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Article

Cross-Sectional Retrospective Observational Study on Lipid-Lowering Therapy for Secondary Prevention in Patients with Peripheral Arterial Disease: LEONIDA Registry

by
Ilaria Radano
1,*,
Fabrizio Delnevo
1,
Tiziana Claudia Aranzulla
1,
Salvatore Piazza
2,
Catia De Rosa
1,
Silvia Muccioli
1,
Maria Chiara Ferrua Trucco
1,
Andrea Ricotti
3,
Simone Quaglino
2,
Michelangelo Ferri
2,
Giuseppe Patti
4,
Andrea Gaggiano
2 and
Giuseppe Musumeci
1
1
Cardiology Department, Mauriziano Hospital, Largo Turati 62, 10128 Torino, Italy
2
Vascular Surgery Department, Mauriziano Hospital, Largo Turati 62, 10128 Torino, Italy
3
Clinical Trial Unit, Mauriziano Hospital, Largo Turati 62, 10128 Torino, Italy
4
Cardiology Department, Major Hospital of Charity, Corso Mazzini 18, 28100 Novara, Italy
*
Author to whom correspondence should be addressed.
J. Vasc. Dis. 2025, 4(3), 27; https://doi.org/10.3390/jvd4030027
Submission received: 8 June 2025 / Revised: 8 July 2025 / Accepted: 14 July 2025 / Published: 17 July 2025
(This article belongs to the Section Peripheral Vascular Diseases)
Browse Figure
Versions Notes

Abstract

Background and aim: Low-density lipoprotein cholesterol (LDL-C) is an important and well-established modifiable risk factor for cardiovascular disease, including peripheral artery disease (PAD). We aimed at evaluating the lipid profile at admission in PAD patients with an indication for invasive treatment. Methods: Among patients with PAD diagnosis admitted to the vascular surgery department, those receiving statins and those with LDL-C values in the recommended target (<55 mg/dL) were identified. The correlation of LDL-C values with different clinical variables was investigated. Results: Of the 399 patients, 259 (65%) were on statin therapy. According to multivariate linear regression analysis, diabetes (p = 0.004), previous CAD history (p < 0.001), and statin therapy (p < 0.001) were independently associated with LDL-C levels. Patients with LDL-C < 55 mg/dL at admission were 89 (22% of the overall cohort). Among these patients, diabetes (48.3% versus 35.8%, p = 0.036), CAD history (52.8% versus 30%, p < 0.001), and statin use (91% versus 57.4%, p < 0.001) were more frequent as compared with patients not at target. Conclusion: Despite the very high cardiovascular risk of our group, the rate of statin prescription was very low and far from ideal. Only a small percentage of patients achieved target LDL-C values. Patients with coexistent diabetes and CAD had lower LDL-C values, suggesting management by specialists with greater attention to lipid profile and pointing out an urgent need for information on cardiovascular disease management.

1. Introduction

Peripheral arterial disease (PAD) is predominantly driven by atherosclerosis and other inflammatory conditions. It is defined as the presence of significant stenosis or occlusion of the carotids and arteries of the upper or lower extremities, aorta, and extracranial circulation [1].
PAD presents with a wide spectrum of clinical manifestations, ranging from asymptomatic disease to acute or chronic symptoms due to a combination of ischemia, thrombosis, and/or embolism.
It affects 10–25% of people aged ≥55 years, and the prevalence increases to approximately 40% among people aged >80 years [2]. Moreover, several studies have shown that PAD is associated with substantial morbidity and mortality [3,4]. In this setting, the literature highlights that management of these patients must first consider that PAD is both a potent risk marker for systemic atherosclerosis degree, as well as a distinct disease with symptoms related specifically to atherosclerosis and thrombotic complications in peripheral vasculature.
As for all phenotypes of atherosclerosis, epidemiological data show that dyslipidemia is one of the most important modifiable cardiovascular risk factors for PAD, along with aging, male gender, smoking, diabetes, and hypertension [5]. The 2019 European Society of Cardiology/EAS dyslipidemia guidelines and the 2024 U.S. guidelines recommend low-density lipoprotein cholesterol (LDL-C) goals according to the estimated 10-year risk for fatal cardiovascular events. As for patients with coronary artery disease (CAD), PAD patients belong to the very-high-risk category [6]. In these patients, a ≥50% reduction in blood LDL-C levels up to <55 mg/dL is recommended in class IA [7,8].
Despite this, and the demonstrated benefit of lipid-lowering therapies (LLT) in PAD [7], there remains suboptimal usage of statins in PAD patients, who often remain underdiagnosed for dyslipidemia and inadequately managed as compared to CAD patients [9].
We performed a real-world analysis of lipid profile and LLT in patients admitted to the vascular surgery department of our tertiary care center with an indication for invasive treatment of PAD.

2. Methods

2.1. Study Population

All patients admitted to the vascular surgery department for invasive treatment of PAD from January 2023 to February 2024 were retrospectively enrolled. Only patients with aortic disease were excluded. Invasive treatment was indicated in patients with critical limb-threatening ischemia or severe intermittent claudication (pain free walking distance < 100 m). Patients with carotid disease underwent invasive treatment if they had a documented 80–99% stenosis, or if they were symptomatic with a stenosis of 50–69% with features suggesting high risk of stroke [10].
All the patients provided informed consent.

2.2. Data Collection

Demographic and clinical features of the overall cohort were collected, as well as LDL-C values and LLT at admission. We considered patients as having dyslipidemia if LDL-C was more than 110 mg/dL and/or if they were taking LLT. CAD history was defined as previous myocardial infarction or previous revascularization (surgical and/or percutaneous) or coronary stenosis > 50% at angiography or coronary TC scan. Chronic kidney disease was defined as an estimated glomerular filtration rate (eGFR) below 60 mL/min.
Our study was conducted in conformity with the guiding principles of the Declaration of Helsinki.

2.3. Statistical Analysis

Continuous variables with normal distribution were reported as mean ± standard deviation. Categorical variables were indicated as percentages.
Chi-squared test was used to compare groups according to statin use and LDL-C targets.
The correlation of LDL-C values at admission with clinical variables was investigated by multivariate logistic regression analysis.
A 2-sided p-value < 0.05 was considered significant. All the analyses were performed with R software (4.3.3 version).

3. Results

3.1. Demographic and Clinical Characteristics

Our analysis included 399 patients: 236 with lower limb arteriopathy and 163 with carotid disease.
Interventions were performed on carotid or limb arteriopathy, no patient had both districts treated during the same admission. Endovascular procedures were performed in the majority of patients (65%).
The mean age was 73.4 ± 8.4 years; 271 patients were males (68%). A total of 140 patients (35%) had CAD history. Demographic characteristics, cardiovascular risk factors, and prevalence of CAD are listed in Table 1.

3.2. Lipid-Lowering Therapy

Out of the 399 patients, 259 (65%) were taking statin therapy. Of those, 164 patients (41% of the overall cohort) were on high-intensity statin; among them, 100 were taking both statin and ezetimibe. Two patients were on ezetimibe monotherapy; a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) was prescribed for one patient.

3.3. LDL-C Cholesterol Level at Admission

The average LDL-C value of the overall cohort was 91 mg/dL.
Patients with statin therapy had an average LDL-C value of 71 mg/dL; statin-naïve patients had an average LDL-C value of 118 mg/dL. Comparing these two subgroups, the former presented a higher prevalence of diabetes (44.4% versus 27.9%, p = 0.001), hypertension (83% versus 70.7%, p = 0.005), dyslipidemia (67.2% versus 34.3%, p < 0.001), and CAD history (44% versus 18.6%, p < 0.001). Lower limb arteriopathy was more prevalent in the statin-naïve subgroup (72.8% versus 60%, p = 0.020) (Table 2). There was no statistical difference in the prevalence of smoking habits and chronic kidney disease.
At multivariate analysis, diabetes (p = 0.004), previous CAD history (p < 0.001), and statin therapy (p < 0.001) were independently associated with lower LDL-C levels (Table 3 and Figure 1).

3.4. LDL-C Targets

Patients with LDL-C < 55 mg/dL were 89 (22% of the overall cohort).
As compared to those not reaching LDL-C target, a higher prevalence of diabetes (48.3% versus 35.8%, p = 0.036), CAD history (52.8% versus 30%, p < 0.001), and statin use (91% versus 57.4%, p < 0.001) was found in the subgroup of patients at target. No significant difference in the prevalence of lower limb and carotid arteriopathy was observed between patients achieving and not achieving LDL-C < 55 mg/dL (Table 4).

4. Discussion

Our analysis shows an important undertreatment of PAD patients: only 65% were receiving statin therapy, a percentage significantly lower than that expected based on the 9.1% rate of statin intolerance [11]. Consequently, rates of LDL-C target achievement were far from ideal. Statin intolerance occurs when a patient is unable to continue statin therapy, either because of the development of side effects (which resolve or improve with dose reduction or discontinuation) or because of significant increase in liver enzyme levels on blood testing and/or muscle function markers. It can be complete or partial and it should be important to distinguish between real intolerance (minimum of two statins should be trailed) and discontinuation for other reasons (social and psychological influences), when possible [12].
Considering the well-known prognostic benefit of LLT [7], guidelines recommendations [7,8], and the fact that five-year mortality with PAD is almost double as compared to CAD (25% versus 13%) and higher than that related to many cancers [13], these findings require urgent attention.
Data from the REACH registry showed that patients with poly-vascular disease had a substantially increased risk for all-cause mortality, nonfatal stroke, and nonfatal myocardial infarction (MI) [3]. Moreover, a Canadian study which included 16,440 patients between 1985 and 1995 noted that the annual mortality was higher among patients with PAD (8.2%) than those having MI (6.3%). Similarly, the five-year mortality among PAD patients (33.2%) was higher than that among patients with a prior myocardial infarction (26.6%) [4].
In addition, PAD-associated mortality has remained substantially unchanged over the past years, unlike the observed decrease for CAD [13,14], and this poor prognosis can be largely attributed to suboptimal management of cardiovascular risk factors [15], as confirmed by our experience.
As with all other atherosclerosis phenotypes, apolipoprotein (apo) B-containing lipoproteins have a key role in atherosclerotic disease onset and progression [16]. Although CAD and PAD are both clinical manifestations of atherosclerosis, the disease processes may be different, as PAD patients present a different plaque composition, characterized by a fibrocalcific process without significant lipid core [17,18]. However, the clinical benefits of LLT have been demonstrated in both groups.
To achieve the recommended LDL-C goal, treatment with high-intensity statin at the maximal tolerated dose is recommended. If patients are unable to attain the goal or report statin intolerance, a combination of statin with ezetimibe and PCSK9i is indicated [19].
In PAD patients, statin therapy has been shown to reduce the risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) [20,21,22,23] by about 25%. In a population of 5,480 patients with PAD without CAD, statin therapy was associated with lower MACE and overall mortality at a mean follow-up of 3.6 years compared to no treatment [24]. In the REACH Registry, among 5,861 patients with symptomatic PAD, statin use was associated with a significant reduction (hazard ratio [HR] = 0.83, p = 0.01) in the primary composite outcome of cardiovascular death, MI, and stroke as compared to placebo [3]. Moreover, high-dose statin treatment and lower LDL-C levels in patients with PAD were independently associated with lower all-cause and cardiac mortality at a 6.4-year follow-up [20]. The addition of a PCSK9i and/or ezetimibe further decreases this risk [25,26]. Statin treatment has also been associated with improved walking performance, including maximum walking distance, pain-free walking distance, and duration [27]. Also, pre-treatment with statins has been associated with better outcomes after carotid endarterectomy and stenting [28].
Regarding high intensity LLT, the addition of ezetimibe has been shown to provide additional benefits in PAD patients taking statins [26], as confirmed by a sub-analysis of the IMPROVE-IT trial in patients with poly-vascular disease, including PAD [29]. Although there have been no randomized controlled trials specifically investigating PCSK9i in patients with PAD, data from studies on patients with CAD showed cardiovascular benefits also in the subset of patients with PAD [25]. In particular, the benefit of an optimal LLT could also lead to carotid plaque regression and prevention of plaque embolization during carotid interventions [28,30].
In addition to the proven effectiveness of the LLT escalation strategy (“the lower is the better”), the advantage is also expressed in terms of costs, since reaching target LDL values and impacting one of the most important cardiovascular disease risk factors allows for a reduction in cardiovascular events, in the number of outpatient visits, and hospital admissions.
Despite all this evidence, differences in statin use in patients with CAD as compared with those with PAD have been found, with a significantly lower statin use in the latter [31]. A previous analysis showed a rate of statin prescription in PAD patients of only 33% [32], and both antiplatelet and lipid-lowering agents were underused in the PAD population of the REACH registry [3]. A meta-analysis showed that in a population with symptomatic and asymptomatic PAD, the utilization of antiplatelet drugs, statins, and ACE inhibitors or ARBs was 75%, 56%, and 53%, respectively [33]. Additionally, a high variability in utilization rates has been recognized in patients with PAD, with statin usage ranging from 11% to 79% [34]. In line with these data, our analysis showed that only 65% of PAD patients undergoing invasive treatment were on LLT, only 41% were on high-intensity statins, and only 22% achieved target LDL-C at admission. In our cohort, there was a greater prevalence of CAD history in patients with LLT. Moreover, we highlighted that diabetes and previous CAD were independently associated with lower LDL-C levels, probably also due to the greater use of statins in these subgroups of patients.
This finding suggests that diagnosing PAD in addition to CAD or diabetes seems to guarantee better risk factor control as compared with diagnosing PAD alone and highlights the urgent need for the standardization of cardiovascular disease management.
Our findings are confirmed by the literature data: a large observational study showed that lipid-lowering therapies were used less often and at lower doses in PAD patients as compared with CAD patients [35]. The PARTNERS (PAD Awareness, Risk, and Treatment: New Resources for Survival) evaluated the prevalence of PAD in primary care practice, showing that 29% of enrolled patients had either a prior history or a diagnosis of CAD [36], and PAD patients were undertreated as compared with those having a history of CAD. Similarly, a lower use of high-intensity statins was reported in patients with isolated lower limb disease (6%) versus patients with either co-existent coronary or carotid artery disease (18.4%) [37]. In another study, statins were prescribed in the following proportions: PAD only patients: 33.9%; CAD only: 51.7%; PAD + prior cerebrovascular disease: 46.5%; PAD + CAD: 50.2%; PAD + CAD + prior cerebrovascular disease: 56.2% [38].
Of note, although there is a greater use of LLT in patients with CAD, even in this category, the real-world evidence, such as the DaVinci Registry [39] and Santorini Registry [40], suggests that a substantial proportion of patients fail to reach target LDL-C levels.
In the Santorini registry [40], the proportion of patients achieving LDL-cholesterol levels below 55 mg/dL was approximately 20%, indicating a substantial number of high- risk patients still remain inadequately treated.
In the evaluation of inadequate LLT management, therapeutic inertia must also be considered. It is defined as the failure to initiate or intensify therapy when indicated and it can depend on both patient and clinician factors: concerns about drug side effects, lack of awareness of new therapeutic options, and complexity of treatment regimens. There are also structural problems related to limited access to advanced lipid-lowering agents in certain healthcare settings, high costs, and restrictive reimbursement policies, particularly for newer drugs [41].
Moreover, LLT use has been demonstrated as a symbol of socio-economic status (defined by income, education, and occupation), which influences lack of awareness, access to healthcare, health behaviors, and lipid metabolism due to incorrect lifestyles [42].
Our study reports on far from ideal LLT use despite the very high cardiovascular risk of PAD patients. Indeed, it highlights significant discrepancies among cardiologists and diabetologists as compared to vascular surgeons and other family practice physicians in managing the same systemic disease, which is atherosclerosis. The latter do not treat PAD as a ‘coronary artery disease equivalent’ and are less likely to prescribe antiplatelets and LLT than cardiologists and diabetologists are, suggesting a greater attention to LLT and the achievement of adequate LDL-C values. Furthermore, since most interventions were endovascular (carotid and limb) procedures, this issue involves the entire community of cardiovascular interventionists. Therefore, despite the presence of guidelines, it would be important to achieve multidisciplinary management of these patients, implementing follow-up protocols (also with telemedicine programs, for example), which allow for the regular therapeutic compliance evaluation and therapeutic changes need.

5. Conclusions

Despite strong evidence showing the association between LLT and improved mortality, MACE, and MALE in PAD patients, our contemporary analysis highlights that the management of this high-risk population remains suboptimal. An increased awareness among healthcare providers managing PAD patients should improve adherence to guidelines and ensure the achievement of optimal LDL-C targets. Furthermore, there is an urgent need for the uniformity of the management of cardiovascular disease between different specialties. Of note, therapeutic inertia in the management of dyslipidemia is a crucial challenge in secondary cardiovascular prevention, and a systematic and multidisciplinary approach is crucial to reducing the high disease burden associated with PAD and improve long-term outcomes for these patients.

Author Contributions

Conceptualization: G.M., F.D. and I.R.; methodology: G.M., T.C.A., G.P. and A.G.; validation: G.M., T.C.A., G.P. and A.G.; formal analysis: A.R.; investigation: I.R., S.M., C.D.R., S.P., S.Q. and M.F.; data curation: F.D., I.R. and M.C.F.T.; writing—original draft preparation: I.R.; writing—review and editing: G.P. and T.C.A.; visualization: all authors; supervision: G.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available on request from the corresponding author due to privacy.

Conflicts of Interest

The authors declare no conflicts of interest.

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Jvd 04 00027 g001
Figure 1. LDL cholesterol in PAD.
Figure 1. LDL cholesterol in PAD.
Jvd 04 00027 g001
Table 1. Demographic features and comorbidities.
Table 1. Demographic features and comorbidities.
VariablesPatients (n = 399)
Mean age (years)73.4 ± 8.4
Male271 (68%)
Smoke283 (71%)
Hypertension314 (78%)
Diabetes mellitus154 (38%)
Dyslipidemia285 (71%)
Chronic kidney disease (eGFR < 60 mL/min)112 (28%)
Coronary artery disease140 (35%)
Lower limb disease257 (64%)
Carotid artery disease237 (59%)
eGFR: estimated glomerular filtration rate.
Table 2. Prevalence of cardiovascular risk factors and comorbidities in patients with and without statin therapy.
Table 2. Prevalence of cardiovascular risk factors and comorbidities in patients with and without statin therapy.
VariablesStatin Therapy
n = 259 (65%)		No Statin Therapy
n = 140 (35%)		p Value
LDL-C at admission (mg/dL)71 ± 34.1119 ± 43.8<0.001
Smoke186 (71.8%)97 (69.2%)0.491
Hypertension215 (83%)99 (70.7%)0.005
Diabetes mellitus115 (44.4%)39 (27.9%)0.001
Dyslipidemia174 (67.2%)48 (34.3%)<0.001
Chronic kidney disease
(eGFR < 60 mL/min)		77 (29.7%)35 (25%)0.351
Coronary artery disease114 (44%)26 (18.6%)<0.001
Lower limb disease155 (60%)102 (72.8%)0.020
Carotid artery disease166 (64%)72 (51.4%)0.049
eGFR: estimated glomerular filtration rate.
Table 3. Multivariate regression analysis of LDL predictors of LDL-C. CAD: coronary artery disease.
Table 3. Multivariate regression analysis of LDL predictors of LDL-C. CAD: coronary artery disease.
LDL at Admission
PredictorsEstimatesClp Value
Statin therapy−37.27−45.04–−29.49<0.001
Diabetes−10.87−18.34–−3.400.004
CAD history−17.80−25.60–−10.01<0.001
Lower limb disease−1.87−10.57–6.830.673
Carotid disease−3.22−12.17–5.730.479
Table 4. Prevalence of cardiovascular risk factors and comorbidities in patients achieving or not achieving LDL-C recommended target of <55 mg/dL.
Table 4. Prevalence of cardiovascular risk factors and comorbidities in patients achieving or not achieving LDL-C recommended target of <55 mg/dL.
VariablesTarget LDL-C
n = 89 (22%)		No Target LDL-C
n = 310 (78%)		p Value
Statin therapy81 (91%)178 (57.4%)<0.001
Smoke62 (69.6%)221 (71.2%)0.205
Hypertension75 (84.3%)239 (77.1%)0.186
Diabetes mellitus43 (48.3%)111 (35.8%)0.036
Dyslipidemia56 (62.9%)166 (53.5%)0.146
Chronic kidney disease
(eGFR < 60 mL/min)		30 (33.7%)82 (26.5%)0.183
Coronary artery disease47 (52.8%)93 (30%)<0.001
Lower limb disease63 (70.7%)194 (62.5%)0.338
Carotid disease51 (57.3%)187 (60.3%)0.906
eGFR: estimated glomerular filtration rate.
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MDPI and ACS Style

Radano, I.; Delnevo, F.; Aranzulla, T.C.; Piazza, S.; De Rosa, C.; Muccioli, S.; Ferrua Trucco, M.C.; Ricotti, A.; Quaglino, S.; Ferri, M.; et al. Cross-Sectional Retrospective Observational Study on Lipid-Lowering Therapy for Secondary Prevention in Patients with Peripheral Arterial Disease: LEONIDA Registry. J. Vasc. Dis. 2025, 4, 27. https://doi.org/10.3390/jvd4030027

AMA Style

Radano I, Delnevo F, Aranzulla TC, Piazza S, De Rosa C, Muccioli S, Ferrua Trucco MC, Ricotti A, Quaglino S, Ferri M, et al. Cross-Sectional Retrospective Observational Study on Lipid-Lowering Therapy for Secondary Prevention in Patients with Peripheral Arterial Disease: LEONIDA Registry. Journal of Vascular Diseases. 2025; 4(3):27. https://doi.org/10.3390/jvd4030027

Chicago/Turabian Style

Radano, Ilaria, Fabrizio Delnevo, Tiziana Claudia Aranzulla, Salvatore Piazza, Catia De Rosa, Silvia Muccioli, Maria Chiara Ferrua Trucco, Andrea Ricotti, Simone Quaglino, Michelangelo Ferri, and et al. 2025. "Cross-Sectional Retrospective Observational Study on Lipid-Lowering Therapy for Secondary Prevention in Patients with Peripheral Arterial Disease: LEONIDA Registry" Journal of Vascular Diseases 4, no. 3: 27. https://doi.org/10.3390/jvd4030027

APA Style

Radano, I., Delnevo, F., Aranzulla, T. C., Piazza, S., De Rosa, C., Muccioli, S., Ferrua Trucco, M. C., Ricotti, A., Quaglino, S., Ferri, M., Patti, G., Gaggiano, A., & Musumeci, G. (2025). Cross-Sectional Retrospective Observational Study on Lipid-Lowering Therapy for Secondary Prevention in Patients with Peripheral Arterial Disease: LEONIDA Registry. Journal of Vascular Diseases, 4(3), 27. https://doi.org/10.3390/jvd4030027

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