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The Lancet Regional Health - Europe logoLink to The Lancet Regional Health - Europe
. 2026 May 14;66:101709. doi: 10.1016/j.lanepe.2026.101709

Lipid-Lowering Treatment in Familial Hypercholesterolaemia, 1996–2021: A Nationwide Study

Jacob Reeh a,b, Anders Berg Wulff a,b, Børge G Nordestgaard a,b, Shoaib Afzal a,b,∗
PMCID: PMC13196471  PMID: 42180319

Summary

Background

In familial hypercholesterolaemia, early and intensive lipid-lowering treatment postpones coronary heart disease and death, effectively shown after introduction of statins and later ezetimibe and PCSK9 inhibitors. However, whether use of lipid-lowering treatment has improved in females and males with familial hypercholesterolaemia over time remains somewhat unclear. In this nationwide study, we tested the hypothesis that lipid-lowering treatment in familial hypercholesterolaemia improved from 1996 through 2021.

Methods

In a nationwide study of 7,976,375 individuals aged 0–113 in Denmark, all with a diagnosis of familial hypercholesterolaemia from 1996 to 2021 were included. Temporal trends in lipid-lowering medication were described by sex and coronary heart disease.

Findings

For females and males with familial hypercholesterolaemia, treatment with lipid-lowering medications increased from 1996 to about 2008 after which little change was seen. In females, any medical treatment increased from 76% (99/130) in 1996 to 86% (879/1027) in 2021 in those with coronary heart disease and from 52% (115/222) to 78% (2716/3462) in those without. Corresponding values for males were 67% (134/199)–90% (1006/1117) and 48% (105/219)–80% (1421/1772). In females with coronary heart disease, use of lipid-lowering combination therapy increased from 16% (21/130) in 1996 to 34% (345/1027) in 2021, high-intensity statin from 0% (0/88) to 41% (331/809), and lipid-lowering therapy initiation within one year of diagnosis from 45% (5/11) to 92% (343/374). Corresponding values for males were from 18% (35/199) to 50% (553/1117), from 0.8% (1/121) to 60% (570/946), and from 77% (23/30) to 92% (275/299). Similar trends were seen for individuals without coronary heart disease, however, with lower percentages.

Interpretation

Nationwide in Denmark from 1996 through 2021, lipid-lowering medication use improved in those with familial hypercholesterolaemia irrespective of sex and coronary heart disease status.

Funding

The Johan and Lise Boserup Foundation; The Independent Research Fund Denmark; and Copenhagen University Hospital–Herlev Gentofte, Denmark.

Keywords: Familial hypercholesterolaemia, Lipid-lowering therapy, Statins, Coronary heart disease, Sex differences in treatment, Electronic health records, Nationwide

Research in context.

Evidence before this study

Guidelines and original research articles published from January 1990 to December 2025 were searched on PubMed using the terms Familial Hypercholesterolemia AND Coronary disease OR Cardiovascular disease AND Lipid-lowering therapy OR Statin. Studies have demonstrated how reduction of LDL-cholesterol with intensive lipid-lowering treatment is imperative to postpone coronary heart disease and premature death in familial hypercholesterolaemia. Over time, guidelines have gradually recommended more intensive lipid-lowering therapy of familial hypercholesterolaemia, but many patients do not receive any therapy despite being at high risk of cardiovascular events. A recent collaborative study reflecting current clinical practice worldwide shows that about 40% of individuals with a familial hypercholesterolaemia diagnosis may not be receiving any lipid-lowering therapy. Amongst those who receive treatment, the treatment is often initiated late in life, for example as secondary prevention after development of coronary heart disease. Furthermore, the treatment intensity is often low (low statin dose, no combination of medications) with inadequate reduction of LDL-cholesterol levels and inadequate prevention of cardiovascular events.

Added value of this study

The use of lipid-lowering treatment has previously been described in specialised settings such as lipid clinics, but prior to this study, it has not been reported for familial hypercholesterolaemia in the general population. Nationwide in Denmark, we found an increased use of lipid-lowering treatment over the past two decades amongst individuals diagnosed with familial hypercholesterolaemia. Despite gradual improvements, treatment is still underused which is exemplified by a high age at initiation of treatment and by 12% of individuals with familial hypercholesterolaemia and coronary heart disease receiving no lipid-lowering treatment in 2021 despite being at high risk of cardiovascular events.

Implications of all the available evidence

Given the benefits of intensive lipid-lowering therapy in individuals with familial hypercholesterolaemia, the inadequate treatment observed in this study highlights the need for optimisation of care. When seeking to address the current undertreatment, it would be valuable if further studies could elucidate if the treatment inadequacy is mostly caused by a lack of treatment initiation or poor adherence and to what extent this is caused by physicians' or patients’ reservations due to fear of adverse effects, medication costs, inadequate awareness of treatment benefit, or other factors.

Introduction

Familial hypercholesterolaemia, affecting approximately 1 in 250 in the general population, is characterised by lifelong elevated low-density lipoprotein (LDL) cholesterol levels that cause premature development of coronary heart disease.1, 2, 3 Lipid-lowering treatment to reduce LDL-cholesterol is used to postpone coronary heart disease and premature death.1,2,4, 5, 6 Nationwide in Denmark, we recently showed that age at death normalised from 1978 to 2021 in those diagnosed with familial hypercholesterolaemia, which was not the case for age at coronary heart disease.7

Over the past decades, consecutive guidelines have recommended increasingly aggressive treatment regimens following introduction of different statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, respectively.8 Current guidelines for familial hypercholesterolaemia recommend high-intensity statin as first-line treatment with add-on of ezetimibe if needed to achieve targets for LDL-cholesterol.4, 5, 6,9 In very-high-risk patients unable to reach target levels, addition of a PCSK9 inhibitor is an option. Other lipid-lowering drugs are only suggested as alternatives in patients who cannot tolerate the recommended treatment.

From observational studies in familial hypercholesterolaemia patients at lipid clinics, the trend and importance of guideline-directed lipid-lowering therapy is already established.10,11 However, in these and other patients in need of lipid-lowering therapy, combination therapy and treatment with high-intensity statin remain underused.12 Nevertheless, the actual use of lipid-lowering medications in familial hypercholesterolaemia in a nationwide setting, including outside lipid clinics, has received little attention.

We therefore tested the hypothesis that lipid-lowering treatment in familial hypercholesterolaemia improved from 1996 through 2021. This was tested using nationwide data from Denmark, where diagnosis of familial hypercholesterolaemia uniquely is available since 1977 as the only country in the world.

Methods

Study design

In this nationwide study, we followed all individuals of all ages (including children) with Danish residency in the national Danish Civil Registration System. For all individuals, we used this registration system to determine the sex assigned at birth, country of origin, and the time of birth, death, immigration, and emigration.13 Individuals were categorised according to diagnosis of familial hypercholesterolaemia and coronary heart disease and were followed from 1 January 1996, date of birth, or immigration (whichever came last) until 31 December 2021, date of death, or emigration (whichever came first). We did not apply any other eligibility criteria than a diagnosis of familial hypercholesterolaemia and time of Danish residency. Data were collected in October 2025.

Lipid-lowering medication

Medication use was identified from the national Danish Prescription Registry, which has complete nationwide coverage of all prescriptions filled at Danish pharmacies as it is required by law.14 At any given time, individuals were defined as being treated with a lipid-lowering medication if they had filled at least one prescription of the medication within the last 12 months. A cut-off at 12 months was used to define the treatment period of filled prescriptions because it reflects common clinical practice in Denmark where, once per year, lipid-lowering treatment is evaluated, and prescriptions are renewed and refilled.

Using the Anatomical Therapeutic Chemical (ATC) codes to identify medicine use,15 lipid-lowering medications were statins (ATC: A10BH51, A10BH52, C10AA, C10BA01–C10BA09, C10BA11, C10BA12, C10BX01–C10BX21), fibrates (ATC: C10AB, C10BA03, C10BA04, C10BA09, C10BA12), bile acid sequestrants (ATC: C10AC), nicotinic acid (ATC: C10AD, C10BA01), ezetimibe (ATC: C10AX09, C10BA02, C10BA05, C10BA06, C10BA11, C10BA12) and PCSK9 inhibitors (ATC: C10AX13, C10AX14). Bempedoic acid and evinacumab were not used in Denmark during the study period.

In analysis of statin treatment intensity, the daily statin dose was estimated using the date of prescription being dispensed and the dispensed amount of statin. The filled statin was assumed to be taken evenly over one year from the date of prescription filling. When multiple prescriptions were filled within the same year, the sum of the dispensed amounts was used to measure the daily dose in the overlapping treatment periods. The dose of statin was measured by Defined Daily Doses (DDD) to allow for potency-adjusted comparison of different statins.14 For example, as adjustment for the different lipid-lowering potency of statins, 1 DDD corresponds to 10 mg rosuvastatin, 20 mg atorvastatin, and 30 mg simvastatin. Low-intensity statin treatment was defined as a daily dose ≤0.67 DDD corresponding to a daily simvastatin dose of ≤20 mg. Moderate-intensity treatment was defined as a daily dose >0.67 DDD and ≤1.33 DDD. High-intensity treatment was defined as a daily dose >1.33 DDD corresponding to >40 mg simvastatin daily.

Familial hypercholesterolaemia and coronary heart disease

Diagnoses of familial hypercholesterolaemia and coronary heart disease were identified from the national Danish Patient Registry, which has complete nationwide coverage of admissions and physician-coded diagnoses from hospitals since 1977 and outpatient clinics and emergency wards since 1995.16 Since results are presented over calendar time, individuals can switch category from being without a diagnosis (e.g., without coronary heart disease) at the beginning of the study period and later be reassigned to the category with the diagnosis.

The WHO ICD-8 and ICD-10 catalogues used outside Denmark do not contain codes specific for familial hypercholesterolemia, only for hypercholesterolemia in general (ICD-8: 279 and ICD-10: E78.0). However, in the Danish implementation, ICD-8: 272.00 (Familial hypercholesterolemia) and ICD-10: E78.0B (Familial hypercholesterolemia), E78.0B1 (Familial hypercholesterolemia, heterozygous), E78.0B2 (Familial hypercholesterolemia, homozygous) were added so lipid experts could code lipid disorders in more detail.17 Consequently, diagnoses of familial hypercholesterolaemia have uniquely been available nationwide in Denmark since 1977, as the only country in the world. The classification of familial hypercholesterolaemia used in this study excluded unspecific codes for hypercholesterolemia (e.g., ICD-10: E78.0) and only included individuals with the specific codes for familial hypercholesterolaemia (ICD-8: 272.00, ICD-10: E78.0B, E78.0B1, E78.0B2). In total, 72% of individuals diagnosed with familial hypercholesterolaemia came from departments with lipid experts, and all were diagnosed at hospitals, not in general practice. After 2016, when efforts to standardise lipid clinics increased in Denmark,18 the proportion of diagnoses from lipid clinics increased to 87%. In the entire period, a diagnosis of familial hypercholesterolaemia was based on clinical criteria, partially supplemented by genetic testing from 1999 and onwards.19 However, we do not have data on whether genetic testing was part of the diagnosis of familial hypercholesterolaemia.

Coronary heart disease was identified as stable angina (ICD-8: 413, ICD-10: I20, I25.1, I25.9), acute coronary syndrome (ICD-8: 410, 411, ICD-10: I20.0, I21, I22), and coronary artery revascularisation, i.e., percutaneous coronary intervention (Danish Operation and Treatment Classification codes: 30240–30354, Nordic Classification of Surgical Procedures codes: KFNF, KFNG) and coronary artery bypass grafting (Danish Classification codes: 30009–30200, Nordic Classification codes: KFNA-KFNE, KNFH20).

Statistical analysis

This article presents simple, descriptive data of proportions and distributions of the population receiving treatment. The study is based on data that are complete for all of Denmark which has certain advantages: Firstly, no missing values needed to be addressed. Secondly, the results are not subject to uncertainty when considering Denmark, but we have nevertheless tested the statistical significance of the observed changes over time and report the resulting p-values. The test for changes over time was done using linear cross-sectional time series models with the parameters estimated by Prais–Winsten regression allowing for non-linear relations by using cubic splines of time.20 Stata software version 18.0 (StataCorp) was used for all analyses.

Ethics approval

This use of nationwide data has been approved by the Danish Data Protection Agency and an institutional review board (approval number P-2022-840). Ethical approval is not needed for registry-based studies of administratively collected data in Denmark.

Role of the funding source

The funding sources had no role in study design, data collection, analysis, interpretation, or writing of the manuscript.

Results

In 7,976,375 individuals followed from 1 January 1996 to 31 December 2021, 9753 individuals aged 0.2–96 years had a diagnosis of familial hypercholesterolaemia of whom 3293 (34%) also had a diagnosis of coronary heart disease (Table 1) and ten were registered with homozygous familial hypercholesterolaemia. The number of individuals with a familial hypercholesterolaemia diagnosis was 766 in 1996 and 7378 in 2021. In those with familial hypercholesterolaemia, females were overrepresented (n = 5681 [58%]), while males were overrepresented in those with both familial hypercholesterolaemia and coronary heart disease (n = 1776 [54%]). For the nationwide cohort, median follow-up time was 24 years (interquartile range: 10–26 years).

Table 1.

Characteristics of individuals with familial hypercholesterolaemia in Denmark in 1996–2021.

With coronary heart disease
 Without coronary heart disease
Females (n = 1527) Males (n = 1766) Females (n = 4154) Males (n = 2306)
Time of birth
 Median Aug 1946 Mar 1952 Oct 1956 Jul 1966
 Interquartile range Feb 1937–Mar 1956 Dec 1940–May 1963 Nov 1944–Jun 1974 Apr 1951–Jul 1983
Time of diagnosis with familial hypercholesterolaemia
 Median Feb 2013 Aug 2011 May 2015 Mar 2016
 Interquartile range Mar 2005–Jan 2018 Sep 2000–Jan 2018 Sep 2011–Oct 2018 Oct 2008–Mar 2019
Country of origin, no. (%)
 Danish descent 1398 (92) 1621 (92) 3793 (91) 2118 (92)
 Emigrant 126 (8) 140 (8) 306 (7) 155 (7)
 Descendant of emigrant 3 (0.2) 5 (0.3) 55 (1) 33 (1)
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Lipid-lowering medication in familial hypercholesterolaemia according to coronary heart disease and sex

In females and males, treatment with at least one lipid-lowering medication increased from 1996 to about 2008 after which it changed little to 2021, irrespective of familial hypercholesterolaemia or coronary heart disease diagnoses (p < 0.001 for all) (Fig. 1). In females with familial hypercholesterolaemia, treatment with at least one medication increased from 76% in 1996 to 86% in 2021 in those with coronary heart disease and from 52% to 79% in those without coronary heart disease. Corresponding values for males were 67%–90% and 48%–80%. Combined across sex, the values were 71%–88% and 50%–79%. In absolute numbers, individuals with familial hypercholesterolaemia treated with at least one lipid-lowering medication increased steadily from 453 (214 females and 239 males) in 1996 to 6022 (3595 females and 2427 males).

Fig. 1.

Fig. 1

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Percentage of females and males treated with any lipid-lowering medication according to diagnosis of familial hypercholesterolaemia and coronary heart disease. +FH: With familial hypercholesterolaemia. −FH: Without familial hypercholesterolaemia. +CHD: With coronary heart disease. −CHD: Without coronary heart disease.

Types of lipid-lowering medications used in familial hypercholesterolaemia

In females and males with familial hypercholesterolaemia, statin treatment increased from 1996 to about 2008 after which it changed little to 2021 (Fig. 2). Though, a slight decrease in statin use could be observed after 2010 in those with coronary heart disease diagnoses.

Fig. 2.

Fig. 2

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Percentage of females and males with familial hypercholesterolaemia treated with different lipid-lowering medications. Please note that each individual can be assigned to multiple medications at the same time. PCSK9i: Proprotein convertase subtilisin/kexin type 9 inhibitor.

In females with familial hypercholesterolaemia, statin treatment increased from 68% in 1996 to 79% in 2021 in those with coronary heart disease and from 50% to 75% in those without coronary heart disease (p < 0.001). Corresponding values for males were 61%–85% and 41%–77% (p < 0.001).

In Denmark, ezetimibe was introduced in 2004 and PCSK9 inhibitors in 2015. These medications saw an overall increasing use from their introduction until the end of the study, irrespective of sex and coronary heart disease diagnoses (p < 0.003). In those treated with PCSK9 inhibitors, 52% received alirocumab and 48% received evolocumab; inclisiran was not used in Denmark during the study period. For fibrates, bile acid sequestrants and nicotinic acids, a decreasing use was observed over the study period.

Number of lipid-lowering medications in familial hypercholesterolaemia

In females and males with familial hypercholesterolaemia, the proportion treated with two or more medications increased from 1996 to 2021, irrespective of sex and coronary heart disease (Fig. 3). In those with coronary heart disease, the increases were largely due to more receiving two medications and fewer receiving one medication and were stepwise with inflection points around 2004 and 2015. In those without coronary heart disease, the pattern was slightly different since use of both single drug and combination treatment increased to about 2008, after this combination treatment increased at the expense of single drug treatment.

Fig. 3.

Fig. 3

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Percentage of females and males with familial hypercholesterolaemia treated with combinations of lipid-lowering medications. Simultaneous treatment with 0, 1, 2, or ≥3 lipid-lowering medications (statin, fibrate, bile acid sequestrant, nicotinic acid, or PCSK9 inhibitor).

In females with familial hypercholesterolaemia and coronary heart disease, 60% in 1996 and 52% in 2021 were treated with one lipid-lowering medication, 14% and 32% were treated with two lipid-lowering medications (p < 0.001), and 2% and 2% were treated with more than two medications. Corresponding values for males were 50% and 41% for one medication, 14% and 47% for two medications (p < 0.001), and 4% and 3% for more than two medications.

In females with familial hypercholesterolaemia and without coronary heart disease, 40% in 1996 and 58% in 2021 were treated with one lipid-lowering medication, 11% and 19% were treated with two lipid-lowering medications (p = 0.07), and 0.9% and 0.7% were treated with more than two medications. Corresponding values for males were 34% and 51%, 13% and 29% (p < 0.001), and 0.9% and 0.7%.

Statin treatment intensity in familial hypercholesterolaemia

In females and males, treatment with moderate- and high-intensity statin treatment increased from 1996 to about 2008 after which it changed little to 2021, irrespective of coronary heart disease diagnoses (Fig. 4). Levels of moderate- and high-intensity statin treatment were generally higher in those with coronary heart disease diagnoses.

Fig. 4.

Fig. 4

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Percentage of statin-treated females and males with familial hypercholesterolaemia treated with different statin intensities. Low intensity statin treatment: daily dose ≤0.67 DDD (equivalent to ≤20 mg simvastatin). Moderate intensity treatment: daily dose >0.67 DDD and ≤1.33 DDD. High intensity treatment: daily dose >1.33 DDD (equivalent to >40 mg simvastatin).

In statin-treated females with familial hypercholesterolaemia and coronary heart disease, 82% in 1996 and 28% in 2021 were on low-intensity statin treatment (daily dose ≤0.67 DDD equivalent to ≤20 mg simvastatin), 18% and 31% were on moderate-intensity statin treatment (>0.67 DDD and ≤1.33 DDD), and 0.0% and 41% were on high-intensity statin treatment (>1.33 DDD equivalent to >40 mg simvastatin) (p < 0.001 for all). Corresponding values for males were 81% and 16%, 18% and 24%, and 0.8% and 60% (p < 0.001 for all).

In statin-treated females with familial hypercholesterolaemia and without coronary heart disease, 85% in 1996 and 40% in 2021 were on low-intensity treatment, 15% and 34% were on moderate-intensity treatment, and 0.0% and 26% were on high-intensity treatment (p < 0.001 for all). Corresponding values for males were 82% and 31%, 18% and 29%, and 0.0% and 40% (p < 0.001 for all).

Coronary revascularisation in familial hypercholesterolaemia

The fraction of females with familial hypercholesterolaemia that had been treated with percutaneous coronary intervention increased from 2% in 1996 to 9% in 2005 after which it changed little to 2021 (Fig. 5) (p < 0.001). For males, the fraction increased steadily throughout the study period from 5% in 1996 to 25% in 2021 (p < 0.001).

Fig. 5.

Fig. 5

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Percentage of females and males with familial hypercholesterolaemia with coronary revascularisation. PCI: percutaneous coronary intervention. CABG: coronary artery bypass grafting.

For individuals with familial hypercholesterolaemia, the fraction that had been treated with coronary artery bypass grafting decreased from around 1999 when 16% of females and 32% of males had been treated to 2021 where 3% of females and 12% of males had been treated (p < 0.001).

Start of lipid-lowering therapy when diagnosed with familial hypercholesterolaemia

In females and males, treatment with lipid-lowering therapy no later than one year after familial hypercholesterolaemia diagnosis increased from 1996 to about 2008 after which it changed little to 2021 (Fig. 6, top panels). In females, 46% in 1996 and 92% in 2020 were treated with lipid-lowering therapy no later than one year after diagnosis (p < 0.001). Corresponding values for males were 77% and 92% (p < 0.001). Except for an initial drop in males, the presence of coronary heart disease at diagnosis with familial hypercholesterolaemia seemed more or less constant within each sex throughout the study period (Fig. 6, bottom panels).

Fig. 6.

Fig. 6

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Females and males on lipid-lowering therapy when diagnosed with familial hypercholesterolaemia. Top panels: Percentage of individuals diagnosed with familial hypercholesterolaemia who were started on lipid-lowering therapy no later than one year after diagnosis. Bottom panels: Percentage who did not have coronary heart disease (primary prevention) or had coronary heart disease (secondary prevention) at diagnosis in individuals diagnosed with familial hypercholesterolaemia and started on lipid-lowering therapy no later than one year after diagnosis.

Age at start of lipid-lowering therapy in familial hypercholesterolaemia

For females and males, those diagnosed with familial hypercholesterolaemia and starting lipid-lowering therapy no later than one year after diagnosis, the number of individuals who had started lipid-lowering medication at the age of 20 increased from the period 1996–2002 to the period 2015–2020 (Fig. 7, green bars). The same tendency was seen for older age groups reflecting an increase in females and males diagnosed with familial hypercholesterolaemia and more starting medication. The percentage of females with familial hypercholesterolaemia, who had started treatment at the age of 20 increased from 3% in 1996–2002 to 9% in 2015–2020. Corresponding values for males were 0.7% in 1996–2002 and 8% in 2015–2020.

Fig. 7.

Fig. 7

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Age at start of lipid-lowering therapy in females and males with familial hypercholesterolaemia. Age at start of lipid-lowering therapy in individuals on lipid-lowering therapy no later than one year after diagnosis of familial hypercholesterolaemia. Separate panels for individuals diagnosed in 1996–2002, 2003–2008, 2009–2014, and 2015–2020. Data not shown for 5-year age intervals with 1–5 individuals (∗) due to European data protection rules.

Supplementary analyses

When combining males and females in analyses, results were similar with regard to overall trends over time (Supplemental appendix Figures S1–S6), though values were naturally somewhere between those of females and males.

Discussion

In this nationwide study of all individuals diagnosed with familial hypercholesterolaemia in Denmark, we found that use of lipid-lowering treatment increased between 1996 and 2021. Also, our results indicate that more are treated with more aggressive lipid-lowering therapy, which could reflect that guidelines over time have gradually recommended more intensive treatment. Despite improvements, our results still show undertreatment in familial hypercholesterolaemia. For example, 12% of individuals with both familial hypercholesterolaemia and coronary heart disease did not receive lipid-lowering treatment in 2021, which is a very-high-risk population for recurrent coronary heart disease.4,5

Several mechanisms could explain the increased use of lipid-lowering medication from 1996 and onwards. First, introduction of effective and safe LDL-cholesterol lowering treatments, i.e., statins in the late 1980s and ezetimibe in the mid-2000s, that lowered cardiovascular events in both individuals with and without familial hypercholesterolaemia could have stimulated increased use.21, 22, 23 Second, there was a general trend in consecutive hyperlipidaemia guidelines to expand treatment indication and recommend higher statin treatment intensities8 because it was demonstrated that high-intensity statin treatment and combination treatment were superior to low-intensity treatment and monotherapy.21,22 Finally, the expiration of drug patents (e.g., simvastatin in 2006, atorvastatin in 2011, rosuvastatin in 2016, ezetimibe in 2016) has allowed for production of cheaper, generic brands, which has made treatment with statin and ezetimibe more cost-effective and accessible. Notably, we observed that the expiration of the ezetimibe patent in 2016 coincided with a marked increased use of ezetimibe in Denmark. In relation to the latter point, it is important to note that in Denmark payment for prescribed treatment is subsidised by the government, and out-of-pocket expenses for patients are relatively low with a reimbursement of 100% for medicine expenses exceeding 650 euros per year. Therefore, we find it unlikely that economic factors explain the observed underutilisation of lipid-lowering medications in Denmark. We speculate that all the developments mentioned above have increased awareness among both healthcare personnel and patients of using maximally tolerable treatments and have led to an increase in the number of people treated with lipid-lowering medications, increased intensity of statin treatment, earlier treatment initiation after diagnosis of familial hypercholesterolaemia, and increased use of combination treatment. Nevertheless, there were some deviations from this overall trend, e.g., after 2009 there was a stagnation in the hitherto increasing use of statins. While the reasons for this stagnation cannot be directly inferred from our results, we speculate that it is related to negative news stories about statins, as previously documented in Denmark.24

Sex-specific differences in lipid-lowering treatment and their clinical implications warrant discussion: In our data, overall treatment rates seemed similar in females and males, but there may have been a tendency towards females receiving lower intensity of treatment than males. This latter finding has also been observed in other settings.25,26 However, the full clinical significance of this difference remains uncertain. Even though females receive less intensive treatment and less often achieve LDL-cholesterol targets, males seem to have higher event rates.25

To our knowledge, no previous studies have investigated use of lipid-lowering therapy over several decades on a nationwide scale in familial hypercholesterolaemia. However, our findings are in line with previous studies which show that many patients with familial hypercholesterolaemia are undertreated despite being at high risk of cardiovascular events. A recent collaborative study reflecting current clinical practice worldwide shows that about 40% of individuals with a familial hypercholesterolaemia diagnosis may not be receiving any lipid-lowering therapy,27 with higher rates of non-treatment among younger patients.28 Likewise, in a Catalan population of primary care patients with high LDL-cholesterol levels consistent with familial hypercholesterolaemia, 14% were not on lipid-lowering therapy, again with higher rates of non-treatment among younger patients.29,30 Amongst those treated, 25% were on high-intensity treatment. Notably, the percentage of females who received high intensity treatment was 9 percentage points lower than in males. These values are comparable to our findings that in 2021, where treatment with high-intensity statin was 18 percentage points lower in females compared to males (30% vs. 48%). The undertreatment observed in our study and the above-mentioned studies can probably only to a minor extent be attributed to different definitions of familial hypercholesterolaemia. Even in patients followed for 11 years with genetically verified familial hypercholesterolaemia at Norwegian specialised lipid clinics, 11% were not treated with a statin, 42% not with ezetimibe, and only 19% reached the recommended treatment goals of LDL-cholesterol below 2.5 or 1.8 mmol/L.31

One way of improving treatment in familial hypercholesterolaemia could be broader use of PCSK9 inhibitors. However, cost-effectiveness analyses of different lipid-lowering therapies for familial hypercholesterolemia in comparable settings to ours show that statin with ezetimibe may be the most cost-effective therapy, unless the yearly cost of treatment with a PCSK9 inhibitor is reduced to <3900 euros per patient.32 Currently, the yearly price for treatment with a PCSK9 inhibitor is around 6300 euros.

A strength of the present study is the use of comprehensive nationwide data which allowed us to follow a large population over an extended period of time with no selection bias for data collection, few losses to follow-up, and high generalisability to the population at large. Also, information on residency, diagnoses, and pharmacy-dispensed medications is from registries with validated quality and completeness.13,14,16

A limitation of the study is the fact that the used nationwide registries do not have information on relevant clinical covariates such as lipid parameters, smoking, and body mass index. Also, we do not have information on genetic testing, and we expect that most diagnoses of familial hypercholesterolaemia (especially those made more than ten years ago) were based on clinical criteria and were not consistently genetically confirmed. That said, we are not aware of any other country in the world that has complete nationwide information on both a clinical diagnosis of familial hypercholesterolemia, prescription medication, lipid parameters, smoking, and body mass index from 1996 through 2021. A diagnosis of familial hypercholesterolaemia is subject to uncertainty because of how LDL-cholesterol is measured. As the cholesterol in lipoprotein(a) is co-measured in measurements of LDL-cholesterol, high lipoprotein(a) can contribute to a clinical diagnosis of familial hypercholesterolaemia in up to one in four of those diagnosed.33,34 Therefore, some of those receiving a clinical diagnosis of familial hypercholesterolaemia naturally could also have contributions to their LDL-measurements from high lipoprotein(a).35 Inherently, when using prescription databases assumptions are made regarding ingested dose. Thus, we do not have information on actual use of the medication that may include gaps and time-dependent variation in intake; however, it is generally accepted that use of medication can be accurately assessed based on pharmacy data on dispensed prescriptions, which is the type of data used in the present study.36

Our findings have some implications for the future. As it is well documented that individuals with familial hypercholesterolaemia and coronary heart disease benefit from aggressive lipid-lowering therapy,4, 5, 6 the lower treatment intensity observed in the present study can reasonably be interpreted as undertreatment. When seeking to address this undertreatment, it would be valuable if further studies could elucidate whether this is mainly caused by physicians' reservations about prescribing lipid-lowering medication, by patients' reservations about taking the prescribed medication, medication costs, or by other factors. In continuation of this, it would be valuable to elucidate the causes of physicians' and patients’ treatment reservations, e.g., symptoms attributed to treatment or inadequate awareness of the benefits of treatment. Finally, as it is well known that low adherence to statin treatment is associated with increased cardiovascular morbidity and mortality,37, 38, 39 it should be a high priority to support increased adherence to lipid-lowering therapy particularly in those with familial hypercholesterolaemia.

An alarming finding was that only 3% of females and 0.7% of males starting lipid-lowering therapy in 1996 through 2002 were less than 20 years old, likely caused by lack of willingness to give lipid-lowering therapy to children during this period which has also been observed in other countries.28,29 Fortunately, however, this fraction increased to 9% for females and 8% for males in 2015 through 2020. It is particularly important that children with familial hypercholesterolaemia are diagnosed early on, as appropriate lipid-lowering therapy in childhood largely mitigates excess coronary heart disease later in life.2

In conclusion, nationwide in Denmark from 1996 through 2021, lipid-lowering medication use improved in those with familial hypercholesterolaemia irrespective of sex and coronary heart disease status. This was reflected in an increased number and proportion of familial hypercholesterolaemia patients receiving treatment, increased dose of statin treatment, and increased use of combination treatment. Despite these advances, a considerable proportion of individuals with familial hypercholesterolaemia remains untreated.

The EU Commission recently proposed that all persons living in the EU should be screened to find those with familial hypercholesterolaemia and high lipoprotein(a) for prevention of coronary heart disease and early death.40 For familial hypercholesterolaemia, a similar process is already under way in Denmark through the Danish Quality Control Database for Familial Hypercholesterolaemia, where the aim is to diagnose and treat everybody with familial hypercholesterolaemia, including those due to high lipoprotein(a), within the next ten years.18

Contributors

JR, ABW, BGN and SA conceptualised and designed the study and interpreted the results. JR and SA prepared and analysed the data. JR wrote the original manuscript draft. SA supervised the study. All authors reviewed and edited the manuscript and agreed on the decision to submit for publication.

Data sharing statement

The data used in this study is managed by Statistics Denmark which may authorise access to researchers affiliated with publicly funded Danish research institutions. The Danish Data Protection Agency does not allow open access to nationwide Danish data; however, upon reasonable request to the corresponding author, additional analyses can be performed.

Declaration of interests

Nordestgaard reports consultancies and talks sponsored by AstraZeneca, Sanofi, Arrowhead, Marea, Amgen, Lilly, Merck, Amarin, Novartis, Novo Nordisk, and Esperion. Afzal reports support from Abbott for travelling to and attending a meeting. Reeh reports funding for prior research from Novo Nordisk Foundation. Wulff reports no financial or other conflicts of interest.

Acknowledgements

The study was funded by grants from The Johan and Lise Boserup Foundation (grant 20795-24); The Independent Research Fund Denmark (grant 1030-00168B); and Copenhagen University Hospital–Herlev Gentofte, Denmark. The researchers were independent from the funding sources which were not involved in the study design, analysis, or writing and submission of the article.

Footnotes

Appendix A

Supplementary data related to this article can be found at https://doi.org/10.1016/j.lanepe.2026.101709.

Appendix A. Supplementary data

Supplementary Figures
mmc1.docx (1.1MB, docx)

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Supplementary Materials

Supplementary Figures
mmc1.docx (1.1MB, docx)

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