitors (PCSK9i) are a relatively recent addition to the assortment of lipid-lowering treatment [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. PCSK9is are expensive biological drugs that are highly effective and have displayed a favorable safety profile compared to statins, both overall and regarding skeletal muscle-related events [\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The first PCSK9i was granted marketing authorization by European Medical Association (EMA) in 2015 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Although PCSK9i have advantages over statins, they are the last-line option for the treatment of dyslipidemia, mainly due to their high cost [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In 2023, it cost approximately 25,000 DKK annually to treat a single patient with a PCSK9i in Denmark without accounting for healthcare staff costs, whereas treatment with a statin cost approximately 200 DKK per year [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Therefore, to improve the balance between healthcare spending and public health, it is valuable to determine whether cheaper lipid-lowering treatment have been employed before a PCSK9i, and to examine PCKS9i initiation and adherence to guidelines in Denmark, which is relatively unexplored.\u003c/p\u003e \u003cp\u003eThe aim of this cohort study is to investigate how the frequency of PCSK9i initiations, as well as the characteristics of initiated patients, including sociodemographics, morbidity and LDL-C, have changed between the year 2017 to 2022 in Denmark. Additionally, this study will examine which other lipid-lowering treatment strategies were employed prior to the initiation of PCSK9i. Finally, this study will explore which specialties of hospital department were responsible for these initiations.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSetting and treatment criteria\u003c/h2\u003e \u003cp\u003ePCSK9i is approved for adults with hypercholesterolemia or combined hyperlipidemia where the combination of a statin at its maximum tolerated dose, a cholesterol absorption inhibitor, and possibly a bile acid sequestrant are unable to produce an LDL-C level of \u0026lt;\u0026thinsp;2.6 mmol/L, or in patients with an LDL-C level of \u0026ge;\u0026thinsp;2.6 mmol/L who are statin intolerant or where statin is contraindicated [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In Denmark, only specialists in cardiology, endocrinology or neurology are authorized to prescribe PCSK9i. The medicine is handed out free of charge from the hospital to the patients [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy population\u003c/h3\u003e\n\u003cp\u003eAll registered patients initiated on PCSK9i treatment in the period from 2017 to 2022 in Denmark were included, with the date of first prescription serving as the index date. Patients were identified in the Danish National Patient Register (DNPR) and the National Hospital Medication Register. To identify all patients in PCSK9i treatment, searches included Anatomical Therapeutic Chemical codes (ATC: C10AX13, C10AX14, C10AX16), procedure codes (MC10AX13, MC10AX14, MC10AX16), active ingredients (evolocumab, alirocumab, inclisiran), and brand names (Repatha, Praluent, Leqvio). To secure full information on treatment history, patients were excluded if they had migrated to or from Denmark five years prior to their first PCSK9i administration (index date), as to avoid missing data issues. The first year 2017 was selected as this was when PCSK9i was beginning to be prescribed in Denmark in larger scale [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/p\u003e\n\u003ch3\u003eData sources\u003c/h3\u003e\n\u003cp\u003eThis nationwide register-based cohort study was approved by Statistics Denmark (DST), the Danish Data Protection Agency and the Danish Health Data Authority. According to Danish law, register-based studies do not require informed patient consent or approval from ethical committees.\u003c/p\u003e \u003cp\u003eWe used data from seven Danish nationwide registers, which all were made available by DST [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The source population was linked through the Danish Civil Registration System (CRS) by CPR numbers, which are unique numbers used for identification purposes. The register was established in 1968 and contains basic information on all Danish citizens, including sex, date of birth, date of death, immigration, or emigration [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDNPR contains information on diagnoses, dates of admission and discharge, some treatments, and examinations from public hospitals in Denmark since 1977 [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The National Hospital Medication Register is a newer register, introduced in 2018 and made available for research in 2022. This register contains information on the administrations and diagnoses related to medication at public hospitals [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The Danish National Prescription Register (NPR) holds information on all prescriptions dispensed at community pharmacies in Denmark since 1994 [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe Danish Education Register contains information on the education levels of individuals who have received education in Denmark, as well as those who have immigrated to Denmark, since 1910 [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The Income Statistics Register has been available since 1970 and contains data on salaries, taxes, capital income, pensions, and benefits of all Danish citizens [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. The Clinical Laboratory Information Register contains information on biomarker results from all laboratories in Denmark since 2015 with partial coverage since 2011[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eVariables\u003c/h3\u003e\n\u003cp\u003eInformation on sex, age and cohabitation was identified using the register CRS. Ages were divided into the following intervals: 18\u0026ndash;55, 55\u0026ndash;65, 65\u0026ndash;75 and \u0026ge;\u0026thinsp;75 years. Information on education was retrieved from the Danish Education Register, and patients were classified according to the following three categories: Low (primary, lower secondary or missing), intermediate (higher secondary) and high (tertiary). Income was extracted from the Income Statistics Register and within each combination of sex, five-year interval age-groups, and calendar year of index date the income was assigned a quartile defined by the same stratification in the general population. As data in the Danish Education Register and Income Statistics Register is updated December each year, data on education and income were extracted from the year prior to index year; if data was missing, a look-back period of up to three years was employed. Morbidities were identified using DNPR. Patients were considered to have a morbidity if the relevant International Classification of Diseases 10th revision (ICD-10) diagnostic code was registered as a diagnosis up to ten years prior to index date. The following morbidities were included as they are either associated with a risk of getting hypercholesterolemia or a possible outcome of hypercholesterolemia: atrial fibrillation (ICD-10: I48), chronic kidney disease (ICD-10: N18), cerebrovascular disease (ICD-10: I630, I631, I632, I633, I634, I635, I638, I639, I66, I672, G458, G459), diabetes mellitus (ICD-10: E10, E11, N083), familial hypercholesterolemia (ICD-10: E780B, E780B1, E780B2), heart failure (ICD-10: I500, I501, I502, I503, I508, I509, I110, I130, I132, I420, I426, I427, I428, I429), hypertension (ICD-10: I10, I11, I12, I13, I15) and peripheral arterial disease (ICD-10: I739, DI702). Patients were divided into following year groups: 2017 to 2018, 2019 to 2020, and 2021 to 2022 to avoid groups with \u0026lt;\u0026thinsp;5 due to rules of data protection.\u003c/p\u003e \u003cp\u003eLDL-C measurements were obtained from the Clinical Laboratory Information Register with a two-year look-back period. If several LDL-C values existed in the period, the measurement closest to index date was chosen. If LDL-C values were missing, but total cholesterol, triglyceride, and high-density lipoprotein cholesterol (HDL-C) values were available, LDL-C was calculated using Friedewald\u0026rsquo;s formula:\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n$$\\:LDLC=Total\\:Cholesterol-HDLC-\\frac{Triglycerides}{5}$$\u003c/div\u003e\u003c/div\u003e,\u003c/p\u003e \u003cp\u003ewith triglyceride/5 being a surrogate measure for very low-density lipoprotein cholesterol (VLDL-C). LDL-C measurements were categorized into four groups based on the Danish guidelines for LDL-C levels: \u0026lt;1.4 mmol/L, 1.4 to 1.8 mmol/L, 1.8 to 2.6 mmol/L, and \u0026ge;\u0026thinsp;2.6 mmol/L [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eInformation about the medical specialties of the departments responsible for PCSK9i initiation, as well as the number of hospitals initiating PCSK9is, was gathered using cross linkage between DNPR and the National Hospital Medication Register. Medical specialties of the department that administrated the initiation of PCSK9i were divided into the following groups: Cardiology, internal medicine and other; where internal medicine included endocrinology, infectious disease, pulmonary disease, gastroenterology, acute medicine, geriatric medicine, nephrology, rheumatology, and hematology.\u003c/p\u003e \u003cp\u003eInformation on prior lipid-lowering treatment strategies was identified using NPR with a look-back period ten years prior to a patient\u0026rsquo;s treatment initiation.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eLDL-C measurements, fraction of patients fulfilling treatment criteria, and medical specialties responsible for PCSK9i initiations were constructed as stacked percentage histograms for each year group of the study, with χ\u003csup\u003e2\u003c/sup\u003e-tests comparing the year groups. Prior lipid-lowering treatment was illustrated as an upset plot for each year group of the study, with χ\u003csup\u003e2\u003c/sup\u003e-tests comparing the year groups[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. As new medication is registered in different ways during the implementation period, it is expected that some patients will be included after PCSK9i treatment initiation, for example if they received PCSK9i as a part of a phase 3 trial. A sensitivity analysis of LDL-C value 28 days before initiation was included to secure an LDL-C value before treatment initiation.\u003c/p\u003e \u003cp\u003e Data management, statistical analyses, and graphics were conducted using SAS Enterprise Guide 8.3, except for the upset plot, which was generated in R version 4.3.2.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe total number of patients initiating PCSK9i was 966 from 2017 to 2022. Out of these, seven patients were excluded due to migration within five years prior to index date. The final study population consisted of 959 patients corresponding to 0.016% of the Danish population, 846 were identified in DNPR and 455 were identified in the National Hospital Medication Register, with 171 patients identified in both registers.\u003c/p\u003e \u003cp\u003eIn 2017 to 2018, 225 patients were initiated, whereas 240 patients were initiated in 2019 to 2020. In 2021 to 2022, the number of patients initiating PCSK9i increased to 494 (see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics for patients initiated on a PCSK9i from 2017 to 2022. \u003cem\u003ep\u003c/em\u003e-values are calculated by χ\u003csup\u003e2\u003c/sup\u003e-tests.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline characteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;959)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2017\u0026ndash;2018\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;225)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2019\u0026ndash;2020\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;240)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2021\u0026ndash;2022\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;494)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.199\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e493 (51%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e106 (47%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e120 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e267 (54%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e466 (49%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e119 (53%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e120 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e227 (46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge group (year), N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cb\u003e0.018\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u0026ndash;55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e224 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e103 (21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e55\u0026ndash;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e310 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79 (35%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e84 (35%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e147 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e65\u0026ndash;75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e347 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e78 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e195 (39%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCohabitation, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.293\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e694 (72%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e172 (76%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e170 (71%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e352 (71%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e265 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70 (29%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e142 (29%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEducation, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.603\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e278 (29%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65 (27%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e150 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntermediate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e374 (39%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e89 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e89 (37%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e196 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e307 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e86 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e148 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIncome, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.176\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;Q1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e230 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54 (23%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e132 (27%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQ1-Q2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e261 (27%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58 (26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e63 (26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e140 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQ2-Q3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e235 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58 (26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e110 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;Q3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e233 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65 (29%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56 (23%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e112 (23%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMorbidity, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtrial fibrillation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e117 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e65 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.6285\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic Kidney Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.2576\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCerebrovascular Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e116 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e57 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.8546\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes Mellitus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e185 (19%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e113 (23%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cb\u003e0.0100\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamilial hypercholesterolemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e262 (27%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e130 (26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.2565\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e105 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e50 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.6878\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e433 (45%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e98 (44%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e109 (45%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e226 (46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.8576\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIschemic Heart Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e606 (63%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e143 (64%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e153 (64%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e310 (63%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.9580\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeripheral Arterial Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e110 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e51 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.2151\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe largest age group was 65\u0026ndash;75 years with 36.2%, followed by age 55\u0026ndash;65 years with 32.2%. There was a change over the calendar years, as more patients aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years were initiated as time passed (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0182).\u003c/p\u003e \u003cp\u003eOverall, 40% of patients belonged to the group with secondary education as their highest achieved education, which mirrors the Danish population well. Out of all initiated patients, over half suffered from ischemic heart disease (63.2%), almost half suffered from hypertension (45.2%), whereas about a quarter of patients suffered from familial hypercholesterolemia (27.3%). A change was seen over the period for diabetes mellitus, as more patients initiated on PCSK9i had diabetes mellitus at the end of period (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0100). PCSK9i treatment was estimated to be mostly used for secondary prevention of CVD, since over half of the initiated patients already suffered from CVD (n\u0026thinsp;=\u0026thinsp;677, 70.6%).\u003c/p\u003e \u003cp\u003eOverall, 56.4% of patients who were initiated on a PCSK9i between 2017 to 2022 had very high LDL-C (\u0026ge;\u0026thinsp;2.6 mmol/L) measured as their last LDL-C measurement prior to initiation (see Fig.\u0026nbsp;1). Meanwhile, 16.3% of patients had LDL-C levels in the 1.8\u0026ndash;2.6 mmol/L range. Interestingly, 16.9% of patients had an LDL-C level in the healthy range (\u0026lt;\u0026thinsp;1.4 mmol/L) prior to initiation. The median LDL-C level of initiated patients was 2.9 mmol/L (IQR of 1.7 to 4.1). The sensitivity analysis only including LDL-values 28 days before treatment initiation resulted in a median LDL-C of 3.2 (IQR of 1.8 to 4.2, n\u0026thinsp;=\u0026thinsp;944). There was no clear change over time from 2017 to 2022 when examining the patient\u0026rsquo;s LDL-C levels prior to PCSK9i initiation (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.1394) (see Fig.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eThe vast majority of patients who were initiated on a PCSK9i from 2017 to 2022 had used a statin at some point during ten years prior to the initiation of a PCSK9i (n\u0026thinsp;=\u0026thinsp;926, 96.6%), whereas slightly fewer had used ezetimibe (n\u0026thinsp;=\u0026thinsp;827, 86.2%). Overall, most patients had used a statin and ezetimibe prior to PCSK9i initiation (n\u0026thinsp;=\u0026thinsp;816, 85.1%), which is in accordance with treatment guidelines (see Fig.\u0026nbsp;2). Many had used a statin and ezetimibe and nothing else prior to the initiation of a PCSK9i (n\u0026thinsp;=\u0026thinsp;628, 65.5%). Prior fibrate and bile acid sequestrant treatment were less common (n\u0026thinsp;=\u0026thinsp;116, 12.1% and n\u0026thinsp;=\u0026thinsp;85, 8.9%, respectively). Use of nicotine acid was least common (n\u0026thinsp;=\u0026thinsp;53, 5.5%). The largest percentage of patients that had used a statin and ezetimibe was found in the year group 2021 to 2022 (87.5%), while the lowest percentage had used a statin and ezetimibe in the year group 2019 to 2020 (79.6%); this difference was significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0184). Some patients had only used a statin before being initiated on a PCSK9i (n\u0026thinsp;=\u0026thinsp;90, 9.4%). Surprisingly, a small but substantial number of patients were completely treatment na\u0026iuml;ve ten years prior to being initiated on a PCSK9i (n\u0026thinsp;=\u0026thinsp;20, 2.1%). Additionally, patients were divided according to LDL-C (\u0026lt;/\u0026ge; 1.4 mmol/L) and treatment (did or did not try statins and ezetimibe as a minimum) prior to PCSK9i initiation. In all year groups, most patients belonged to the group with high LDL-C and previous statin and ezetimibe treatment (Fig.\u0026nbsp;3). Thus, most patients were initiated on a PCSK9i in accordance with treatment guidelines, with 671 (70.0%) patients having tried both statin and ezetimibe treatment and having an LDL-C\u0026thinsp;\u0026ge;\u0026thinsp;1.4 mmol/L. In contrast, the smallest group across all year groups was the low LDL-C and, no treatment group.\u003c/p\u003e \u003cp\u003eThe majority of the first PCSK9i prescriptions initiating treatment were issued from cardiology departments (76.0%), as shown in Fig.\u0026nbsp;4. Overall, internal medicine departments accounted for 17.5% of prescriptions, and other departments accounted for 6.5%. No significant change was observed over the period (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0925). The number of hospitals prescribing PCSK9is was four in 2017, 12 in 2018, 16 in 2019, 17 in 2020, 12 in 2021, and 19 in 2022.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this nationwide cohort register study investigating initiation of PCSK9i in the years 2017 to 2022 in Denmark we found relatively few, but increasing, number of patients initiating PCSK9i treatment with 225 patients in 2017 to 2018, to 494 patients in 2021 to 2022. The majority of PCSK9i initiations originated from cardiology departments (76.0%). The number of hospitals initiating PCSK9is was four in 2017 and grew to 19 in 2022. Overall, 56.4% of patients had very high LDL-C (\u0026ge;\u0026thinsp;2.6 mmol/L) prior to PCSK9i initiation, whereas 16.9% of patients had an LDL-C already lower than the treatment goal (\u0026lt;\u0026thinsp;1.4 mmol/L). Also, 85.1% of the patients were in accordance with the treatment guidelines and tried both statin and ezetimibe prior to PCSK9i initiation, and in addition to having tried these treatments 70% also had an LDL-C\u0026thinsp;\u0026ge;\u0026thinsp;1.4 mmol/L. Nearly all patients had used a statin prior to the initiation of a PCSK9i (96.6%).\u003c/p\u003e \u003cp\u003eThe number of PCSK9i initiations appears to be low in Denmark compared to the US. In total, 959 patients were initiated on a PCSK9i from 2017 to 2022 in Denmark, corresponding to 0.016% of the Danish population. For comparison, 470,018 patients were initiated from 2019 to 2021 in the US [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], which corresponds to 0.14% of the US population. The US study had a study period that spanned only three years, compared to six years in the present study; even so, the percentage of the US population initiated on a PCSK9i was nearly tenfold higher compared to the Danish population. To our knowledge, there are no studies that report the number of PCSK9i initiations by years in any European country besides Denmark.\u003c/p\u003e \u003cp\u003eOne study found that between 0.1\u0026ndash;1.7% of the Spanish population was eligible for PCSK9i treatment, following the same treatment criteria as in Denmark [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Assuming the percentage of ? is similar for Denmark, as both countries have very similar age distributions of their populations, there are many Danish patients who could benefit from PCSK9i treatment that are not currently on it. This may be attributed to a lack of knowledge about the long-term safety and effectiveness of PCSK9i, as they represent a relatively new lipid-lowering treatment, but it also may be due to their high cost; it has been claimed that it would be unrealistic for any country to finance the utilization of PCSK9i treatment in all eligible patients [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eStill, it is apparent that more and more patients are being initiated on PCSK9i in Denmark. The most recent year group, 2021 to 2022, saw the highest number of initiations by a wide margin. The number of hospitals responsible for PCSK9i initiations also rose during the study period, indicating PCSK9 slowly becoming more widespread in Denmark during the timeframe.\u003c/p\u003e \u003cp\u003eSome patients had an LDL-C level lower than the treatment goal (\u0026lt;\u0026thinsp;1.4 mmol/L) prior to being initiated on a PCSK9i (16.9%). Danish guidelines state that PCSK9i treatment should not be initiated at such low LDL-C levels [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The median LDL-C level of initiated patients was 2.9 mmol/L; this median is low compared to what has been found in other studies. Mulder et al. (Netherlands) found a median LDL level of 4.2 mmol/L for initiated patients [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Lehrke et al. (Germany) found a median of 3.7 mmol/L [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Sudano et al. (Switzerland) observed a median of 3.6 mmol/L [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Thus, as far as we are aware, the median found in the present study is the lowest to date in any PCSK9i utilization study, although when restricting LDL-C to 28 before or earlier a slightly higher median of 3.2 mmol/L was found.\u003c/p\u003e \u003cp\u003eAlmost all patients had used a statin at some point prior to PCSK9i initiation (96.6%). Fewer patients had used ezetimibe prior to initiation, although the number was still high (86.2%). In Denmark, it is a requirement that patients have tried, at the very least, a statin and ezetimibe before being initiated on a PCSK9i [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Thus, in the present study, most patients (85.1%) fulfilled this treatment requirement, and many also had an LDL-C\u0026thinsp;\u0026ge;\u0026thinsp;1.4 mmol/L (70%). Surprisingly, a few patients were completely treatment na\u0026iuml;ve prior to being initiated on a PCSK9i (2.1%), which is strongly contradictory to the national guidelines, although it could be explained by previous statin intolerance over 10 years prior to index date. This study does not contain any data on statin intolerance, as this is not registered, which can be viewed as a limitation. It would have been interesting to explore, whether the patients having only used a statin prior to being initiated on a PCSK9i were statin intolerant; perhaps some physicians skip ezetimibe monotherapy and go straight to PCSK9i treatment. However, it is not possible to draw any conclusions on this from the obtained data.\u003c/p\u003e \u003cp\u003eOther studies have also found that most patients had used a statin and/or ezetimibe prior to PCSK9i initiation. Jensen et al. (Denmark) found that 100% of patients who were initiated from 2016 to 2017 had used a statin prior to initiation, whereas 94.9% had used ezetimibe [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. However, this study had a small study population of only 137 patients, and the study period was only 15 months. Similarly, Derington et al. (US) found that 94.5% of patients had used a statin prior to being initiated in the period 2018 to 2019 [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Upon review of existing literature, it appears that most PCSK9i utilization studies focus on which lipid-lowering treatments were used shortly before PCSK9i initiation rather than which were used at any point in patients\u0026rsquo; lives [\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA strength of this study is that data was retrieved from nationwide registers with high validity and completeness, which are not affected by selection bias, except for the National Hospital Medication Register, which is a newer register whose validation cannot be ensured. To identify all patients, we used two registers and searched for ATC codes, procedure codes, active ingredients, and brand names.\u003c/p\u003e \u003cp\u003eA few limitations should be taken into consideration when evaluating this study. There can be misclassification in the DNPR regarding procedure codes, resulting in patients registered with an incorrect code for treatment. Thus, we cannot be sure that all patients initiated on a PCSK9i are included in this study, which is indicated by the only 271 patients out of 959 appearing in both registers. Errors regarding patients\u0026rsquo; LDL-C levels prior to treatment initiation could also exist; it is possible that some patients\u0026rsquo; LDL-C values were measured \u003cem\u003eafter\u003c/em\u003e treatment initiation instead of prior to it if there was a lack of registration of PCSK9i initiations. This would explain why a substantial number of patients appeared to have an LDL-C level already lower than the treatment goal before being initiated, however the median LDL-C level did not change greatly in the sensitivity analysis where LDL-C levels were examined 28 days or earlier before treatment initiation. It is also a limitation that we only know the medical specialties of departments initiating PCSK9is rather than those of individual doctors, since doctors may work for a department, whose medical specialty is different than their own.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe findings of this nationwide cohort register study suggest that PCSK9i initiations increased between the years 2017 to 2022, but the number of PCSK9i users is still low in Denmark. Most PCSK9i initiations originated from cardiology departments. Prior to initiation, more than half of patients had very high LDL-C, while a smaller percentage of patients had an LDL-C already lower than the treatment goal. The number of hospitals initiating patients on PCSK9is increased almost five-fold in the period. Almost all patients had used a statin prior to PCSK9i initiation, and most had used ezetimibe \u0026ndash; prior use of other lipid-lowering treatments was not as common, with 85% of patients having tried both ezetimibe and statins, and 70% having LDL-C\u0026thinsp;\u0026ge;\u0026thinsp;1.4 mmol/L in addition to having tried these treatments. A few patients were treatment na\u0026iuml;ve prior to PCSK9i initiation. In the present study, most patients were initiated in accordance with national guidelines.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003cp\u003eNo funding has been received for the conduct of this study and/or preparation of the manuscript. However, Flege, Jensen, and Petersen are all associated with the Copenhagen Phase IV Unit. The Copenhagen Phase IV Unit conduct research regarding cardiovascular disease funded by Novartis and Amgen, all funds were given to the institution. Klitgaard was a part-time student assistant at Pfizer during the conduction of the study. Jacobsen has no conflicts of interest to disclose.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eEK and MF contributed equally to the study. MF and JP conceptualized ideas. EK and MF conducted data management and performed analyses. MF, RJ, and JP provided surpervision and help with interpretation. EK wrote the manuscript in consultation with all other authors. All authors have read and approved the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHill MF, Bordoni B, Hyperlipidemia (2024) StatPearls, Treasure Island (FL): StatPearls Publishing\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNelson RH (2013) Hyperlipidemia as a Risk Factor for Cardiovascular Disease. Prim Care Clin Off Pract 40:195\u0026ndash;211. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.pop.2012.11.003\u003c/span\u003e\u003cspan address=\"10.1016/j.pop.2012.11.003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePirillo A, Norata GD (2023) The burden of hypercholesterolemia and ischemic heart disease in an ageing world. 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Ther Adv Cardiovasc Dis 18:17539447231213288. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/17539447231213288\u003c/span\u003e\u003cspan address=\"10.1177/17539447231213288\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDerington CG, Colantonio LD, Herrick JS, Cook J, King JB, Rosenson RS et al (2021) Factors Associated With PCSK9 Inhibitor Initiation Among US Veterans. J Am Heart Assoc 10:e019254. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1161/JAHA.120.019254\u003c/span\u003e\u003cspan address=\"10.1161/JAHA.120.019254\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaufman TM, Warden BA, Minnier J, Miles JR, Duell PB, Purnell JQ et al (2019) Application of PCSK9 Inhibitors in Practice. Circ Res 124:32\u0026ndash;37. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1161/CIRCRESAHA.118.314191\u003c/span\u003e\u003cspan address=\"10.1161/CIRCRESAHA.118.314191\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"hypercholesterolemia, PCSK9i, lipid-lowering treatment, drug utilization, register study","lastPublishedDoi":"10.21203/rs.3.rs-5259548/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5259548/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction: \u003c/strong\u003eStatins are the first-line treatment for high cholesterol, but 10 to 20% of patients discontinue due to intolerance. Proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) have a favorable safety profile. Despite this, PCSK9is represent the last-line treatment option, primarily due to their high cost. This study aims to examine changes in PCSK9i initiation frequency and patient characteristics in Denmark from 2017 to 2022, investigate previous lipid-lowering treatments before PCSK9i initiation, and describe the medical specialties prescribing PCSK9i.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eNational registry study including all patients initiated on a PCSK9i in the period from 2017 to 2022. Patients were identified by the first PCKS9 prescription in the Danish National Patient Register and/or the National Hospital Medication Register.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe final study population consisted of 959 patients. In 2017 to 2018, 225 patients were initiated on a PCSK9i, which increased to 494 patients in 2021 to 2022. Most PCSK9i initiations originated from cardiology departments (76.0%). Overall, 56.4% of patients had very high LDL-C (≥2.6 mmol/L) before being initiated on a PCSK9i, while 16.9% of patients had an LDL-C already lower than the treatment goal (\u0026lt;1.4 mmol/L). The majority of patients had tried a statin prior to PCSK9i initiation (96.6%), whereas 86,2% patients had used ezetimibe – 85.1% of patients had used both a statin and ezetimibe. The number of hospitals initiating PCSK9is was four in 2017 and rose to 19 in 2022.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003ePCSK9i initiations in Denmark increased between the years 2017 to 2022, but the number of PCSK9i users is still low in Denmark. Almost all patients had used a statin before being initiated on PCSK9i treatment, and prior ezetimibe use was also very common, although 14% did not try ezetimibe before PCSK9i; thus, most patients were initiated in accordance with national guidelines. When, over time, a larger number of patients have been initiated in PCSK9i further real-world evidence studies should be performed.\u003c/p\u003e","manuscriptTitle":"Characterizing Hypercholesterolemia Patients Initiated in PCSK9 Inhibitor Treatment in Denmark from 2017 to 2022 – a National Registry-Based Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-28 11:43:43","doi":"10.21203/rs.3.rs-5259548/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f5bb38fb-16e0-41c8-b5e6-a1d74a91d5bc","owner":[],"postedDate":"October 28th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-28T17:23:41+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-28 11:43:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5259548","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5259548","identity":"rs-5259548","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}