Sex Differences in Low-Density Lipoprotein Cholesterol Treatment Among Young Israeli Patients Following Premature Acute Coronary Syndrome

Abstract

Introduction:

Effective management of dyslipidemias is crucial for reducing morbidity and mortality among patients after acute coronary syndrome (ACS). Sex differences in dyslipidemia management after premature ACS in Israeli patients have not been extensively studied. This study aimed to investigate potential disparities between men and women in managing dyslipidemia, considering current guidelines.

Methods:

This retrospective cohort study examined patients who were 55 years old or younger and admitted to Meir Medical Center for ACS from January 2018 to February 2019. The study aimed to evaluate the use of lipid-lowering therapy (LLT), measure the achievement of target low-density lipoprotein cholesterol (LDL-C) levels, and analyze the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) in both male and female patients.

Results:

The study included a total of 687 participants, of which 23.3% were identified as females. Upon discharge, ∼80% of the patients were prescribed high-intensity statins. After 1 year, it was observed that females had higher levels of LDL-C and lower rates of achieving target LDL-C levels (<70 and 55 mg/dL) as compared with males (45% vs. 54.6% and 30% vs. 42.2%, respectively). The use of non-statin LLT at the 1-year mark was minimal in both groups. Finally, it was found that the occurrence of MACCE was similar between males and females.

Conclusion:

Sex disparities in dyslipidemia management after a premature ACS were apparent, with females having higher LDL-C levels and lower rates of target achievement. Intervention is necessary to address these disparities and encourage greater use of non-statin LLT.

Introduction

The management of dyslipidemias is vital in reducing the risk of morbidity and mortality among patients who have had acute coronary syndrome (ACS).^1,2 The 2018 American College of Cardiology/American Heart Association/Multi-society (2018 ACA/AHA/MS) Guidelines and the European Society of Cardiology (ESC) Dyslipidemia Guidelines both recognize individuals with established coronary artery disease as high risk for future cardiovascular events.

Therefore, they recommend intensive lipid-lowering strategies for these patients.^3,4 In common practice, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) remain a mainstay of lipid-lowering therapy (LLT) given that they substantially reduce cardiovascular morbidity and mortality when administered as both primary and secondary prevention agents.^5
–7 When combined with statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) provide additional cardiovascular benefits and increase the rates of attainment of target low-density lipoprotein cholesterol (LDL-C) level.^8

–14

Although substantial advancements have been achieved in dyslipidemia treatment, a noticeable sex-based discrepancy warrants further exploration. Although current guidelines offer recommendations that are not sex-specific, prior studies consistently reveal that female patients tend to exhibit a less favorable lipid profile when compared with their male counterparts.^15,16 This gap is particularly significant, given the heightened impact of risk factors such as dyslipidemia on female patients.¹⁷

In the context of this background, there exists a limited body of research concerning sex differences in dyslipidemia management among Israeli patients, especially in the aftermath of premature ACS. Consequently, our study aimed to investigate potential variations in the management of dyslipidemia after premature ACS between men and women, with specific regard to adherence to current guidelines.

Methods

We performed a retrospective cohort study that included patients with ACS aged ≤55 years who had been admitted to the department of cardiology at Meir Medical Center between January 2018 and February 2019. The diagnosis and type of ACS were determined according to the ESC guidelines.^18,19 After discharge, patients were referred to Meir Medical Center outpatient cardiovascular clinics for serial follow-up. The follow-up visits occurred 3 months and 1 year after the discharge. As a part of the follow-up, lipid levels were measured 1 year post-index hospitalization. The adjustment of LLT was carried out either by the family doctors or the cardiologist responsible for follow-up during the 3-month visit.

In this study, we performed a comparison between men and women in terms of (1) the proportion of those discharged and on high-intensity statin therapy; (2) the proportions of those who had achieved LDL-C levels <70 and <55 mg/dL (defined as target levels according to 2016 and 2019 ESC guidelines)⁴ at their 1-year follow-up visit; (3) the proportions of those who were treated with PCSK9i and ezetimibe at their 1-year follow-up visit; and (4) the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE), which was defined as the composite of all-cause death, acute myocardial infarction (MI), cerebrovascular accident or stroke, and repeated coronary revascularization (including percutaneous coronary intervention and coronary artery bypass surgery).

Data regarding cardiovascular risk factors (hypertension, a family history of coronary disease, diabetes, and smoking history), patient demographics, and diagnostic and laboratory tests before, during, or after hospitalization were extracted from the Meir Medical Center electronic records. Similarly, a detailed review of the electronic medical records was used to determine the prescribed medical interventions, with an emphasis on lipid-lowering agents administered 1 year after discharge.

The intensity of statin therapy was classified as “high” based on an average expected LDL-C reduction of ≥50%, as defined in the 2018 ACC/AHA/MS guidelines.³ Patients with concurrent untreated hypothyroidism, those with a known history of nephrotic syndrome, those with missing LDL-C data, and those who did not attend the 1-year visit were excluded from the study.

Data are presented as numbers and percentages for nominal parameters and as means and standard deviations for continuous parameters. Differences between the two groups with nominal variables were analyzed using the chi-squared or Fisher's exact test, as appropriate. Continuous variables were examined for normality (Shapiro–Wilk test), and data were analyzed accordingly. The t-test was applied for normally distributed variables, whereas the Mann–Whitney or Kruskal–Wallis test was used for nonparametric variables. Statistical significance was set at a P value <0.05. Data were analyzed using SPSS version 25 (IBM Corporation, Armonk, NY).

The study was approved by the local institutional ethics committee according to the principles of the Declaration of Helsinki. In accordance with the Ministry of Health regulations, the institutional ethics committee did not require written informed consent because data were collected anonymously from electronic medical records without active patient participation.

Results

Baseline characteristics

This study comprised 687 patients, with a median age of 48.5 ± 6.5 years, who were admitted to the department of cardiology for ACS; 23.3% (n = 160) were identified as females. Table 1 shows the demographics and baseline characteristics of the patients upon index hospitalization. The prevalence of most coexisting conditions at baseline characteristics were similar, except for active smoking, which was more abundant among male patients at admission (45% vs. 25%, P < 0.001).

Table 1.

Baseline Patient Characteristics and Clinical Factors

	Males N = 527	Females N = 160	P
Demographics
Age at presentation (years)	47.6 ± 6.1	51.5 ± 4.4	<0.001
Jews	306 (58.1%)	100 (62.5%)	0.31
Arabs	221(42.9%)	60 (37.5%)	0.31
Clinical features
Family history of premature CVD	125 (23.7%)	47 (29.4%)	0.15
Diabetes	155 (29.7%)	52 (32.5%)	0.21
Hypertension	279 (52.9%)	88 (55%)	0.3
Active smoking at admission	240 (45.5%)	40 (25%)	<0.001
Statin therapy before admission	149 (28.2%)	49 (30.6%)	0.33
Height (cm)	175.55 ± 13.83	162.80 ± 6.73	<0.001
Weight (kg)	92.45 ± 19.32	79.54 ± 16.90	<0.001
Biomarkers at admission
LDL-C (mg/dL)	109.8 ± 48	113.3 ± 47.7	0.21
HDL-C (mg/dL)	39.1 ± 22.9	45.42 ± 12.1	<0.001
LDL >190 at baseline	42 (8.0%)	19 (11.9%)	0.13
Total cholesterol (mg/dL)	173.7 ± 52.1	186.6 ± 50.7	0.003
Triglycerides (mg/dL)	182.1 ± 113.4	183.51 ± 123.8	0.45
Hemoglobin A1c (%)	6.2 ± 2	6 ± 1.2	0.2
Creatinine (mg/dL)	0.95 ± 0.34	0.84 ± 0.58	0.003
Hemoglobin (g/dL)	14.26 ± 2.3	12.89 ± 1.6	<0.001

Values are mean ± standard deviation or N (%).

CVD, cardiovascular disease; ESC, European Society of Cardiology; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

Baseline laboratory biomarkers, including LDL-C, were similar among the two groups, except for high-density lipoprotein-cholesterol (HDL-C) and total cholesterol, which were higher among female patients (45.4 ± 12.1 vs. 39.1 ± 22.9, P < 0.001). Notably, 28.2% of the female patients were on statins before admission compared with 30.6% of male patients (P = 0.23).

Diagnosis and management during index hospitalization

As shown in Table 2, male patients had higher rates of acute MI, whereas females had higher rates of unstable angina. One vessel disease was predominant in both groups. Both groups had similar rates of percutaneous coronary intervention, cardiopulmonary bypass surgery, and left ventricular systolic dysfunction.

Table 2.

Diagnosis, Management, Angiographic Findings, and Systolic Left Ventricle Function Before Discharge

	Males N = 527	Females N = 160	P
Diagnosis
ST-elevation MI	232 (44%)	56 (35%)	0.048
NSTEMI	174 (33%)	39 (24.3%)	0.03
Unstable angina	117 (22.2%)	62 (38.8%)	<0.001
Procedures
Cardiac catheterization^a	527 (100%)	160 (100%)	—
PCI	388 (73.6%)	122 (76.2%)	0.27
CABG	75 (14.2%)	18 (11.2%)	0.31
Angiographic findings
One-vessel disease	239 (45.3%)	90 (56.2%)
Two-vessel disease	162 (30.7%)	31 (19.3%)
Multivessel disease	113 (21.4%)	27 (16.8%)	0.003
LV function before discharge^b
Normal LV function	352 (67.4%)	112 (70.0%)
Mild LV dysfunction	106 (20.3%)	30 (18.8%)
Moderate LV dysfunction	50 (9.6%)	17 (10.6%)
Severe LV dysfunction^a	14 (2.7%)	1 (0.6%)	0.43

Values are N (%).

p-value not calculated.

On echocardiography: normal (≥50% ejection fraction), mild (40–49% ejection fraction), moderate (30–39% ejection fraction), and severe (>30% ejection fraction).

CABG, coronary artery bypass graft procedure; LV, left ventricle; MI, myocardial infarction; NSTEMI, non-ST segment elevation myocardial infarction; PCI, percutaneous coronary intervention.

Medical therapy at discharge

Among the male patients, 433 (82.1%) were discharged on high-intensity statin therapy, whereas only 9 (1.7%) were discharged on ezetimibe (Table 3). Comparable rates were observed among female patients; moreover, none of the patients were prescribed PCSK9i at the time of discharge (Table 3).

Table 3.

Medical Therapy at Discharge

	Males N = 527	Females N = 160	P
High-intensity statin^a	433 (82.1%)	125 (78.1%)	0.07
Low-/moderate-intensity statin	58 (11.0%)	24 (15.06%)	0.18
Fibrate	20 (3.8%)	4 (2.5%)	0.42
Ezetimibe	9 (1.7%)	2 (1.3%)	0.68
PCSK9 inhibitor^b	0 (0%)	0 (0%)	-
Aspirin	502 (95.2%)	150 (93.7%)	0.71
P2Y12 receptor blockers	411 (77.9%)	110 (68.7%)	0.01
ACEi	336 (63.7%)	79 (49.4%)	0.001
ARB	33 (6.2%)	14 (8.8%)	0.28
MRAs	6 (1.1%)	1 (0.6%)	0.57
Diuretics	25 (4.7%)	14 (8.8%)	0.06
BB	423 (80.2%)	105 (65.6%)	<0.001
PPI	102 (19.4%)	41 (25.6%)	0.08

Values are N (%).

Intensity of statin based on the ESC Dyslipidemia guidelines [7].

p-Value not calculated.

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta receptor blocker; MRA, mineralocorticoid receptor antagonist; PCSK9, proprotein convertase subtilisin/kexin type 9; PPI, proton pump inhibitor.

LDL-C 1 year post-ACS

As shown in Table 4 female patients had higher levels of LDL-C at 1 year (83.81 ± 38.7 vs. 76.68 ± 37.7 mg/dL, P = 0.02), despite both groups having a similar proportional reduction (−22.9% ± 36.3% vs. −22.9% ± 36.3%, P = 0.15) in LDL-C. At 1 year, the frequency of female patients achieving LDL-C levels <55 and <70 mg/dL was significantly lower than that of male patients (30% vs. 44.2%, P = 0.001; and 45% vs. 54.6%, respectively, P = 0.04). In the female group, 21.9% (n = 35) had a reduction in LDL-C levels of >50%, compared with 26.9% (n = 142) in the male group (P = 0.15).

Table 4.

Low-Density Lipoprotein Cholesterol Levels at 1-Year Follow-Up

	Males N = 527	Females N = 160	P
LDL-C at 1 year (mg/dL)	76.68 ± 37.7	83.81 ± 38.7	0.02
Percentage change in LDL-C at 1 year^a	-22.9 ± 36.3	-19.5 ± 33.9	0.15
The proportion of patients with LDL-C < 70 mg/dL at 1 year	288 (54.6%)	72 (45.0%)	0.03
The proportion of patients with LDL-C < 55 mg/dL at 1 year	233 (44.2%)	48 (30.0%)	0.001
The proportion of patients with >50% reduction in LDL-C at 1 year	142 (26.9%)	35 (21.9%)	0.19

Values are mean ± standard deviation or N (%).

Unimputed LDL-C at baseline was used to calculate the change.

Medication utilization 1 year post-discharge

Patients in both the male and female groups demonstrated high rates of high-intensity statin utilization 1-year post-discharge (90.5% [n = 477] and 91.3% [n = 146], respectively, P = 0.8) (Table 5). Compared with male patients, females hid lower rates of ezetimibe utilization (17.5% vs. 26.4%, P = 0.02). Among female patients, only 4.4% received PCSK9i at 1 year follow-up. Comparable rates were observed among male patients (Table 4).

Table 5.

Lipid-Lowering Therapies Received by Patients at 1-Year Follow-Up Visit

	Males N = 527	Females N = 160	P
High-intensity statin	477 (90.5%)	146 (91.3%)	0.8
Low-/moderate-intensity statin^a	16 (3%)	12 (7.5%)	0.21
Ezetimibe	139 (26.4%)	28 (17.5%)	0.02
Fibrates	25 (4.7%)	8 (5.0%)	0.89
PCSK9 inhibitor	26 (4.9%)	7 (4.4%)	0.77

Values are N (%).

p-Value not calculated.

MACCE incidence during follow-up period

Table 6 shows the incidences of MACCE and its components during the first 30 months of follow-up post-discharge. MACCE occurred at similar rates in both groups (25.6% and 23.8% for male and female patients respectively, P = 0.68). All-cause death occurred slightly more often among females. Acute MI, cerebrovascular events, and repeated coronary revascularization occurred at similar rates in both groups.

Table 6.

Major Adverse Cardiovascular And Cerebrovascular Events and Their Components Among Patients With/Without Familial Hypercholesterolemia During 30 Months of Follow-Up

Event	Males N = 527	Females N = 160	P
MACCE^a	135 (25.6%)	38 (23.8%)	0.63
All-cause death	4 (0.8%)	5 (3.1%)	0.02
Acute MI	39 (7.4%)	11 (6.9%)	0.82
Cerebrovascular event	12 (2.3%)	3 (1.9%)	0.76
Repeated coronary revascularization	100 (19.0%)	26 (16.3%)	0.43

Values are N (%).

Showing patients who had at least 1 event.

MACCE, major adverse cardiovascular and cerebrovascular events.

Discussion

Our study is the first to categorize differences in dyslipidemia management among female and male Israeli patients who experienced premature ACS. At the time of discharge, ∼80% of the female and male patients were prescribed high-intensity statins. At 1-year post-discharge, the mean LDL-C levels were significantly higher among females and only a minority of them reached the target levels defined by the current ESC guidelines. At 1 year follow-up, ∼4% of the female and male patients were prescribed PCSK9i. Finally, our study showed that MACCE occurred at the same frequency in both groups.

In our research, we observed that male participants were younger compared with females upon admission, which is consistent with previous studies.^20,21 We also showed that female patients exhibited higher total cholesterol levels, primarily attributable to notably higher baseline HDL levels. These findings might be attributed to the protective effect of estrogen as it is associated with higher HDL levels²² as well as the late onset of coronary artery disease.^23,24 The higher occurrence of male patients actively smoking at the time of admission in our study may also explain these findings. Active smoking is associated with decreased levels of HDL-C²⁵ and an increased incidence of HDL-C dysfunction,²⁶ along with higher rates of premature ACS particularly among middle-aged Israelis.²⁷

It is worth noting that a considerable proportion (∼70%) of patients in both groups did not receive statin therapy before admission, indicating the possibility of undiagnosed dyslipidemia or patient unawareness or nonadherence to medical treatment. This pattern aligns with previous studies that have also identified undertreatment trends.^28,29 Interestingly, these trends contradict the 2019 ESC dyslipidemia guidelines, which recommend risk factor screening, including lipid profile assessment, for men >40 years old and women >50 years old or postmenopausal.

This recommendation is particularly relevant to our study population, given the high prevalence of concomitant cardiovascular risk factors observed at baseline. The underutilization of statins and ezetimibe is perplexing, given that these medications are included in the coverage of the national Israeli health care system and easily accessible for patients with hyperlipidemia.³⁰ Taken together, these findings indicate the necessity for a reassessment of the existing screening and primary prevention strategies implemented by the Israeli health care system.

Although not the primary focus of our study, it is worth noting that ST-elevation MI was more prevalent among male patients, whereas unstable angina and non-ST-elevation MI were more common among females. These findings align with the data reported in the ACS Israeli Survey.²⁷ In line with earlier investigations on premature ACS,^27,31,32 both groups exhibited a heightened prevalence of single-vessel disease. The correlation between lipid profiles and the angiographic features of coronary artery disease in Israeli patients experiencing premature ACS necessitates additional exploration in forthcoming research endeavors.

In our study, the percentage of female patients achieving target LDL-C levels of <70 and <55 mg/dL at 1 year was only 45% and 30%, respectively, compared with 65.6% and 44.2% among male patients. Furthermore, the mean LDL-C level was higher among female patients at 1 year. Despite 78.1% of female patients being prescribed high-intensity statins upon discharge, only 21.9% of them achieved a >50% reduction in LDL-C levels after 1 year.

Similarly, the rate of achieving LDL-C target levels was unsatisfactory among male patients, although statistically higher than in female patients. These findings align with data from the European Action on Secondary and Primary Prevention by Intervention to Reduce Events V Survey, which revealed suboptimal management of LDL-C levels in most patients with coronary disease.³³ The EU-Wide Cross-Sectional Observational Study of Lipid-Modifying Therapy Use in Secondary and Primary Care also demonstrated that only 44% of patients with established coronary disease achieved the LDL-C goal of <70 mg/dL, with greater likelihood among those treated with statins in combination with ezetimibe or PCSK9 inhibitors.⁸

In addition, data from the Hyperlipidemia Therapy in Tertiary Cardiological Center registry suggested that ∼70% of ACS patients did not reach target LDL-C levels at the 1-year follow-up.³⁴ The international cholesterol management practice study reported that only 32.1% of very high-risk patients achieved the required LDL-C goals.³⁵ Therefore, there remains a critical need for ongoing efforts to optimize lipid-lowering strategies for high-risk patients.

Furthermore, our study highlights the significant problem of undertreatment, as demonstrated by the low utilization of non-statin LLT in both groups. Particularly remarkable was the significantly lower utilization of ezetimibe among female patients, mirroring trends observed in real-world clinical settings. These findings are consistent with prior studies indicating a general reluctance among young adults to pursue intensive LLT regimens.^36,37

Furthermore, our data reveal that a considerable proportion of patients in secondary prevention fail to receive optimal LLT dosages, highlighting a pervasive gap between clinical guidelines and real-life practice.^38,39 Even when patients are prescribed appropriate LLT regimens, adherence to medication regimens remains suboptimal, as demonstrated by the alarming statistic that 57% of patients were nonadherent to LLT within 6 months of experiencing an MI.⁴⁰

This pattern of underutilization starkly contradicts established guidelines from the 2018 ACC/AHA/MS and ESC, which advocate for the reassessment of LDL-C levels post-discharge and the consideration of adjunctive therapies such as ezetimibe or PCSK9 inhibitors for patients failing to achieve target levels.³ The demonstrated benefits of ezetimibe, when added to ongoing statin therapy, include incremental reductions in LDL-C levels and improved cardiovascular outcomes.¹²

In addition, the successful use of evolocumab in conjunction with high-intensity statin therapy during the acute phase of ACS, resulting in >95% of patients reaching target LDL-C levels, underscores the potential of aggressive lipid-lowering strategies in improving patient outcomes.⁴¹ Given these evidence-based advantages, addressing the identified undertreatment is paramount to enhancing the quality of care for patients after ACS.

Our study reveals a notable disparity in achieving target lipid levels between male and female patients, despite similar medication prescriptions. This observation is particularly significant as it provides real-life data in the context of current guidelines, shedding light on treatment disparities after premature ACS. Data from results from the POLASPIRE study have shown that women generally have less optimal lipid profiles than men.⁴² In the study by Zhao et al., which enrolled 10,112 patients including Mediterranean patients, 29% of whom were women, women were less likely to achieve the target level of LDL-C.¹⁶

Poor adherence to medical therapy might explain these gaps. Data from the USAGE survey showed that women were more likely to be dissatisfied with their statin, with how their clinician explained their cholesterol treatment, and less adherent to their statin than men.⁴³ Similar trends of nonadherence were demonstrated in other studies.⁴⁴ Statin-induced myalgia was reported more often among women, which might explain this trend.^43,45 Lack of effective communication with female patients might also explain this gap.⁴³

Understanding that female patients might need a different communicative approach might be crucial for enhancing medication adherence after ACS.⁴⁶ Lack of healthy lifestyle might be related, as previous studies have shown lower rates of exercise activity among females after ACS.¹⁵ The rate of female referral and participation in cardiac rehabilitation programs is significantly lower than men.⁴⁷ The rate of physical activity and eating habits among Israeli patients after premature ACS should be evaluated in future research.

Variations in psychological stress and coping mechanisms between genders can impact cardiovascular risk and treatment response, with chronic stress correlating with dyslipidemia and adverse cardiovascular outcomes.⁴⁸ Gender-specific differences in dietary habits and nutrient intake may contribute to variations in lipid profiles, with disparities in saturated fats, trans fats, and dietary cholesterol consumption potentially influencing lipid levels and treatment responses.⁴⁹

In addition, differences in body composition, particularly muscle mass, between men and women can affect lipid metabolism and the effectiveness of lipid-lowering therapies, as women typically possess higher body fat percentages and lower muscle mass, leading to reduced lipid substrate oxidation compared with men.⁵⁰ Lower skeletal muscle mass index has been associated with less favorable lipid profiles.⁵¹ Furthermore, discrepancies in metabolic rate and energy expenditure may influence lipid levels differently in men and women, potentially impacting treatment outcomes.⁵²

Notably, Nakashima et al. found that among Japanese females, glycemic load exhibited a notably stronger inverse association with HDL-cholesterol and a positive correlation with non-HDL-cholesterol levels when compared with males.⁵³ Provider-related barriers can be related to suboptimal lipid treatment. Under-implementation of the clinical practice guidelines might be related to the lack of specialized personnel, stressful workload, and short allotted time per patient.⁵⁴

Other barriers among health care professionals could include a lack of knowledge, unfamiliarity with the guidelines, unawareness of their existence, and disagreement with the recommendations.⁵⁵ Taken all together, the awareness of dyslipidemia as a disease, its risk factors, therapy adherence, and healthy living behavior might be affected in female patients.

Despite the slight yet significant disparity in all-cause death, the occurrence of MACCE and its various components was comparable between both groups during the follow-up period. This observation can potentially be attributed to the relatively small size of the cohort and the relatively short duration of the follow-up. In addition, it is worth noting that our study lacked sufficient statistical power for this particular analysis due to the low incidence of fatal events in the young population under investigation.

A previous Israeli study indicated higher 5-year mortality among women who experienced premature ACS.²⁷ However, it is important to note that this study did not specifically focus on nonfatal cardiovascular endpoints. Future research should, therefore, aim to investigate the risk of MACCE among Israeli patients with premature ACS while considering adjustments for LDL-C goal achievement.

Our study had some limitations worth mentioning. Similar to previous retrospective studies,^56
–58 we did not include data on treatment adherence. A previous meta-analysis has shown that female patients were less adherent to lipid-lowering medication than male patients.⁵⁹ Future studies addressing LLT adherence among Israeli female patients are warranted. As in previous studies,^60,61 we included LDL-C levels at 1 year and did not consider interim levels.

The clinical significance of lipid variability has recently emerged as a topic of interest, mainly in terms of long-term (visit-to-visit) variability.⁶² A post hoc analysis from the Treating to New Targets trial, which enrolled patients with stable coronary artery disease, demonstrated that LDL-C variability predicted cardiovascular outcomes, independent of mean LDL-C levels.⁶³ Another limitation of our study is the lack of data regarding dietary habits and physical examination practices among the participants, which are essential for secondary prevention and lipid management after ACS, as per the ESC guidelines on secondary prevention 2021.⁶⁴

Future studies should address this gap. Although the study examined the utilization of ezetimibe and PCSK9i, it did not comprehensively investigate other non-statin lipid-lowering therapies. Finally, this was a retrospective analysis performed at a single institution; therefore, our findings may not reflect the general population and should be further investigated in a larger cohort.

This study investigated sex differences in dyslipidemia management after premature ACS in Israeli patients. Significant disparities were observed in lipid control and achievement of target LDL-C levels at the 1-year follow-up. Females had higher LDL-C levels and lower target attainment rates, indicating the need for further intervention to optimize dyslipidemia management in female patients with premature ACS. Strategies to improve adherence to LLT and achieve target LDL-C levels should be explored to enhance long-term cardiovascular outcomes. The underutilization of non-statin LLT in female and male patients emphasizes the importance of educating health care providers and patients about alternative options such as ezetimibe and PCSK9i, especially when statin therapy alone is insufficient to reach target LDL-C levels.

Data Statement

The data underlying this article are available upon reasonable request, subject to approval by the Meir Medical Center Research Unit. Requests for access to the data should be directed to the first author, and access will be granted following the policies and guidelines of the Meir Medical Center Research Unit.

Authors' Contributions

F.H. participated in methodology, investigation, data analysis, and article writing. K.A. and R.H. participated in resources and article writing. A.K. participated in conceptualization, article writing, supervision, and project administration.

Footnotes

Author Disclosure Statement

No conflicting financial interests exist.

Funding Information

No funding was received for this article.

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