# Persistent gaps in the implementation of lipid-lowering therapy in patients with established atherosclerotic cardiovascular disease: A French nationwide study

Matthieu Wargny, Thomas Goronflot, Pierre-Guillaume Piriou, Mathilde Pouriel, Alexandre Bastien, Julie Prax, Christophe Leux, Valéry-Pierre Riche, Jean-Noël Trochu, Sophie Béliard, et al.

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Matthieu Wargny, Thomas Goronflot, Pierre-Guillaume Piriou, Mathilde Pouriel, Alexandre Bastien, et al. Persistent gaps in the implementation of lipid-lowering therapy in patients with established atherosclerotic cardiovascular disease: A French nationwide study. Diabetes & Metabolism, 2025, 51 (3), pp.101638. 10.1016/j.diabet.2025.101638. hal-05525620

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Original article

# Persistent gaps in the implementation of lipid-lowering therapy in patients with established atherosclerotic cardiovascular disease: A French nationwide study

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Matthieu Wargny<sup>a,b,*</sup>, Thomas Goronflot<sup>b</sup>, Pierre-Guillaume Piriou<sup>a</sup>, Mathilde Pouriel<sup>c</sup>,
Alexandre Bastien<sup>d</sup>, Julie Prax<sup>d</sup>, Christophe Leux<sup>e</sup>, Valéry-Pierre Riche<sup>f</sup>, Jean-Noël Trochu<sup>a</sup>,
Sophie Béliard<sup>g</sup>, Nadège Costa<sup>h</sup>, Jean Ferrières<sup>i</sup>, Stéphanie Duret<sup>d</sup>, Bertrand Cariou<sup>a,*</sup>

ARTICLE INFO

Keywords:

Health care information system

LDL-cholesterol

Real-word evidence

Secondary prevention

Statins

Underuse

ABSTRACT

**Background:** According to international guidelines, lowering LDL-cholesterol is the cornerstone of atherosclerotic cardiovascular disease (ASCVD) prevention. However, observational studies have identified current gaps in the implementation of lipid-lowering therapy (LLT). This whole-population study aimed to evaluate the prevalence and determinants of LLT use in ASCVD patients.

**Methods:** Using the national health data system, all French adults with established ASCVD between 2012 and 2021 were identified using specific ICD-10 and/or procedure codes. LLT use was defined as ≥1 dispensing in the last quarter of 2021. Logistic regression was used to identify factors associated with the absence of LLT use.

**Findings:** In 2021, 2,206,305 individuals (4.89 % among 45,082,270 adults) had established ASCVD (mean age: 72.2 years; 36.9 % women), including 56.1 % with coronary artery disease, 40.4 % with cerebrovascular disease, and 14.5 % with revascularized peripheral artery disease (PAD). Among the 2,056,354 patients alive on 31st December 2021, 32.5 % did not receive any LLT, while 64.8 % received a statin (27.0 % a high-intensity statin), 13.0 % a combination of statin and ezetimibe, and 0.25 % a PCSK9 inhibitor. The absence of LLT use was significantly associated with female sex (adjusted odds ratio [aOR]:1.42, 95 %CI, 1.41–1.43); lowest/highest ages: < 50 years (aOR (/65–74 years): 2.23, 95 %CI 2.20–2.27) and ≥ 85 years (aOR: 2.10, 95 %CI 2.08–2.13); and stroke and PAD, compared to myocardial infarction (aOR: 2.21, 95 %CI 2.19–2.23 and 1.88, 95 %CI 1.86–1.91, respectively).

**Interpretation:** In real life, one-third of French ASCVD patients was not regularly treated with LLT, highlighting the urgent need to develop implementation strategies for lipid management.

**Abbreviations:** apoB, Apolipoprotein B; aOR, Adjusted odds ratio; ASCVD, Atherosclerotic cardiovascular disease; ATC, Anatomical, therapeutic and chemical drug classification; ATIH, French national technical agency for hospital information system (Agence technique de l'information sur l'hospitalisation); CAD, Coronary artery disease; CI, Confidence interval; CKD, Chronic kidney disease; CVD, Cerebrovascular disease; ESKD, End-stage kidney disease; GP, General practitioner; ICD-10. International Classification of Diseases, 10th revision; LDL-C, Low-density lipoprotein cholesterol; LLT, Lipid-lowering therapy; MACE, Major adverse cardiovascular event; PAD, Peripheral artery disease; PCSK9i, Proprotein convertase subtilisin/kexin-9 inhibitor; PY, Person-years; RECORD, Reporting of studies conducted using observational routinely collected data; SNDS, French National Health Data System (Système National des Données de Santé).

* Corresponding authors at: l'institut du thorax, Inserm UMR 1087 / CNRS UMR 6291, IRS – UN, 8 quai Moncousu, BP 70721, 44007 NANTES Cedex.

E-mail addresses: matthieu.wargny@chu-nantes.fr (M. Wargny), bertrand.cariou@univ-nantes.fr (B. Cariou).

<footnote><sup>a</sup> Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes, France</footnote>

<footnote><sup>b</sup> Nantes Université, CHU Nantes, Pôle Hospitalo-Universitaire 11: Santé Publique, Clinique des données, INSERM, CIC 1413, F-44000 Nantes, France</footnote>

<footnote><sup>c</sup> IT&M stats, Boulogne Billancourt, France</footnote>

<footnote><sup>d</sup> Novartis, Rueil-Malmaison, France</footnote>

<footnote><sup>e</sup> Nantes Université, CHU Nantes, Pôle Hospitalo-Universitaire 11: Santé Publique, Service d'Information Médicale, F-44000 Nantes, France</footnote>

<footnote><sup>f</sup> Nantes Université, CHU Nantes, Service Evaluation Economique et Développement des Produits de Santé, Direction de la Recherche et de l'Innovation, Nantes, France</footnote>

<footnote><sup>g</sup> Aix Marseille Univ, APHM, INSERM, INRAE, C2VN, Marseille, France, Department of Nutrition, Metabolic Diseases, Endocrinology, La Conception Hospital, Marseille, France</footnote>

<footnote><sup>h</sup> Unité d'évaluation médico-économique, CHU de Purpan, Toulouse, France</footnote>

<footnote><sup>i</sup> Department of Cardiology, Toulouse Rangueil University Hospital, Toulouse, France, Department of Epidemiology, Toulouse University School of Medicine, INSERM UMR 1295, Toulouse, France</footnote>
## Introduction

Atherosclerotic cardiovascular disease (ASCVD), which includes coronary artery disease (CAD), cerebrovascular disease (CVD), and peripheral artery disease (PAD), remains the leading cause of morbidity and mortality in most countries [1]. Among the multiple cardiovascular risk factors involved in the development of atherosclerosis and ASCVD-related events, low-density lipoprotein cholesterol (LDL-C) plays a prominent role [2]. Indeed, the retention and accumulation of LDL and other apolipoprotein B (apoB)-containing lipoproteins within the arterial intima at sites of predilection are among the key events for the initiation of atherosclerosis and plaque formation. In the INTERHEART study, abnormal lipids with raised apoB-containing lipoproteins accounted, with active smoking, for about two-thirds of the attributable risk of an acute myocardial infarction [3]. The 2019 Global Burden of Disease study reported that elevated LDL-C concentration is the second highest contributor to disability-adjusted life years lost globally [4]. In this study, males suffered worse health outcomes attributed to high LDL-C when compared to females and the burden attributed to high LDL-C increased with age and deprivation index [5].

Since the discovery of statins and the first randomized controlled cardiovascular outcomes trial 30 years ago, concordant evidence has demonstrated that LDL-C-lowering pharmacotherapy is an effective strategy for preventing both incident and recurrent ASCVD events [2,6]. In addition to statins, this has been demonstrated with the use of ezetimibe [7], proprotein convertase subtilisin/kexin-9 inhibitors (PCSK9i) [8,9] and, more recently, bempegic acid [10].

Based on this evidence, international guidelines promote increasingly aggressive management of LDL-C according to the level of cardiovascular risk, with more stringent goals [11]. Particularly, in patients with a history of an ASCVD-related event, the aim is to achieve an LDL-C value < 55 mg/dL (< 1.40 mmol/L).

Nevertheless, implementing these recommendations in real life remains a major challenge. Indeed, observational studies have shown that it is difficult to achieve LDL-C targets. For instance, only 20.7 % of individuals with a history of ASCVD achieved their LDL-C goal in the multinational European observational SANTORINI study. It is also worrying to note that 21.4 % of these very high-risk patients were not taking any lipid-lowering treatment (LLT) [12]. Even though it was carefully conducted, the SANTORINI study was constrained however by the usual limitations of clinical cohort studies, in particular a selection bias due to the research setting, a limited size (9000 patients) and indirect information on drug delivery.

In this study, we took advantage of the exhaustiveness of real-world data from the French National Health Data System (SNDS), which includes in particular all ambulatory drug dispensing on a national scale, to estimate the prevalence of LLT use among individuals with a previous history of ASCVD in the French population in 2021. We also sought to identify the factors associated with the absence of LLT use in order to highlight the population sub-groups most at risk, for whom the implementation of strategies for lipid management should be reinforced.

## Material and methods

### *Study design and data source*

The ASCVD population-based study used a retrospective, nationwide cohort based on the SNDS, which covers more than 99 % of the French population (≥65 million beneficiaries) [13,14]. The SNDS contains individual data for all healthcare expenditures reimbursed by the French National Health Insurance (Caisse Nationale d'Assurance Maladie). Full access to national data was granted in accordance with French reference methodology MR-007.

The primary data of interest included: i) all hospital stays (public or private) with diagnoses based on ICD-10 codes and medical procedures based on the French Common Classification of Procedures; ii) the status

of long-term illnesses reported for 100 % coverage of healthcare costs, allowing the identification of specific diseases such as cancer or heart failure (ICD-10 declared by general practitioners (GP)); and iii) the delivery of all reimbursed drugs, identified using the anatomical therapeutic and chemical classification (ATC).

The RECORD (reporting of studies conducted using observational routinely collected data) guidelines were applied to report the study design and results, as detailed in *Supplementary Material, section E*.

### *Population*

All individuals aged over 18 years on 31st December 2020 and affiliated to the compulsory French health insurance were considered for analysis. The “ASCVD 2021 population” was defined as all individual having presented CAD (defined as myocardial infarction, coronary revascularization, and/or unstable angina), CVD (defined as ischemic stroke and/or carotid revascularization) and/or PAD (defined as lower limb artery revascularization) between 1st January 2012 and 31st December 2021. Data sources, codes and algorithms used to identify these pathologies (ICD-10 codes and other codes for medical or surgical procedures) are detailed in the *Supplementary Material, section A*. Individuals living in the French overseas territory of Mayotte were excluded because of lack of data. The “ASCVD 2021 survivors” were defined as the ASCVD 2021 population after exclusion of individuals deceased during 2021. The “incident ASCVD 2021 population” was defined as those without any prior ASCVD detected between 2012 and 2020 and with ≥ 1 hospital stay for an acute ASCVD event in 2021, based on primary diagnoses and revascularization procedures.

### *Data collection and outcomes*

Age was calculated using the date of the first acute ASCVD event in 2021 for incident patients and on 1st January 2021 for the others. Sex assigned at birth was extracted from the 2021 insured covered scheme. Cardiovascular risk factors (overweight or obesity, smoking history, anti-hypertensive treatment, diabetes mellitus) and other comorbidities of interest (excessive alcohol consumption, cardiac arrhythmias, heart failure, depressive disorder, cancer, chronic kidney disease (CKD) and end-stage kidney disease (ESKD)) were defined according to the data available during the period 2017–2021. These characteristics were defined based on the combination of hospital stays diagnoses, procedures and labels, long-term diseases diagnoses and drug deliveries, as detailed in *Supplementary Material, sections B and C*.

For a given therapy, 2021 drug use was defined as ≥1 delivery in 2021, and ongoing drug use on 31st December 2021 as ≥ 1 delivery within the last quarter of 2021 (relevant only for ASCVD 2021 survivors). Statin intensity was assessed as follows: high- (atorvastatin ≥ 40 mg or rosuvastatin ≥ 20 mg), moderate- (atorvastatin: 10 to 20 mg; rosuvastatin: 5 to 10 mg; simvastatin: 20 to 40 mg; pravastatin: 40 to 80 mg; fluvastatin: 80 mg) or low-intensity (simvastatin: 10 mg; pravastatin: 10 to 20 mg; fluvastatin: 20 to 40 mg). No LLT use was defined as no LLT delivery (statin, ezetimibe, PCSK9i, fibrates or colestyramine) in the last quarter of 2021. Medical follow-up of interest in 2021 was ≥ 1 LDL-C dosing in medical analysis laboratory (whole lipid profile and/or specific LDL-C test), frequency of consultation with GP (sum of distinct days with ≥ 1 consultation) and ASCVD specialist (≥ 1 consultation with cardiologist, neurologist, or vascular physician). See *Supplementary Material, section D* for code details.

### *Statistical analyses*

A Venn diagram was drawn to represent the distribution and overlaps of the different ASCVD subtypes (CAD, CVD and PAD). The ASCVD 2021 population and its subtypes were described, with categorical data presented by population size (%) and quantitative data presented by mean ± SD, median (25th-75th percentile), and minimum and
maximum values of the distribution. In the ASCVD 2021 survivors, the same description was applied according to status for ongoing LLT on 31st December 2021 (none/at least one).

Uni- and multivariable logistic regression models were fitted to assess the association between patient characteristics (demographics, comorbidities, ASCVD vascular beds) and LLT use, in the ASCVD 2021 survivors, excluding patients with unstable angina and/or carotid revascularization only. The choice of variables was based on clinical background knowledge, without statistical selection.

As a sensitivity analysis, the latter logistic regression models were replicated in the sub-population who received ≥ 1 drug delivery during last quarter of 2021, in order to exclude patients who may have received drugs not identified in the SNDS, such as patients hosted in nursing homes with an in-house pharmacy.

Data management was performed using SAS Enterprise Guide 8.3. All statistical analyses were performed on available data, without imputation, using R software version 4.3.3.

## Results

### Prevalence of ASCVD and distribution of affected vascular beds

On 31st December 2020, 45,082,270 French adult individuals were eligible. The ASCVD 2021 population included 2,206,305 (4.9 %) individuals who had documented ASCVD between 2012 and 2021, among whom 149,951 (6.8 %) died during 2021 versus 0.89 % in the population without ASCVD (see flowchart, Fig. 1). ASCVD was first identified before 2018 in 61.5 % of the population, whereas 8.8 % individuals experienced their first acute ASCVD event in 2021, constituting the incident ASCVD 2021 population.

Regarding the number of vascular beds affected, 89.9 % of ASCVD patients were affected on one bed (CAD, CVD or PAD), whereas 9.3 % and 0.8 % had atherosclerotic lesions affecting two and three ASCVD beds, respectively (see Venn diagram, Fig. 2). CAD was the most frequent injury in patients with two affected beds (82.3 %).

In the 1,236,802 individuals (56.1 %) with CAD, 54.3 % presented with myocardial infarction, 38.2 % with coronary revascularization without myocardial infarction, and 7.5 % with unstable angina without the latter. Among the 891,790 individuals (40.4 %) with CVD, 91.0 % presented with stroke and 9.0 % with carotid revascularization without stroke. Finally, 319,530 patients (14.5 %) presented with lower limb artery revascularization.

### Characteristics of the ASCVD population according to vascular beds

The characteristics of the 2021 ASCVD population and of the subgroups defined by affected vascular beds are given in Table 1. The proportion of women was similar between CAD and PAD subgroups (29.6 and 29.2 %, respectively) and much higher in the CVD subgroup (47.4 %). Mean (± SD) age was 71.5 ± 12.6 years in CAD, 73.8 ± 14.2 in CVD and 72.3 ± 12.1 in PAD, with a higher percentage of patients aged ≥ 85 in the CVD subgroup. Concerning cardiovascular risk factors, smoking history was more frequent in people with PAD (31.1 %) than with CAD (19.0 %) or CVD (13.4 %), as it was observed for diabetes mellitus (35.5 %, 32.0 % and 26.0 %, respectively). Anti-hypertensive treatments were more frequent in people with CAD (90.3 %) than with PAD (81.1 %) or CVD (75.4 %). Regarding other comorbidities, people with CAD presented more frequently with heart failure than those with PAD or CVD (20.4 % versus 17.7 and 13.5 %, respectively). Individuals with CVD had also more frequently a history of depressive disorder (38.0 %) than those with PAD or CAD (29.9 and 26.5 % respectively). On the other hand, people with PAD presented more frequently with a history of cancer (20.3 % versus 16.6 and 15.5 %, respectively, for CVD and CAD patients), and CKD/ESKD (16.7 % versus 11.4 and 11.1 %, respectively). Patient characteristics of the ASCVD 2021 survivors population, by precise type of qualifying ASCVD event (myocardial infarction, coronary revascularization, unstable angina, stroke, and carotid revascularization), are shown in *Supplemental Tables 1 and 2*.

<figure><img src="image_3.png" /><figcaption>Fig. 1. Flowchart.</figcaption></figure>

ASCVD: atherosclerotic cardiovascular disease; SNDS: French national health data system (Système national des données de santé).

* Excluding Mayotte (overseas territory) due to lack of data (< 0.5 % among French adults).

** Data inconsistency identified: hospital stay started after the patient death was reported.
<figure><img src="image_4.png" /><figcaption>**Fig. 2.** ASCVD distribution sites.</figcaption></figure>

Venn diagram giving the distribution sites of the ASCVD 2021 population (n = 2,206,305). Numbers presented: percentage of the total. ASCVD: atherosclerotic cardiovascular disease; CAD: coronary artery disease; CVD: cerebrovascular disease; PAD: peripheral artery disease; LLL: lipid-lowering therapy.

* Coronary revascularization with no report of myocardial infarction.

** Unstable angina with no report of myocardial infarction or coronary revascularization.

*** Carotid revascularization with no report of ischemic stroke.

## LLT use in population with ASCVD

In the ASCVD 2021 survivors (n = 2,056,354), 32.5 % of the patients did not receive any LLL during the last quarter of 2021. This figure reached 23.1 % of individuals with CAD, 43.8 % of people with CVD, and 31.8 % of people with PAD (Table 2). Regarding LLL distribution, 51.7 % of patients received statin in monotherapy and 13.0 % a combination of statin and ezetimibe in the whole ASCVD population, against respectively 55.6 and 18.3 % in the population with CAD, 47.3 and 6.6 % in the population with CVD, and 52.5 and 12.7 % in the population with PAD. As regards the use of high-intensity statins, they were delivered to 39.7 % of the ASCVD 2021 survivors taking statins as monotherapy and 48.3 % of patients receiving statin and ezetimibe as bitherapy, with differences according to vascular beds: 45.7 % and 51.5 %, respectively, for CAD, 34.9 % and 41.6 % for CVD and 29.3 % and 40.3 % for PAD. Figures according to the type of coronary or cerebrovascular damage are detailed in the **Supplemental Table 3**. Patients who had undergone coronary revascularization without prior myocardial infarction were the most treated with 81.4 % of them taking LLL, including 58.3 % with statin as monotherapy and 19.6 % with statin and ezetimibe combination therapy. Conversely, patients with a history of stroke were much less well treated, with only 54.3 % of them on LLL, including 46.4 % with statin as monotherapy and 5.6 % with statin and ezetimibe combination therapy. It is worth noting that a majority of patients (54.7 %) classified as having unstable angina did not receive LLL (Table 2). It should be noted that PCSK9i were barely used, corresponding to less than 0.2 % of ASCVD patients.

LLT delivered in the whole ASCVD 2021 population is also detailed in the **Supplemental Table 4**.

## Other treatments of interest and medical follow-up in 2021

Regarding antithrombotic therapies dispensed over the same period, antiplatelet agents were delivered to 70.3 % of ASCVD 2021 survivors (78.0 % with CAD, 57.4 % with CVD, and 80.3 % with PAD) (Table 2). For antihypertensive treatments, these figures reached 78.8 % in the whole ASCVD population (86.5 % in CAD, 71.1 % in CVD and 76.9 % in PAD). Details for each class of anti-hypertensive treatment are detailed

in Table 2, as are those for other non-cardiovascular treatments (anti-diabetic and antidepressant). In 2021, 69.1 % of the ASCVD 2021 survivors had ≥ 1 LDL-C test (74.4 % with CAD, 62.4 % with CVD, and 69.0 % with PAD).

The frequency of visits to GPs and specialists (cardiologist, neurologist or vascular physician) in 2021 is also shown in Table 2.

## Factors associated with the absence of LLL use in ASCVD

In order to better identify patients at higher risk of absence of LLL use, the characteristics of the ASCVD 2021 survivors were analyzed based on the absence of LLL dispensing in community-based pharmacies during the last quarter of 2021, after exclusion of the population with unstable angina and/or carotid revascularization only (1,935,755 individuals remaining, 94.1 % of the ASCVD 2021 survivors) (Table 3). Among patients without any LLL delivery, the percentage of women (46.9 versus 30.7 %) and elderly subjects was higher than in those taking LLL, with twice as many patients aged over 85 (28.4 versus 13.0 %). There was also a lower prevalence of diabetes (21.2 versus 32.0 %) and a higher prevalence of CVD (56.0 versus 32.2 %). The medical follow-up in patients without LLL was poorer, with less frequent LDL-C tests (49.3 versus 78.3 %) and fewer visits to GPs (12.0 versus 1.7 % without any visit) and specialists.

As a next step, uni- and multivariable logistic regression models were performed in the same population to identify the factors associated with the absence of LLL use. As shown in Table 4, the main factors associated with the absence of LLL use were i) female sex (adjusted odds ratio [aOR] 1.42, 95 % confidence interval [95 %CI] 1.41; 1.43); ii) age, with a U-shaped risk relationship: the aOR compared to the 65–74 age class years was 2.23 [2.20; 2.27] for 18–50 years, and 2.10 [2.08; 2.13] for ≥ 85 years; iii) anti-hypertensive treatment: aOR 0.31 [0.31; 0.32] and diabetes: aOR 0.76 [0.75; 0.76]; iv) LDL-C dosing: aOR 0.48 [0.47; 0.48]; v) 2021 medical follow-up with ≥ 1 GP visit: aOR from 0.26 [0.26; 0.27] to 0.58 [0.56; 0.59] or ≥ 1 ASCVD specialist visit: aOR 0.66 [0.65; 0.66]. In addition, the recent occurrence of an ASCVD event (i.e. in 2021) was inversely associated with the absence of LLL use: OR 0.75 [0.74; 0.76].

When looking more specifically at the risk of absence of LLL use
<caption>**Table 1**</caption>

Socio-demographic and comorbidities of the ASCVD 2021 population, by vascular beds.

<table><thead><tr><th></th><th>ASCVD<br>n =<br>2,206,305</th><th>CAD<br>n =<br>1,236,802</th><th>CVD<br>n =<br>891,790</th><th>PAD<br>n =<br>319,530</th></tr></thead><tbody><tr><td><strong>Demographics</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Female sex</td><td>815,016<br>(36.9 %)</td><td>366,220<br>(29.6 %)</td><td>422,350<br>(47.4 %)</td><td>93,384<br>(29.2 %)</td></tr><tr><td>Age, years</td><td>72.2 ± 13.4,<br>73 [63; 82],<br>18/117</td><td>71.5 ± 12.6,<br>72 [63; 81],<br>18/117</td><td>73.8 ±<br>14.2,<br>75 [65;<br>85], 18/<br>117</td><td>72.3 ±<br>12.1,<br>72 [64;<br>81], 18/<br>110</td></tr><tr><td>Age class</td><td></td><td></td><td></td><td></td></tr><tr><td>18 to 50 years</td><td>115,564 (5.2<br>%)</td><td>56,402 (4.6<br>%)</td><td>53,314 (6.0<br>%)</td><td>9407 (2.9<br>%)</td></tr><tr><td>50 to 64 years</td><td>490,554<br>(22.2 %)</td><td>299,406<br>(24.2 %)</td><td>157,875<br>(17.7 %)</td><td>73,171<br>(22.9 %)</td></tr><tr><td>65 to 74 years</td><td>604,488<br>(27.4 %)</td><td>363,995<br>(29.4 %)</td><td>212,667<br>(23.8 %)</td><td>101,087<br>(31.6 %)</td></tr><tr><td>75 to 84 years</td><td>552,195 (25<br>%)</td><td>309,474 (25<br>%)</td><td>236,898<br>(26.6 %)</td><td>78,771<br>(24.7 %)</td></tr><tr><td>≥85 years</td><td>443,504<br>(20.1 %)</td><td>207,525<br>(16.8 %)</td><td>231,036<br>(25.9 %)</td><td>57,094<br>(17.9 %)</td></tr><tr><td><strong>Cardiovascular<br>risk factors</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Overweight or<br>obesity</td><td>320,347<br>(14.5 %)</td><td>203,600<br>(16.5 %)</td><td>116,161<br>(13.0 %)</td><td>50,814<br>(15.9 %)</td></tr><tr><td>Smoking history</td><td>388,855<br>(17.6 %)</td><td>235,060<br>(19.0 %)</td><td>119,810<br>(13.4 %)</td><td>99,418<br>(31.1 %)</td></tr><tr><td>Anti-hypertensive<br>treatment</td><td>1828,061<br>(82.9 %)</td><td>1116,764<br>(90.3 %)</td><td>672,514<br>(75.4 %)</td><td>259,217<br>(81.1 %)</td></tr><tr><td>Diabetes mellitus</td><td>638,860<br>(29.0 %)</td><td>396,285<br>(32.0 %)</td><td>231,555<br>(26.0 %)</td><td>113,466<br>(35.5 %)</td></tr><tr><td><strong>Other<br>comorbidities</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Excessive alcohol<br>consumption</td><td>203,751 (9.2<br>%)</td><td>97,291 (7.9<br>%)</td><td>94,246<br>(10.6 %)</td><td>44,492<br>(13.9 %)</td></tr><tr><td>Cardiac arrhythmia</td><td>506,184<br>(22.9 %)</td><td>291,218<br>(23.5 %)</td><td>227,017<br>(25.5 %)</td><td>70,338<br>(22.0 %)</td></tr><tr><td>Heart failure</td><td>356,849<br>(16.2 %)</td><td>252,045<br>(20.4 %)</td><td>120,673<br>(13.5 %)</td><td>56,492<br>(17.7 %)</td></tr><tr><td>Depressive disorder</td><td>679,134<br>(30.8 %)</td><td>327,181<br>(26.5 %)</td><td>338,591<br>(38.0 %)</td><td>95,383<br>(29.9 %)</td></tr><tr><td>Cancer</td><td>356,562<br>(16.2 %)</td><td>191,482<br>(15.5 %)</td><td>148,320<br>(16.6 %)</td><td>64,952<br>(20.3 %)</td></tr><tr><td>Chronic kidney<br>disease</td><td>212,200 (9.6<br>%)</td><td>124,708<br>(10.1 %)</td><td>89,756<br>(10.1 %)</td><td>44,366<br>(13.9 %)</td></tr><tr><td>End-stage kidney<br>disease</td><td>26,176 (1.2<br>%)</td><td>164,44 (1.3<br>%)</td><td>8679 (1.0<br>%)</td><td>8857 (2.8<br>%)</td></tr><tr><td><strong>ASCVD incident in<br>2021</strong></td><td>195,211 (8.8<br>%)</td><td>110,420 (8.9<br>%)</td><td>62,315 (7.0<br>%)</td><td>28,584 (8.9<br>%)</td></tr></tbody></table>

ASCVD: atherosclerotic cardiovascular disease. CAD: coronary artery disease; CVD: cerebrovascular disease; PAD: peripheral artery disease.

Categorical data are expressed giving size (%) of the category. Quantitative data are expressed giving mean ± SD, median (25th-75th percentile); minimum/ maximum. Comorbidities are identified by the analysis of data from 1st January 2017 to 31st December 2021, based on hospital stay, ambulatory medical treatment, and long-term diseases. Please see the data statement for code details.

according to the different vascular beds, individuals with stroke or PAD only were the most at risk of not receiving treatment (aOR 2.21 [2.19; 2.23] and 1.88 [1.86; 1.91], respectively) compared to those with myocardial infarction alone. The sensitivity analysis conducted after exclusion of patients who did not receive any drug delivery in the last quarter 2021 showed very similar results, with the exception of the weakening of the strength of the association with number of GP consultations (Table 4).

Discussion

The present work, which has the advantage of being able to study more than 2 million ASCVD patients identified in the entire population

<caption>**Table 2**</caption>

Drug treatment and medical follow-up of the ASCVD 2021 survivors on 31st December 2021, by vascular beds.

<table><thead><tr><th></th><th>ASCVD<br>n =<br>2,056,354</th><th>CAD<br>n =<br>1,167,137</th><th>CVD<br>n =<br>812,055</th><th>PAD<br>n =<br>291,216</th></tr></thead><tbody><tr><td><strong>LLT</strong></td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Monotherapy</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Any statin</td><td>1,062,735<br>(51.7 %)</td><td>648,602<br>(55.6 %)</td><td>383,748<br>(47.3 %)</td><td>152,923<br>(52.5 %)</td></tr><tr><td>with high-intensity<br>statin</td><td>421,568<br>(39.7 %)</td><td>296,425<br>(45.7 %)</td><td>133,993<br>(34.9 %)</td><td>44,735<br>(29.3 %)</td></tr><tr><td>with moderate-<br>intensity statin</td><td>568,629<br>(53.5 %)</td><td>317,857<br>(49.0 %)</td><td>218,129<br>(56.8 %)</td><td>94,668<br>(61.9 %)</td></tr><tr><td>with low-intensity<br>statin</td><td>72,538 (6.8<br>%)</td><td>34,320 (5.3<br>%)</td><td>31,626<br>(8.2 %)</td><td>13,520<br>(8.8 %)</td></tr><tr><td>Ezetimibe</td><td>32,295 (1.6<br>%)</td><td>21,731 (1.9<br>%)</td><td>9741 (1.2<br>%)</td><td>4704 (1.6<br>%)</td></tr><tr><td>PCSK9i</td><td>1312 (0.06<br>%)</td><td>1210 (0.10<br>%)</td><td>180 (0.02<br>%)</td><td>126 (0.04<br>%)</td></tr><tr><td><strong>Fibrates</strong></td><td>19,746<br>(0.94 %)</td><td>8556 (0.73<br>%)</td><td>8853 (1.1<br>%)</td><td>3502 (1.2<br>%)</td></tr><tr><td><strong>Bitherapy</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Any statin &<br>ezetimibe</td><td>267,417<br>(13.0 %)</td><td>213,835<br>(18.3 %)</td><td>53,262<br>(6.6 %)</td><td>36,921<br>(12.7 %)</td></tr><tr><td>with high-intensity<br>statin</td><td>129,181<br>(48.3 %)</td><td>110,197<br>(51.5 %)</td><td>22,182<br>(41.6 %)</td><td>14,862<br>(40.3 %)</td></tr><tr><td>with moderate-<br>intensity statin</td><td>134,357<br>(50.2 %)</td><td>100,691<br>(47.1 %)</td><td>30,171<br>(56.6 %)</td><td>21,535<br>(58.3 %)</td></tr><tr><td>with low-intensity<br>statin</td><td>3879 (1.5<br>%)</td><td>2947 (1.4<br>%)</td><td>909 (1.7<br>%)</td><td>524 (1.4<br>%)</td></tr><tr><td>Any statin & PCSK9i</td><td>912 (0.04<br>%)</td><td>861 (0.07<br>%)</td><td>95 (0.01<br>%)</td><td>90 (0.03<br>%)</td></tr><tr><td>Ezetimibe & PCSK9i</td><td>525 (0.03<br>%)</td><td>491 (0.04<br>%)</td><td>56 (0.01<br>%)</td><td>45 (0.02<br>%)</td></tr><tr><td><strong>Tritherapy</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Any statin, ezetimibe<br>& PCSK9i</td><td>2303 (0.11<br>%)</td><td>2164 (0.19<br>%)</td><td>267 (0.03<br>%)</td><td>229 (0.08<br>%)</td></tr><tr><td>None dispensed<sup>5</sup></td><td>668,405<br>(32.5 %)</td><td>269,235<br>(23.1 %)</td><td>355,396<br>(43.8 %)</td><td>92,509<br>(31.8 %)</td></tr><tr><td><strong>Other treatments</strong></td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Anti-hypertensive<br>treatment</strong></td><td>1,621,217<br>(78.8 %)</td><td>1,009,035<br>(86.5 %)</td><td>577,316<br>(71.1 %)</td><td>223,978<br>(76.9 %)</td></tr><tr><td>Beta-blocker</td><td>1,020,092<br>(49.6 %)</td><td>764,587<br>(65.5 %)</td><td>273,687<br>(33.7 %)</td><td>114,744<br>(39.4 %)</td></tr><tr><td>Calcium channel<br>inhibitor</td><td>599,925<br>(29.2 %)</td><td>323,653<br>(27.7 %)</td><td>253,305<br>(31.2 %)</td><td>102,894<br>(35.3 %)</td></tr><tr><td>Loop diuretic</td><td>324,869<br>(15.8 %)</td><td>212,086<br>(18.2 %)</td><td>118,421<br>(14.6 %)</td><td>51,527<br>(17.7 %)</td></tr><tr><td>Thiazide</td><td>304,350<br>(14.8 %)</td><td>155,249<br>(13.3 %)</td><td>130,762<br>(16.1 %)</td><td>52,380<br>(18.0 %)</td></tr><tr><td>Potassium-sparing<br>diuretic</td><td>119,589<br>(5.8 %)</td><td>83,714 (7.2<br>%)</td><td>37,356<br>(4.6 %)</td><td>16,044<br>(5.5 %)</td></tr><tr><td>Eplerenone or<br>spironolactone</td><td>106,007<br>(5.2 %)</td><td>77,091 (6.6<br>%)</td><td>31,261<br>(3.8 %)</td><td>13,761<br>(4.7 %)</td></tr><tr><td>Angiotensin-<br>converting enzyme<br>inhibitor</td><td>689,097<br>(33.5 %)</td><td>457,550<br>(39.2 %)</td><td>223,135<br>(27.5 %)</td><td>92,335<br>(31.7 %)</td></tr><tr><td>Angiotensin-receptor<br>blocker</td><td>481,992<br>(23.4 %)</td><td>279,755<br>(24.0 %)</td><td>183,590<br>(22.6 %)</td><td>75,485<br>(25.9 %)</td></tr><tr><td>Sacubitril/valsartan</td><td>38,696 (1.9<br>%)</td><td>33,856 (2.9<br>%)</td><td>7577 (0.9<br>%)</td><td>4740 (1.6<br>%)</td></tr><tr><td><strong>Antithrombotic<br>therapies</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Antiplatelet agent</td><td>1,445,498<br>(70.3 %)</td><td>910,560<br>(78.0 %)</td><td>465,961<br>(57.4 %)</td><td>233,890<br>(80.3 %)</td></tr><tr><td>Anticoagulants</td><td>437,733<br>(21.3 %)</td><td>226,370<br>(19.4 %)</td><td>211,375<br>(26.0 %)</td><td>63,905<br>(21.9 %)</td></tr><tr><td><strong>Diabetes treatment</strong></td><td>489,205<br>(23.8 %)</td><td>317,839<br>(27.2 %)</td><td>161,695<br>(19.9 %)</td><td>83,668<br>(28.7 %)</td></tr><tr><td>Metformin</td><td>336,988<br>(16.4 %)</td><td>219,164<br>(18.8 %)</td><td>109,121<br>(13.4 %)</td><td>53,625<br>(18.4 %)</td></tr><tr><td>Sulfonylurea</td><td>147,615<br>(7.2 %)</td><td>98,356 (8.4<br>%)</td><td>45,352<br>(5.6 %)</td><td>25,126<br>(8.6 %)</td></tr><tr><td>DPP4i</td><td>133,950<br>(6.5 %)</td><td>87,242 (7.5<br>%)</td><td>43,420<br>(5.3 %)</td><td>22,306<br>(7.7 %)</td></tr></tbody></table>

(continued on next page)
<table><caption>**Table 2 (continued)**</caption><thead><tr><th></th><th>ASCVD<br>n =<br>2,056,354</th><th>CAD<br>n =<br>1,167,137</th><th>CVD<br>n =<br>812,055</th><th>PAD<br>n =<br>291,216</th></tr></thead><tbody><tr><td>GLP1-RA</td><td>77,111 (3.7<br>%)</td><td>54,965 (4.7<br>%)</td><td>21,347<br>(2.6 %)</td><td>12,989<br>(4.5 %)</td></tr><tr><td>SGLT2i</td><td>33,730 (1.6<br>%)</td><td>27,755 (2.4<br>%)</td><td>7383 (0.9<br>%)</td><td>4641 (1.6<br>%)</td></tr><tr><td>Insulin</td><td>157,157<br>(7.6 %)</td><td>101,597<br>(8.7 %)</td><td>53,456<br>(6.6 %)</td><td>33,350<br>(11.5 %)</td></tr><tr><td><strong>Other drugs</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Antidepressant</td><td>322,561<br>(15.7 %)</td><td>148,435<br>(12.7 %)</td><td>168,812<br>(20.8 %)</td><td>41,895<br>(14.4 %)</td></tr><tr><td>Nicotine substitute</td><td>40,366 (2.0<br>%)</td><td>24,076 (2.1<br>%)</td><td>11,301<br>(1.4 %)</td><td>10,309<br>(3.5 %)</td></tr><tr><td><strong>Medical follow-up in<br>2021</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>≥ 1 LDL-C dosing</td><td>1421,161<br>(69.1 %)</td><td>868,213<br>(74.4 %)</td><td>506,470<br>(62.4 %)</td><td>200,800<br>(69.0 %)</td></tr><tr><td>Number of visits to<br>the GP</td><td></td><td></td><td></td><td></td></tr><tr><td>None</td><td>101,377<br>(4.9 %)</td><td>48,518 (4.2<br>%)</td><td>50,322<br>(6.2 %)</td><td>10,619<br>(3.6 %)</td></tr><tr><td>1</td><td>63,484 (3.1<br>%)</td><td>35,179 (3.0<br>%)</td><td>25,960<br>(3.2 %)</td><td>7118 (2.4<br>%)</td></tr><tr><td>2 to 5</td><td>681,983<br>(33.2 %)</td><td>398,846<br>(34.2 %)</td><td>256,243<br>(31.6 %)</td><td>81,611<br>(28.0 %)</td></tr><tr><td>6 to 11</td><td>823,517<br>(40.0 %)</td><td>474,457<br>(40.7 %)</td><td>316,797<br>(39.0 %)</td><td>123,237<br>(42.3 %)</td></tr><tr><td>12 and more</td><td>385,993<br>(18.8 %)</td><td>210,137<br>(18.0 %)</td><td>162,733<br>(20.0 %)</td><td>68,631<br>(23.6 %)</td></tr><tr><td>≥ 1 visit to ASCVD<br>specialist**</td><td>1254,883<br>(61.0 %)</td><td>838,591<br>(71.9 %)</td><td>397,218<br>(48.9 %)</td><td>171,587<br>(58.9 %)</td></tr></tbody></table>

The population analyzed is all the ASCVD 2021 population alive on 31st December 2021. Treatments were considered as ongoing on 31st December 2021 if ≥ 1 delivery was recorded between 1st October and 31st December 2021. ASCVD: atherosclerotic cardiovascular disease; CAD: coronary artery disease; CVD: cerebrovascular disease; DPP4i: dipeptidyl peptidase-4 inhibitors. GLP1-RA: glucagon-like peptide 1 receptor agonist; GP: general practitioner; LLT: lipid-lowering therapy; PAD: peripheral artery disease; PCSK9i: proprotein convertase subtilisin/kexin-9 inhibitor; SGLT2i: sodium-glucose cotransporter-2-inhibitor.

of a country (i.e., France), shows that ASCVD patient management remains far from optimal in 2021. In particular, at least one-third of ASCVD patients were not given any LLT, despite it being recommended with the highest level of evidence in international guidelines [11]. Furthermore, the proportion of patients on high-intensity statins did not exceed 30 % of the ASCVD 2021 survivors, while the use of combination therapies was below 15 %. Disparities were observed depending on the vascular bed affected, with the use of LLT being more optimized in the case of CAD than in the case of CVD or PAD. Other factors associated with LLT underuse include being female, being old (≥ 85 years) or young (< 50 years), and not having anti-hypertensive or diabetes treatment. LLT underuse was also associated with less medical surveillance, with fewer GP visits and fewer lipid tests.

These data echo those of other recent studies on smaller populations. In a cohort of 322,153 ASCVD patients receiving outpatient care across 92 different health systems in the United States in 2017–2018, 28.3 % were not on any statin and only 39.4 % were on high-intensity statin therapy [15]. In the ASCVD population of the multi-country European SANTORINI study (n = 6954) conducted between 2020 and 2021, 21.4 % of patients were not taking LLT [12]. This figure was comparable to that in the total study population, including patients at high and very high cardiovascular risk (21.8 %, n = 9044), suggesting that an ASCVD event did not further increase adherence to the guidelines. The fact that the percentage of patients not taking LLT in the SANTORINI study was slightly lower than in the present study is potentially linked to a selection bias, as the inclusion process was based on physicians interested in

<caption>**Table 3**</caption>

ASCVD 2021 survivors characteristics according to LLT use on 31st December 2021.

<table><thead><tr><th></th><th>No LLT, n = 611,291</th><th>LLT, n = 1,324,464</th></tr></thead><tbody><tr><td><strong>Demographics</strong></td><td></td><td></td></tr><tr><td>Female sex</td><td>286,703 (46.9 %)</td><td>406,771 (30.7 %)</td></tr><tr><td>Age, years</td><td>72.7 ± 16.1, 75 [62; 86], 18/117</td><td>70.9 ± 11.6, 71 [63; 79], 18/107</td></tr><tr><td>Age class</td><td></td><td></td></tr><tr><td>18 to 50 years</td><td>56,486 (9.2 %)</td><td>50,293 (3.8 %)</td></tr><tr><td>50 to 64 years</td><td>120,642 (19.7 %)</td><td>332,979 (25.1 %)</td></tr><tr><td>65 to 74 years</td><td>125,771 (20.6 %)</td><td>421,799 (31.8 %)</td></tr><tr><td>75 to 84 years</td><td>135,040 (22.1 %)</td><td>346,961 (26.2 %)</td></tr><tr><td>≥ 85 years</td><td>173,352 (28.4 %)</td><td>172,432 (13.0 %)</td></tr><tr><td><strong>Cardiovascular risk factors</strong></td><td></td><td></td></tr><tr><td>Overweight or obesity</td><td>69,440 (11.4 %)</td><td>209,891 (15.8 %)</td></tr><tr><td>Smoking history</td><td>87,284 (14.3 %)</td><td>262,966 (19.9 %)</td></tr><tr><td>Anti-hypertensive treatment</td><td>410,604 (67.2 %)</td><td>1216,594 (91.9 %)</td></tr><tr><td>Diabetes mellitus</td><td>129,419 (21.2 %)</td><td>423,506 (32.0 %)</td></tr><tr><td><strong>Other comorbidities</strong></td><td></td><td></td></tr><tr><td>Excessive alcohol consumption</td><td>61,347 (10.0 %)</td><td>114,618 (8.7 %)</td></tr><tr><td>Cardiac arrhythmia</td><td>148,968 (24.4 %)</td><td>265,200 (20.0 %)</td></tr><tr><td>Heart failure</td><td>94,941 (15.5 %)</td><td>185,003 (14.0 %)</td></tr><tr><td>Depressive disorder</td><td>213,267 (34.9 %)</td><td>363,308 (27.4 %)</td></tr><tr><td>Cancer</td><td>96,000 (15.7 %)</td><td>190,754 (14.4 %)</td></tr><tr><td>Chronic kidney disease</td><td>57,435 (9.4 %)</td><td>107,364 (8.1 %)</td></tr><tr><td>End-stage kidney disease</td><td>6780 (1.1 %)</td><td>13,601 (1.0 %)</td></tr><tr><td><strong>ASCVD features</strong></td><td></td><td></td></tr><tr><td>Incident ASCVD event in 2021</td><td>38,453 (6.3 %)</td><td>129,046 (9.7 %)</td></tr><tr><td>Coronary Artery Disease</td><td>225,151 (36.8 %)</td><td>863,949 (65.2 %)</td></tr><tr><td>Cerebrovascular Disease</td><td>342,206 (56.0 %)</td><td>426,660 (32.2 %)</td></tr><tr><td>Peripheral Artery Disease</td><td>92,509 (15.1 %)</td><td>198,707 (15.0 %)</td></tr><tr><td><strong>Anti-hypertensive treatment</strong></td><td>340,344 (55.7 %)</td><td>1192,644 (90.0 %)</td></tr><tr><td>Beta-blocker</td><td>178,351 (29.2 %)</td><td>795,549 (60.1 %)</td></tr><tr><td>Calcium channel inhibitor</td><td>124,901 (20.4 %)</td><td>435,760 (32.9 %)</td></tr><tr><td>Loop diuretic</td><td>95,941 (15.7 %)</td><td>211,669 (16.0 %)</td></tr><tr><td>Thiazide</td><td>57,186 (9.4 %)</td><td>224,784 (17.0 %)</td></tr><tr><td>Potassium-sparing diuretic</td><td>25,219 (4.1 %)</td><td>88,136 (6.7 %)</td></tr><tr><td>Eplerenone or spironolactone</td><td>21,855 (3.6 %)</td><td>79,128 (6.0 %)</td></tr><tr><td>Angiotensin-converting<br>enzyme inhibitor</td><td>108,582 (17.8 %)</td><td>552,077 (41.7 %)</td></tr><tr><td>Angiotensin-receptor blocker</td><td>94,553 (15.5 %)</td><td>355,676 (26.9 %)</td></tr><tr><td>Sacubitril/valsartan</td><td>6660 (1.1 %)</td><td>30,925 (2.3 %)</td></tr><tr><td><strong>Antithrombotic therapies</strong></td><td></td><td></td></tr><tr><td>Antiplatelet agent</td><td>278,358 (45.5 %)</td><td>1102,418 (83.2 %)</td></tr><tr><td>Anticoagulant</td><td>139,074 (22.8 %)</td><td>276,212 (20.9 %)</td></tr><tr><td><strong>Diabetes treatment</strong></td><td>79,977 (13.1 %)</td><td>382,158 (28.9 %)</td></tr><tr><td>Metformin</td><td>46,226 (7.6 %)</td><td>271,585 (20.5 %)</td></tr><tr><td>Sulfonylurea</td><td>21,570 (3.5 %)</td><td>117,348 (8.9 %)</td></tr><tr><td>DPP4i</td><td>20,519 (3.4 %)</td><td>105,634 (8.0 %)</td></tr><tr><td>GLP1-RA</td><td>8577 (1.4 %)</td><td>64,304 (4.9 %)</td></tr><tr><td>SGLT2i</td><td>3748 (0.6 %)</td><td>28,647 (2.2 %)</td></tr><tr><td>Insulin</td><td>28,958 (4.7 %)</td><td>120,346 (9.1 %)</td></tr><tr><td><strong>Other drugs</strong></td><td></td><td></td></tr><tr><td>Antidepressant</td><td>101,177 (16.6 %)</td><td>202,576 (15.3 %)</td></tr><tr><td>Nicotine substitute</td><td>6605 (1.1 %)</td><td>32,010 (2.4 %)</td></tr><tr><td><strong>Medical follow-up in 2021</strong></td><td></td><td></td></tr><tr><td>≥ 1 LDL-C dosing</td><td>301,557 (49.3 %)</td><td>1037,598 (78.3 %)</td></tr><tr><td>Number of visits to the GP</td><td></td><td></td></tr><tr><td>None</td><td>73,132 (12.0 %)</td><td>22,413 (1.7 %)</td></tr><tr><td>1</td><td>31,487 (5.2 %)</td><td>27,967 (2.1 %)</td></tr><tr><td>2 to 5</td><td>189,393 (31.0 %)</td><td>454,164 (34.3 %)</td></tr><tr><td>6 to 11</td><td>201,122 (32.9 %)</td><td>573,380 (43.3 %)</td></tr><tr><td>12 and more</td><td>116,157 (19.0 %)</td><td>246,540 (18.6 %)</td></tr><tr><td>≥ 1 visit to ASCVD specialist**</td><td>271,417 (44.4 %)</td><td>917,071 (69.2 %)</td></tr></tbody></table>

The population analyzed is all the ASCVD 2021 population alive on 31st December 2021, after exclusion of patients with unstable angina and/or carotid revascularization (n = 1,935,755 remaining). Treatments were considered as ongoing on 31st December 2021 if ≥ 1 delivery was recorded between 1st October and 31st December 2021. ASCVD: atherosclerotic cardiovascular disease; DPP4i: dipeptidyl peptidase-4 inhibitor. GLP1-RA: glucagon-like peptide 1 receptor agonist; GP: general practitioner; LLT: lipid-lowering therapy; SGLT2i: sodium-glucose cotransporter-2-inhibitor. Categorical data are expressed giving size (%) of the category. Quantitative data are expressed giving mean ± SD, median (25th-75th percentile); minimum/maximum. Please see the data statement for code details.

<footnote>* statin, ezetimibe or PCSK9i.</footnote>

<footnote>** Defined as cardiologist, neurologist or vascular physician.</footnote>

<footnote>* Defined as the last drug delivery between 1st October 2021 and 31st December 2021.</footnote>
the management of ASCVD. Our results also echo previous French observational studies. For example, in the Esteban cross-sectional study conducted between 2014 and 2016, only 29.7 % of the 2011 representative adult patients with established ASCVD had a delivery of LLT [16]. Among them, 37.4 % had a good adherence to LLT with > 80 % of days covered by a treatment. In a previous study also using the SNDS (2011–2013 period), only 49.8 % of the French population with a history of myocardial infarction was on high-intensity statin therapy or combination therapy with statin and ezetimibe [17].

In addition to the high frequency of patients not taking any LLT in real-life conditions, our study confirmed the low percentage of patients taking intensified LLT. In particular, statin and ezetimibe combination therapy, which is recommended as second-line therapy to achieve the LDL-C target [11] and to reduce ASCVD events [7], was used in only 13 % of ASCVD 2021 survivors, reaching a maximum of 18.3 % in patients with CAD. This observation is all the more damaging given that studies have shown that this therapeutic strategy enables the LDL-C target to be reached more frequently when it is used [18–20]. Notably, the 1-year follow-up of the SANTORINI study showed that LLT was escalated in one-third of patients and unchanged in two-thirds, with the use of

combination therapy raising from 25.6 % to 37.9 %. Although still not optimal, LDL-C goal attainment was greater with combination therapy compared with monotherapy at follow-up (39.4 versus 25.5 %) [19]. Importantly, it has been shown previously in an observational study that higher intensity and/or adherence to statins was associated with a lower risk of major adverse cardiovascular event (MACE) recurrence [17]. Meta-analyses also suggest that the early in-hospital use of PCSK9i in acute coronary syndrome patients can safely and effectively lower LDL-C levels, reducing the risk of short-term adverse cardiovascular events [21]. In addition, benefit from longer-term exposure to LDL-C lowering siRNA versus initial randomization to placebo on less MACE-related safety events has been observed [22]. Thus, delaying combination therapy until after monotherapy failure may lead to prolonged periods of inadequate LDL-C control, increasing the risk of recurrent ASCVD events. However, there is currently no randomized controlled trial comparing the two strategies, progressive intensification of LLT versus early combination therapy, to formally validate this statement.

Also, despite a favorable reimbursement decision issued in France in 2020 on statins and ezetimibe combination therapy for ASCVD patients with LDL-C level still above > 70 mg/dl, the use of PCSK9i remained

<table><caption>**Table 4**
Factors associated with no LLT use in ASCVD 2021 survivors.</caption><thead><tr><th rowspan="2"></th><th colspan="2">All, n = 1,935,755</th><th colspan="2">≥ 1 drug delivery (any) on the last quarter of 2021, n = 1,792,213</th></tr><tr><th>Univariable models</th><th>Multivariable model</th><th>Univariable models</th><th>Multivariable model</th></tr></thead><tbody><tr><td><strong>Demographics</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Female/male sex</td><td>1.99 [1.98; 2.00]</td><td>1.42 [1.41; 1.43]</td><td>2.12 [2.11; 2.14]</td><td>1.45 [1.44; 1.46]</td></tr><tr><td>Age class</td><td></td><td></td><td></td><td></td></tr><tr><td>18–50 years</td><td>3.76 [3.71; 3.81]</td><td>2.23 [2.20; 2.27]</td><td>3.27 [3.23; 3.32]</td><td>2.21 [2.17; 2.25]</td></tr><tr><td>50 to 64 years</td><td>1.21 [1.20; 1.22]</td><td>1.06 [1.05; 1.07]</td><td>1.14 [1.13; 1.15]</td><td>1.05 [1.04; 1.06]</td></tr><tr><td>65 to 74 years</td><td>1.00 (ref.)</td><td>1.00 (ref.)</td><td>1.00 (ref.)</td><td>1.00 (ref.)</td></tr><tr><td>75 to 84 years</td><td>1.30 [1.29; 1.31]</td><td>1.18 [1.17; 1.20]</td><td>1.33 [1.32; 1.34]</td><td>1.18 [1.16; 1.19]</td></tr><tr><td>≥ 85 years</td><td>3.37 [3.34; 3.40]</td><td>2.10 [2.08; 2.13]</td><td>3.37 [3.33; 3.40]</td><td>2.12 [2.09; 2.14]</td></tr><tr><td><strong>Comorbidities and/or treatments</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Overweight or obesity</td><td>0.68 [0.67; 0.68]</td><td>0.91 [0.90; 0.92]</td><td>0.72 [0.71; 0.72]</td><td>0.89 [0.88; 0.90]</td></tr><tr><td>Smoking history</td><td>0.67 [0.66; 0.67]</td><td>0.76 [0.75; 0.77]</td><td>0.66 [0.65; 0.66]</td><td>0.74 [0.74; 0.75]</td></tr><tr><td>Anti-hypertensive treatment</td><td>0.18 [0.17; 0.18]</td><td>0.31 [0.31; 0.32]</td><td>0.30 [0.29; 0.30]</td><td>0.41 [0.40; 0.41]</td></tr><tr><td>Diabetes mellitus</td><td>0.57 [0.56; 0.57]</td><td>0.76 [0.75; 0.76]</td><td>0.58 [0.57; 0.58]</td><td>0.73 [0.72; 0.73]</td></tr><tr><td>Excessive alcohol consumption</td><td>1.17 [1.16; 1.18]</td><td>1.27 [1.25; 1.28]</td><td>1.17 [1.16; 1.19]</td><td>1.25 [1.23; 1.26]</td></tr><tr><td>Cardiac rhythm disorder</td><td>1.28 [1.27; 1.29]</td><td>1.34 [1.33; 1.35]</td><td>1.39 [1.38; 1.40]</td><td>1.34 [1.33; 1.35]</td></tr><tr><td>Heart failure</td><td>1.13 [1.12; 1.14]</td><td>1.32 [1.30; 1.33]</td><td>1.17 [1.16; 1.18]</td><td>1.30 [1.29; 1.31]</td></tr><tr><td>Depressive disorder</td><td>1.41 [1.40; 1.42]</td><td>1.09 [1.08; 1.10]</td><td>1.57 [1.56; 1.58]</td><td>1.12 [1.11; 1.13]</td></tr><tr><td>Cancer</td><td>1.10 [1.09; 1.11]</td><td>1.16 [1.15; 1.17]</td><td>1.22 [1.21; 1.23]</td><td>1.19 [1.18; 1.20]</td></tr><tr><td>Chronic kidney disease (ref.: none)</td><td>1.00 (ref.)</td><td>1.00 (ref.)</td><td>1.00 (ref.)</td><td>1.00 (ref.)</td></tr><tr><td>Chronic kidney disease</td><td>1.17 [1.16; 1.18]</td><td>1.16 [1.15; 1.18]</td><td>1.20 [1.19; 1.22]</td><td>1.14 [1.12; 1.16]</td></tr><tr><td>End-stage kidney disease</td><td>1.09 [1.06; 1.12]</td><td>1.34 [1.29; 1.38]</td><td>1.24 [1.20; 1.28]</td><td>1.55 [1.50; 1.61]</td></tr><tr><td><strong>Medical follow-up in 2021</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>≥ 1 LDL-C dosing</td><td>0.26 [0.26; 0.27]</td><td>0.48 [0.47; 0.48]</td><td>0.35 [0.35; 0.36]</td><td>0.52 [0.51; 0.52]</td></tr><tr><td>Number of visits to the GP (ref.: none)</td><td>1.00 (ref.)</td><td>1.00 (ref.)</td><td>1.00 (ref.)</td><td>1.00 (ref.)</td></tr><tr><td>1</td><td>0.34 [0.33; 0.35]</td><td>0.58 [0.56; 0.59]</td><td>0.85 [0.83; 0.88]</td><td>0.95 [0.92; 0.98]</td></tr><tr><td>2 to 5</td><td>0.12 [0.12; 0.12]</td><td>0.29 [0.28; 0.30]</td><td>0.52 [0.50; 0.53]</td><td>0.68 [0.66; 0.69]</td></tr><tr><td>6 to 11</td><td>0.10 [0.10; 0.10]</td><td>0.26 [0.26; 0.27]</td><td>0.49 [0.48; 0.50]</td><td>0.66 [0.64; 0.67]</td></tr><tr><td>12 and more</td><td>0.14 [0.14; 0.14]</td><td>0.31 [0.31; 0.32]</td><td>0.67 [0.66; 0.69]</td><td>0.79 [0.77; 0.81]</td></tr><tr><td>≥ 1 visit to ASCVD specialist**</td><td>0.35 [0.35; 0.35]</td><td>0.66 [0.65; 0.66]</td><td>0.44 [0.44; 0.45]</td><td>0.71 [0.70; 0.71]</td></tr><tr><td><strong>ASCVD features</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>2021 incident ASCVD</td><td>0.62 [0.61; 0.62]</td><td>0.75 [0.74; 0.76]</td><td>0.65 [0.64; 0.66]</td><td>0.72 [0.71; 0.73]</td></tr><tr><td>ASCVD sites, defined as mutually exclusive (ref.: 1 bed, MI)</td><td>1.00 (ref.)</td><td>1.00 (ref.)</td><td>1.00 (ref.)</td><td>1.00 (ref.)</td></tr><tr><td>1 bed: coronary revasc.</td><td>0.82 [0.81; 0.82]</td><td>0.97 [0.96; 0.98]</td><td>0.90 [0.88; 0.91]</td><td>1.01 [1.00; 1.02]</td></tr><tr><td>1 bed: stroke</td><td>3.41 [3.38; 3.44]</td><td>2.21 [2.19; 2.23]</td><td>3.54 [3.51; 3.57]</td><td>2.36 [2.34; 2.38]</td></tr><tr><td>1 bed: PAD</td><td>2.12 [2.09; 2.14]</td><td>1.88 [1.86; 1.91]</td><td>2.30 [2.28; 2.33]</td><td>2.05 [2.02; 2.08]</td></tr><tr><td>2 beds: MI and stroke</td><td>1.39 [1.36; 1.43]</td><td>1.06 [1.03; 1.09]</td><td>1.36 [1.33; 1.40]</td><td>1.04 [1.01; 1.07]</td></tr><tr><td>2 beds: MI and PAD</td><td>0.81 [0.78; 0.83]</td><td>0.89 [0.86; 0.92]</td><td>0.83 [0.80; 0.86]</td><td>0.85 [0.83; 0.89]</td></tr><tr><td>2 beds: coronary revasc. and stroke</td><td>1.02 [0.99; 1.05]</td><td>0.99 [0.96; 1.02]</td><td>1.06 [1.03; 1.10]</td><td>0.98 [0.95; 1.02]</td></tr><tr><td>2 beds: coronary revasc. and PAD</td><td>0.73 [0.71; 0.75]</td><td>0.92 [0.89; 0.94]</td><td>0.80 [0.78; 0.83]</td><td>0.93 [0.90; 0.96]</td></tr><tr><td>2 beds: stroke and PAD</td><td>1.84 [1.79; 1.90]</td><td>1.47 [1.42; 1.52]</td><td>1.87 [1.81; 1.93]</td><td>1.48 [1.43; 1.54]</td></tr><tr><td>3 beds: MI and stroke and PAD</td><td>1.14 [1.06; 1.22]</td><td>1.04 [0.96; 1.13]</td><td>1.08 [1.00; 1.18]</td><td>0.95 [0.87; 1.03]</td></tr><tr><td>3 beds: coronary revasc. and stroke and PAD</td><td>0.92 [0.85; 0.99]</td><td>0.98 [0.90; 1.06]</td><td>0.91 [0.84; 0.99]</td><td>0.92 [0.84; 1.00]</td></tr></tbody></table>

The population analyzed is all the ASCVD 2021 population alive on 31st December 2021, before and after exclusion of patients without any drug delivery on the last quarter of 2021 (sensitivity analysis). Patients with unstable angina and/or carotid revascularization only were excluded (n = 1,935,755 remaining). ORs were assessed using non-conditional logistic regression models.

ASCVD: atherosclerotic cardiovascular disease; GP: general practitioner; MI: myocardial infarction; OR: odds ratio; PAD: peripheral arterial disease; LLT: lipid-lowering therapy.
marginal in 2021 (< 0.5 %).

One of the strengths of our study is its exhaustive coverage of the atheromatous sites responsible for ASCVD events, without selection bias depending on specific care pathways. CAD (mostly myocardial infarction) was the leading cause of ASCVD, ahead of CVD (mostly stroke) and PAD. It should be stressed here that the overall PAD population was underestimated because it was only diagnosed through arterial revascularization of the lower limbs. In any case, the use of LLL varied greatly depending on the type of ASCVD event. Patients with confirmed CAD remain the most treated, in comparison with the lower use of LLTs in post-CVD patients. This is particularly striking with regard to the low use of high-intensity statins (< 20 %) and dual statin and ezetimibe therapy (~5 %) in this population. The PAD population lays between the CAD and CVD populations. The population with unstable angina, an ill-defined coding diagnosis entity, behaved differently from the other CAD patients (more women, much less LLL use). This also explains why we chose to exclude this population from the multivariable analyses.

This lower intake of statins in the CAD and PAD populations has already been demonstrated in a recent study [15]. This is all the more damaging as these are vulnerable populations at very high cardiovascular risk [23,24]. Furthermore, a recent study of post-ischemic stroke patients clearly demonstrated the benefit of lowering LDL-C target (≤70 mg/dl) to reduce cardiovascular morbidity and mortality, without increasing the risk of hemorrhagic stroke [25]. To achieve such LDL-C goal, 97.3 % of patients were on LLL at 1 year with 20 % of high-intensity as monotherapy and 33 % with statin and ezetimibe as monotherapy, which is considerably higher than that we observed in the post-ischemic stroke population of our real-life study (< 20 % and ~5 %, respectively). Taken together, these observations suggest that awareness-raising and implementation strategies need to be actively pursued in populations with CVD and PAD.

Other factors associated with the risk of lower LLL use include being a woman. Women are at risk of more severe forms of ASCVD, with a significant increase in mortality compared with men [26]. Reduced LLL intake and poorer tolerance of LLTs in women have already been reported in numerous studies [15,27]. In particular, it has been shown very recently in the INTERASPIRE study that, after a coronary event, women reached the LDL-C target of < 1.40 mmol/L less frequently than men (13.7 versus 18.6 %) [28].

Elderly patients (≥ 85 years) are also treated less frequently, as previously reported [15]. Nevertheless, it should be emphasized that it has been clearly demonstrated in randomized controlled trials that older ASCVD patients, like others, benefit from the cardiovascular protection provided by LLTs, particularly statins [29]. In addition, in the FAST-MI registry, high-intensity LLL at discharge after acute myocardial infarction was associated with reduced all-cause mortality at 5 years in patients aged ≥ 80 years [30]. Another study, which also used data from the SNDS, demonstrated that statin discontinuation was associated with a 33 % increased risk of admission for ASCVD event in 75-year-old primary prevention patients [31]. More unexpectedly, younger patients (< 50 years; 5.2 % of the ASCVD population) were treated > 3.5 times less than those in the reference age group (65–74 years), exposing them to a significant risk of recurrence of ASCVD events. The reasons for this LLL underuse remain to be clarified. It is noteworthy that in familial hypercholesterolemia, one of the main causes of ASCVD at a young age, the use of LLL is not optimal with 40.5 % of individuals not taking any LLL [32].

Finally, we should mention the association of medical monitoring with LLL use. Patients who do not receive LLL have fewer medical consultations with GPs and specialists, with lipid levels less frequently checked. This certainly reflects disparities in socio-economic determinants, which are known to play a critical role in the ASCVD risk [33]. Therefore, it is important to develop implementation strategies to improve the practical application of guidelines concerning the ASCVD management, via the development of telemedicine or the design of new care pathways [34,35]. Reassuringly, LLL use was more frequently

observed in patients who have had an ASCVD within the year.

Our study has the advantage of being almost exhaustive and providing a fairly accurate estimate of prevalence of ASCVD and of the delivery of LLL and other cardiovascular therapies of interest on a national scale. Moreover, France's universal healthcare reimbursement system means that taking medication is less subject to a selection bias linked to patients' financial income.

However, this approach is not without limitations, which need to be highlighted. Firstly, we decided not to include all combination therapies with fibrates, as they are not referenced as a standard treatment in international guidelines, and these treatments were delivered only marginally (1.3 % of treated patients, including 0.94 % on monotherapy). Second, we do not have any biological data enabling us to determine whether patients achieved LDL-C targets. If we refer to recent data from the SANTORINI study [12], we can extrapolate that less than 20 % of patients would be at target. Moreover, there may be some doubts about the identification of ASCVD events using ICD-10 codes, particularly with regard to the atheromatous ischemic origin of stroke or unstable angina. Also, the 5-year assessment of other comorbidities means that they are underestimated, even if this has the advantage of considering only the most active ones. The approach used in the SNDS database to identify treatments makes it possible to accurately estimate their delivery, but without being able to ascertain whether drugs were effectively taken as prescribed. Lastly, the study limitation to France restricts the generalizability of its conclusions, particularly due to potential specificities concerning physician prescribing behaviors, patient adherence challenges and national healthcare policies.

## Conclusions

This nationwide population-based study involving more than 2 million people confirmed the huge gap between international recommendations and usual clinical practice regarding LLL use in ASCVD patients in 2021. This failure to optimize the management of major modifiable risk factors may explain, at least in part, the stagnation that is beginning to be observed in the prevention of ASCVD. Indeed, the 20-year trend of ASCVD risk among 40–79-year-old NHANES participants, shows a non-linear downward trend from 1999 to 2000 to 2017–18 [36]. There is therefore an urgent need to implement strategies – such as enhanced physician education, patient engagement programs, and policy-driven initiatives – aiming to increase LLL intensity and to improve patient adherence, and thus reduce therapeutic inertia, particularly in the most at-risk populations.

## Funding

This study was co-funded by Novartis and Nantes University Hospital (CHU Nantes), and conducted under the responsibility and promotion of Nantes University Hospital.

## Data availability

Due to French law requisite, individual data associated with the manuscript are not publicly available. However, all the data used are directly accessible to French health safety authorities (Haute Autorité de Santé, Agence Nationale de Sécurité du Médicament et des produits de santé), to researchers from various public bodies (such as INSERM - French national health and medical research institute, and all French University Hospital centers), and to private societies on request from CESREES and the CNIL. Most of the nomenclature codes are available in Supplementary, and more detailed coding information can be sent on request.

## Ethical approval

Full access to national data was granted in accordance with French reference methodology (Méthodologie de Référence) MR-007.
Particularly, compliance with this methodology means that patient consent is not actively sought, justified here by the large number of concerned individuals.

## CRediT authorship contribution statement

**Matthieu Wargny:** Writing – review & editing, Writing – original draft, Funding acquisition, Formal analysis, Data curation, Conceptualization. **Thomas Goronflot:** Writing – review & editing, Formal analysis, Data curation. **Pierre-Guillaume Piriou:** Writing – review & editing. **Mathilde Pouriel:** Writing – review & editing, Conceptualization. **Alexandre Bastien:** Writing – review & editing, Conceptualization. **Julie Prax:** Writing – review & editing, Conceptualization. **Christophe Leux:** Writing – review & editing. **Valéry-Pierre Riche:** Writing – review & editing. **Jean-Noël Trochu:** Writing – review & editing. **Sophie Béliard:** Writing – review & editing, Conceptualization. **Nadège Costa:** Writing – review & editing, Conceptualization. **Jean Ferrières:** Writing – review & editing, Conceptualization. **Stéphanie Duret:** Writing – review & editing, Conceptualization. **Bertrand Cariou:** Writing – review & editing, Writing – original draft, Supervision, Funding acquisition, Conceptualization.

## Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Matthieu Wargny travel expenses were covered by Novartis for the presentation of the present work. He also received consulting fees from Novo Nordisk and Boston Scientific outside the present work. Alexandre Bastien, Julie Prax and Stéphanie Duret are employees of Novartis France. Mathilde Pouriel is a service provider for Novartis. Jean-Noël Trochu has served on scientific advisory boards and/or received honoraria or consulting from Abbott, AstraZeneca, Bristol Myers Squibb, ViforPharma, Bayer, Novartis, Boehringer-Ingelheim outside the present work. Sophie Béliard has received honoraria for board, conferences, clinical trial or congress from Amarin, Amryt, Amgen, Akcea, Chiesi, Novartis, Sanofi, Ultragenyx. Bertrand Cariou has served on scientific advisory boards and/or received honoraria or consulting fees from Amgen, Abbott, AstraZeneca, Eli Lilly, Merck (MSD), Novartis, Novo-Nordisk, Sanofi and Ultragenyx outside the present work.

The other authors have nothing to disclose.

## Acknowledgements

The authors wish to thank the *Caisse Nationale de l'Assurance Maladie*, and especially the project leader Ms Marjorie Boussac, for their valuable help in making SNDS data available for researcher. They also extend their thanks to Ms. Emilie Varey, project leader at CHU de Nantes, for her unwavering support and attentive oversight throughout the project.

## Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.diabet.2025.101638.

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