Introduction

Lipoprotein(a) (Lp[a]) is a highly atherogenic variant of low-density lipoprotein (LDL), which is an independent causal risk factor for atherosclerotic cardiovascular disease (ASCVD).1 Total ASCVD risk increases with the Lp(a) concentration.2 Moreover, the 2022 European Atherosclerosis Society (EAS) Consensus Statement identified Lp(a) as a new risk factor for aortic stenosis.3 Lp(a) may also play a pathophysiological role in atrial fibrillation (AF).4

According to the recommendations of the Polish Cardiac Society and the Polish Lipid Association, Lp(a) should be measured at least once in a lifetime in all adults.5 The 2025 Focused Update of the 2019 European Society of Cardiology (ESC) / EAS Guidelines for the management of dyslipidemias recommends considering Lp(a) levels above 50 mg/dl as a factor increasing cardiovascular risk in all adults (class IIa, level B).6,7

Lp(a) levels are predominantly determined by genetics, which can account for up to 90% of interindividual variability.8 Lifestyle changes only slightly affect Lp(a) concentrations.9 Since there is no approved, targeted Lp(a)-lowering therapy as of yet, individuals with elevated Lp(a) levels, who are at an increased ASCVD risk, require rigorous action to control other modifiable risk factors, including smoking cessation,10 LDL cholesterol reduction,11 and optimal blood pressure control.12 However, several Lp(a)-lowering drugs are currently under investigation, and the results from the randomized controlled trials evaluating their influence on major adverse cardiovascular event (MACE) reduction are highly anticipated. The Lp(a)HORIZON (Assessing the Impact of Lipoprotein[a] Lowering With Pelacarsen [TQJ230] on Major Cardiovascular Events in Patients With CVD) trial,13 which is currently at its phase 3, compares pelacarsen (antisense oligonucleotide) with placebo in patients with established ASCVD and Lp(a)levels equal to or greater than 70 mg/dl for MACE reduction with 4-year follow-up. Another phase 3 trial (ongoing), OCEAN(a) (Olpasiran Trials of Cardiovascular Events and Lipoprotein[a] Reduction) assesses olpasiran (small interfering ribonucleic acid) in comparison with placebo in patients with a history of ASCVD and Lp(a) levels equal to or greater than 200 nmol/l. The results of these and other trials will answer whether the marked reduction in Lp(a) levels observed for these novel drugs translates into ASCVD risk reduction.

In the Polish population, high prevalence of increased Lp(a) highlights the need for routine testing and early risk factor management. The results from the registry of Polish Mother’s Memorial Hospital Research Institute showed that 27.8% of the included patients had Lp(a) levels above 30 mg/dl, whereas 19.8% had a Lp(a) concentration above 50 mg/dl.14 In our recent study, we obtained similar findings: 20.8% of the participants had a Lp(a) level equal to or greater than 30 mg/dl.15

In women aged 50 years, Lp(a) concentration increases modestly, a phenomenon not observed in men.15 Several other studies have also aimed to investigate sex-based differences in relation to Lp(a) and its impact on cardiovascular outcomes,16,17 but have not provided definite conclusions regarding the sex-associated differences in Lp(a).

Considering this evidence gap, we aimed to assess sex-based differences in the associations between elevated Lp(a) levels and clinical characteristics in Polish patients.

Methods

Study design and participants

In this observational, cross-sectional study, we included consecutive patients hospitalized between March 1, 2024, and October, 2024, in the Clinical Department of Internal Medicine, Endocrinology, Diabetology, and Nephrology of the Czerniakowski Hospital in Warsaw. The detailed total cohort characteristics have previously been described.15 This is an exploratory sex-stratified analysis, investigating the differences between the high and low Lp(a) groups within each sex. We used a 30-mg/dl threshold to divide the patients into high (≥30 mg/dl) and low (<⁠30 mg/dl) Lp(a) groups. Although most recent ESC guidelines6 indicate the Lp(a) level above 50 mg/dl as a risk enhancer, we chose the cutoff value of 30 mg/dl to retain consistency with our previous work where we described total cohort characteristics. Nevertheless, to investigate the robustness, the final analyses were also run with the cutoff value of 50 mg/dl.

Ethics

Given the retrospective, observational design of this research, written informed consent and ethics committee approval were not required.

Data collection

Medical records were used to collect demographic and clinical data, including medical history, comorbidities, pharmacotherapy, laboratory, and echocardiographic findings.

The following laboratory parameters were extracted: hemoglobin (g/dl), white blood cell count 103/µl), platelet count (103/µl), creatinine (mg/dl), glycated hemoglobin (HbA1c; %), N-terminal pro–B-type natriuretic peptide (pg/ml), C-reactive protein (mg/l), homocysteine (µmol/l), total cholesterol (mg/dl), high-density lipoprotein (HDL) cholesterol; mg/dl), non-HDL cholesterol (mg/dl), LDL cholesterol (mg/dl), and triglycerides (mg/dl).

The following echocardiographic parameters were extracted: left ventricular end-diastolic diameter (mm), left ventricular end-systolic diameter (mm), posterior wall diameter (PWD, mm), interventricular septal thickness at end-diastole (IVSd, mm), left atrial size (mm), left ventriclularjection fraction (LVEF, %), right ventricular end-diastolic diameter (mm), and tricuspid annular plane systolic excursion (mm).

Study end points

In the exploratory analysis, we defined within-sex differences between the high and low Lp(a) groups. In the confirmatory stage, we assessed the interaction between sex and Lp(a) group for the variables identified in the exploratory phase.

Statistical analysis

The analyses were performed using GraphPad Prism for macOS software, version 10.6.0 (Dotmatics, Boston, Massachusetts, United States). We used the Shapiro–Wilk test to assess continuous data for normal distribution. In the exploratory phase, within-sex comparisons between the high and low Lp(a) groups were performed with the Mann–Whitney test for continuous data and the Fisher exact test for categorical data. Categorical data are reported as counts (percentages) while continuous data are reported as medians (interquartile ranges [IQRs]). In the confirmatory phase, variables that differed between the Lp(a) groups within at least 1 sex were analyzed with multiple linear (for continuous data) or logistic (for binary data) regression, including sex, Lp(a) group, and their 2-way interaction. The female low-Lp(a) group was set as a reference group. A P value below 0.05 was considered significant.

Results

Baseline patient characteristics

We included a total of 562 patients in our cohort. Of the 367 women, 84 (22.9%) had a high Lp(a) concentration. Of the 195 men, 33 (16.9%) had a high Lp(a) level. Table 1 shows baseline characteristics of the included patients, divided into subgroups based on sex and Lp(a) concentration. The women with high Lp(a), as compared with those with low Lp(a), more frequently had ischemic heart disease (14.3% vs 6.7%; P = 0.04), AF (17.9% vs 9.2%; P = 0.046), a history of myocardial infarction (MI; 8.3% vs 2.5%; P = 0.02), and a history of prior percutaneous coronary intervention (PCI; 6% vs 1.1%; P = 0.02). None of these associations were noted within the male subgroup.

Table 1. Baseline characteristics of the patients with high (≥30 mg/dl) and low (<⁠30 mg/dl) lipoprotein(a) concentration

Parameter

Women (n = 367)

Men (n = 195)

High Lp(a), n = 84

Low Lp(a), n = 283

P value

High Lp(a), n = 33

Low Lp(a), n = 162

P value

Age, y

58.5 (42–71.8)

51 (38–68)

0.05

52 (39.5–72)

54.5 (42.8–70.3)

0.66

Height, m

1.62 (1.59–1.67)

1.64 (1.6–1.68)

0.07

1.78 (1.76–1.83)

1.78 (1.73–1.81)

0.14

Weight, kg

83 (65.3–98.8)

80 (68–97)

0.88

103 (83.5–124)

93.5 (77–109.3)

0.08

BMI, kg/m2

30.6 (23.9–37.1)

29.7 (25–35.6)

0.84

31.3 (27.1–37.7)

29.1 (25.1–35.3)

0.27

Prior MI

7 (8.3)

7 (2.5)

0.02

5 (15.2)

17 (10.5)

0.54

Prior PCI

5 (6)

3 (1.1)

0.02

3 (9.1)

17 (10.5)

>0.99

Prior CABG

1 (1.2)

0

0.23

2 (6.1)

1 (0.6)

0.07

Prior stroke

4 (4.8)

3 (1.1)

0.05

0

9 (5.6)

0.36

KTx

0

0

n/a

0

1 (0.6)

>0.99

Nephrectomy

0

0

n/a

0

1 (0.6)

>0.99

FH

0

0

n/a

0

0

n/a

Aortic stenosis

2 (2.4)

4 (1.4)

0.62

2 (6.1)

7 (4.3)

0.65

IHD

12 (14.3)

19 (6.7)

0.04

8 (24.2)

27 (16.7)

0.32

AF

15 (17.9)

26 (9.2)

0.046

6 (18.2)

24 (14.8)

0.6

CKD

10 (11.9)

27 (9.5)

0.54

4 (12.1)

22 (13.6)

>0.99

DM

25 (29.8)

90 (31.8)

0.79

14 (42.4)

57 (35.2)

0.43

DM type

1

1

16

0.12

2

3

0.25

2

23

73

12

54

3

1

1

0

0

Hypertension

50 (59.5)

141 (49.8)

0.14

21 (63.6)

99 (61.1)

0.85

COPD

5 (6)

12 (4.2)

0.55

2 (6.1)

7 (4.3)

0.65

Hyperthyroidism

1 (1.2)

6 (2.1)

>0.99

2 (6.1)

3 (1.9)

0.2

Hypothyroidism

24 (28.6)

79 (27.9)

0.89

4 (12.1)

14 (8.6)

0.51

Chronic liver disease

0

4 (1.4)

0.58

0

5 (3.1)

0.59

Smoking status

Current smoker

16

60

0.95

10

34

0.18

Former smoker

5

18

2

28

Nonsmoker

59

189

18

91

Categorical data are presented as numbers (percentages). Continuous data are presented as medians (interquartile ranges).

Abbreviations: AF, atrial fibrillation; BMI, body mass index; CABG, coronary artery bypass grafting; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; FH, familial hypercholesterolemia; IHD, ischemic heart disease; KTx, kidney transplant; Lp(a), lipoprotein(a); MI, myocardial infarction; n/a, not applicable; PCI, percutaneous coronary intervention

Drug intake and lipoprotein(a) concentration

In Table 2, pharmacotherapy divided into subgroups based on sex and Lp(a) concentration is presented. The men with high Lp(a), as opposed to those with low Lp(a), had a more frequent intake of sodium-glucose cotransporter-2 inhibitors (SGLT2-is; 30.3% vs 14.2%; P = 0.04) and a history of radioactive iodine therapy (6.1% vs 0%; P = 0.03). Neither of these observations were found within the female subgroup.

Table 2. Drug intake of the patients with high (≥30 mg/dl) and low (<⁠30 mg/dl) lipoprotein(a) concentration

Drug

Women (n = 367)

Men (n = 195)

High Lp(a) (n = 84)

Low Lp(a) (n = 283)

P value

High Lp(a) (n = 33)

Low Lp(a) (n = 162)

P value

Statins

28 (33.3)

65 (23)

0.06

14 (42.4)

57 (35.2)

0.43

Ezetimibe

1 (1.2)

5 (1.8)

>0.99

3 (9.1)

6 (3.7)

0.18

Alirocumab

0

0

n/a

0

0

n/a

Evolocumab

0

0

n/a

0

0

n/a

Inclisiran

0

1 (0.4)

>0.99

0

0

n/a

Insulin

8 (9.5)

28 (9.9)

>0.99

6 (18.2)

17 (10.5)

0.24

Metformin

19 (22.6)

61 (21.6)

0.88

13 (39.4)

45 (27.8)

0.21

Sulfonylureas

3 (3.6)

9 (3.2)

0.74

0

7 (4.3)

0.6

GLP-1 agonists

15 (17.9)

47 (16.6)

0.87

8 (24.2)

21 (13)

0.11

DPP-4 inhibitors

3 (3.6)

8 (2.8)

0.72

0

6 (3.7)

0.59

SGLT-2 inhibitors

7 (8.3)

33 (11.7)

0.55

10 (30.3)

23 (14.2)

0.04

Pioglitazone

0

0

n/a

0

0

n/a

Acarbose

0

0

n/a

0

0

n/a

Growth hormone

0

0

n/a

0

0

n/a

Levothyroxine

21 (25)

77 (27.2)

0.78

3 (9.1)

13 (8)

0.74

Antithyroid agents

0

1 (0.4)

>0.99

0

1 (0.6)

>0.99

Radioactive iodine

1 (1.2)

7 (2.5)

0.69

2 (6.1)

0

0.03

Tocilizumab

0

0

n/a

0

0

n/a

Proteases inhibitors and / or antiretroviral drugs

0

0

n/a

0

1 (0.6)

>0.99

Peritoneal dialysis

0

0

n/a

0

0

n/a

Lipoprotein apheresis

0

0

n/a

0

0

n/a

Data are presented as numbers (percentages).

Abbreviations: DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT-2, sodium-glucose cotransporter 2; others, see Table 1

Laboratory findings

In Table 3, the laboratory findings, divided into subgroups based on sex and Lp(a) concentration, is outlined. None of the analyzed factors differed between the 2 groups, neither within the female nor male subgroup.

Table 3. Laboratory findings of the patients with high (≥30 mg/dl) and low (<⁠30 mg/dl) lipoprotein(a) concentration

Parameter

Women (n = 367)

Men (n = 195)

High Lp(a) (n = 84)

Low Lp(a) (n = 283)

P value

High Lp(a) (n = 33)

Low Lp(a) (n = 162)

P value

Hemoglobin, g/dl

13.1 (11.8–14.1)

13.4 (12.4–14.1)

0.12

14.9 (13.6–15.6)

14.6 (13.1–15.5)

0.61

WBC, × 109/l

7.1 (5.6–8.9)

6.6 (5.4–8.4)

0.15

7.7 (6.05–10.5)

6.75 (5.8–9.3)

0.12

PLT, × 109/l

241 (209–297)

256 (210–303)

0.48

213 (165–267)

224 (190–272)

0.45

Creatinine, mg/dl

0.8 (0.7–0.9)

0.7 (0.7–0.9)

0.19

0.9 (0.8–1.2)

1 (0.8–1.2)

0.43

HbA1c, %

5.7 (5.3–6.3)

5.5 (5.2–6)

0.17

5.7 (5.3–7.35)

5.8 (5.4–6.7)

0.83

NT-proBNP, pg/ml

156 (68–1764)

161 (63–835)

0.49

40 (26–1831)

187 (42–1727)

0.44

CRP, mg/l

0.32 (0.1–1.15)

0.26 (0.1–0.76)

0.24

0.29 (0.12–1.05)

0.26 (0.11–1.18)

>0.99

Homocysteine, µmol/l

9.96 (8.1–11.85)

9.15 (7.4–12.62)

0.49

11.04 (8.59–12.52)

10.56 (8.4–14.04)

0.71

Total cholesterol, mg/dl

176 (151–206)

178 (149–205)

0.83

167 (132–203)

163 (132–198)

0.88

HDL cholesterol, mg/dl

48 (39–57)

48 (40–57)

0.56

37 (34–44)

41 (34–49)

0.22

Non-HDL cholesterol, mg/dl

126 (103–156)

127 (102–157)

0.91

125 (94–158)

126 (90–155)

0.83

LDL cholesterol, mg/dl

105 (80–128)

105 (81–132)

0.87

97 (65–136)

98 (70–126)

0.75

Triglycerides, mg/dl

108 (82–143)

102 (71–140)

0.19

130 (93–174)

118 (79–166)

0.23

Data are presented as medians (interquartile ranges).

SI conversion factors: to convert hemoglobin to g/l, multiply by 10; creatinine to µmol/l, by 88.4; CRP to mg/l, by 0.1; total cholesterol, LDL cholesterol, HDL cholesterol, and non-HDL cholesterol to mmol/l, by 0.02586; triglycerides to mmol/l, by 0.01129.

Abbreviations: CRP, C-reactive protein; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NT-proBNP, N-terminal pro–B-type natriuretic peptide; PLT, platelet; WBC, white blood cell; others, see Table 1

Echocardiographic findings

In Table 4, the echocardiographic findings of subgroups based on sex and Lp(a) concentration are illustrated. Women with high Lp(a), as compared with those with low Lp(a), had higher median (IQR) PWD of 11 (10–12) vs 10 (9–12) mm (P = 0.03) and IVSd of 12 (10.8–12) vs 11 (10–12) mm (P = 0.01), and lower median (IQR) LVEF of 60% (58.8%–65%) vs 65% (60%–65%; P = 0.01). None of these differences were observed within the male subgroup.

Table 4. Echocardiographic findings of the patients with high (≥30 mg/dl) and low (<⁠30 mg/dl) lipoprotein(a) concentration

Parameter

Women (n = 367)

Men (n = 195)

High Lp(a) (n = 84)

Low Lp(a) (n = 283)

P value

High Lp(a) (n = 33)

Low Lp(a) (n = 162)

P value

LVEDD, mm

46 (44–48)

46 (44–48)

0.95

51 (47–53.3)

50 (46–53)

0.29

LVESD, mm

28 (25–29.5)

26 (24–30)

0.47

30 (28–33)

29 (26–33)

0.62

PWD, mm

11 (10–12)

10 (9–12)

0.03

12 (11–12)

11 (10–12)

0.11

IVSd, mm

12 (10.8–12)

11 (10–12)

0.01

12 (12–13)

12 (11–13)

0.06

LA, mm

39 (36–42)

38 (34–42)

0.08

43 (39.8–46)

42 (38–44)

0.23

LVEF, %

60 (58.8–65)

65 (60–65)

0.01

62.5 (55–65)

60 (57.5–65)

0.69

RVEDD, mm

28 (26–31)

30 (26–33)

0.48

32 (29.8–34.5)

31 (28–35)

0.6

TAPSE, mm

22.5 (20–24)

23 (21–25)

0.05

22.5 (21–25.3)

23 (21–25)

0.76

Data are presented as medians (interquartile ranges).

Abbreviations: IVSd, interventricular septal thickness at end-diastole; LA, left atrium; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic diameter; PWD, posterior wall diameter; RVEDD, right ventricular end-diastolic diameter; TAPSE, tricuspid annular plane systolic excursion; others, see Table 1

Multiple linear regression

The effects of Lp(a) (high vs low) and sex (men vs women), as well as their interaction were assessed in multiple linear regressions for PWD, IVSd, and LVEF (Table 5). No significant Lp(a) group-sex interactions were found for any of the analyzed continuous variables. There were also no Lp(a) group-sex interactions with a cutoff value of 50 mg/dl (Supplementary material, Table S1).

Table 5. Results of the multiple linear regression for posterior wall diameter, interventricular septal thickness at end-diastole, and left ventricular ejection fraction

Variable

Lp(a) group, high vs low

Sex, men vs women

Interaction between sex and Lp(a) group

β1

95% CI

P value

β2

95% CI

P value

β3

95% CI

P value

PWD, mm

0.54

0.11–0.97

0.01

0.88

0.55–1.22

<⁠0.001

–0.03

–0.81–0.76

0.95

IVSd, mm

0.58

0.12–1.04

0.01

0.99

0.63–1.35

<⁠0.001

0.05

–0.8–0.89

0.91

LVEF, %

–2.24

–4.6–0.11

0.06

–4.22

–6.05 to –2.38

<⁠0.001

2.16

–2.18–6.46

0.32

Abbreviations: see Tables 1 and 4

Multiple logistic regression

The effects of Lp(a) (high vs low) and sex (men vs women), as well as their interaction were assessed in multiple logistic regressions for prior MI, prior PCI, ischemic heart disease, AF, and SGLT-2i use (Table 6). A notable Lp(a) group-sex interaction was found for prior PCI (OR, 0.14; 95% CI, 0.02–0.93; P = 0.04) and SGLT-2i use (OR, 3.82; 95% CI, 1.15–13.28; P = 0.03). However, there were no Lp(a) group-sex interactions with a cutoff value of 50 mg/dl (Supplementary material, Table S2).

Table 6. Results of the multiple logistic regression for the parameters listed below

Variable

Lp(a) group, high vs low

Sex, men vs women

Interaction between sex and Lp(a) group

OR

95% CI

P value

OR

95% CI

P value

OR

95% CI

P value

Prior MI

3.58

1.19–10.77

0.02

4.62

1.95–12.19

<⁠0.001

0.43

0.09–1.91

0.27

Prior PCI

5.91

1.42–29.3

0.02

10.94

3.6–47.4

<⁠0.001

0.14

0.02–0.93

0.04

IHD

2.32

1.05–4.94

0.04

2.78

1.5–5.25

0.001

0.69

0.21–2.23

0.54

AF

2.15

1.06–4.24

0.03

1.72

0.95–3.11

0.07

0.59

0.17–1.93

0.39

SGLT-2 inhibitor use

0.69

0.27–1.53

0.38

1.25

0.7–2.21

0.44

3.82

1.15–13.28

0.03

Abbreviations: OR, odds ratio; others, see Tables 1 and 2

Discussion

Regarding sex-specific differences in the high vs low Lp(a) group comparisons, our study found that prior PCI was more common in women with high than those with low Lp(a), while no such difference was observed in their male counterparts. Also, the use of SGLT-2is was more common in men with high than those with low Lp(a), while no such difference was noted in the female population.

We observed more frequent incidence of ischemic heart disease, a history of PCI, and MI in the women with high Lp(a) in comparison with those with low Lp(a). It is consistent with more frequent ASCVD in individuals with increased Lp(a) concentration. No such observation in the male subgroup may be partially explained by a considerably smaller sample size, which might have precluded reaching significance. As per the literature search, in patients undergoing PCI, elevated Lp(a) was associated with an increased risk of long-term MACEs,18 also confirmed in a recent meta-analysis.19

The observation concerning the use of SGLT-2is and the interaction between sex and Lp(a) group should be interpreted with caution. In our view, it might be the result of the sex-based disparity in prescribing these drugs,20 with more frequent administration in men, rather than the biological interaction with Lp(a). We did not find any other similar findings in the literature. These observations may reflect sample size limitations rather than true biological differences. Therefore, they should be treated mainly as speculative and hypothesis-generating.

An interesting and somewhat surprising finding is the lack of differences in statin use between the patients with high and low Lp(a) levels. However, in this analysis, we observed an insignificant trend towards more frequent statin use among the women with elevated Lp(a). As shown in Table 2, 33.3% of the women in the high Lp(a) group were receiving statin therapy, as compared with 23% in the low Lp(a) group, indicating a directional association that did not reach significance. Given that elevated Lp(a) is usually associated with higher overall cardiovascular risk, one might expect more frequent statin therapy in these patients. On the other hand, clinicians guide their decisions regarding initiating statin therapy based on LDL cholesterol levels, which are independent of Lp(a). Further, these differences could be more subtle and hence require larger sample size to reach significance.

The data presented in this manuscript support the need for routine Lp(a) screening among all individuals and controlling all modifiable risk factors in patients with high Lp(a) who are at an increased ASCVD risk. The final evidence regarding the role of Lp(a)-lowering therapies on ASCVD risk reduction is awaited. New ESC/EAS guidelines for dyslipidemia management list several risk modifiers, including elevated Lp(a), but also sex-specific factors, such as a history of premature menopause or hypertensive disorders of pregnancy. Therefore, an individualized patient-based approach, including sex-specific factors, is required in risk assessment and management.

We must mention several limitations of our study, which are important for the cautious interpretation of the presented results. First, this was an exploratory subgroup analysis that aimed to generate new hypotheses, such as a more prominent association between elevated Lp(a) and prior PCI among women rather than men. Nevertheless, the findings are important for providing real-world data on the sex-specific associations for Lp(a). Secondly, we did not adjust the primary analysis for multiple comparisons, which was caused by an exploratory character seeking variables for further confirmation. Last, the multiple logistic (for binary variable) and linear (for continuous data) regressions were not adjusted for other covariates than sex and Lp(a) group, which might introduce some confounding.

Conclusions

We found 2 sex-specific associations between Lp(a) and clinical characteristics: women with high Lp(a) were more likely to have a history of PCI than those with low Lp(a), and men with high Lp(a) were more commonly prescribed SGLT-2is than those with low Lp(a). Given the cross-sectional exploratory nature of this analysis, our findings should be interpreted with caution and as hypothesis-generating. Future studies could further explain the observed associations and their clinical relevance.