Lipoprotein(a) and Women's Cardiovascular Health: A Review.

Several medical societies recommend Lp(a) testing in individuals with a personal or family history of premature ASCVD and/or elevated Lp(a) ( Table 1 ). 33 , 34 Notably, the NLA, the ESC/EAS, the American Heart Association/American College of Cardiology, and the Canadian Cardiovascular Society all recommend ≥1 measurement of Lp(a) in all adults, regardless of family history, to identify individuals at elevated CVD risk ( Table 1 ). 7 , 29 , 32 , 33 , 34 However, the measurement of Lp(a) remains low in clinical practice. The global Lp(a)HERITAGE study reported that only 14% of patients with clinical ASCVD had their Lp(a) measured before enrollment in the study. 82 Furthermore, in the United States, the rate of Lp(a) testing has been reported to be <1%. 83 Importantly, knowledge of elevated Lp(a) levels can help to identify individuals at higher risk of adverse CV outcomes who may benefit from taking steps to lower risk, such as implementing a heart-healthy lifestyle, managing other CV risk factors including hypertension, and initiation of lipid-lowering therapies for more intensive LDL-C management. In the NLA’s recent recommendation, 32 the authors advocate for universal Lp(a) screening in both men and women as part of the first lipid panel. In addition, cascade testing in relatives of patients found to have high Lp(a) is recommended. 5 , 33 Specific guidance from medical societies on testing and management of Lp(a) levels in women is limited ( Table 1 ). The EAS notes that current guideline recommendations, based on family history or a once-in-a-lifetime approach, may not capture the fluctuations in Lp(a) levels that occur in women throughout their lives, and that repeat testing may be necessary. 17 Women with low Lp(a) levels (ie, 125 nmol/L) and may not require additional Lp(a) measurements. However, in the 2024 statement from the NLA, it is recommended that for premenopausal women with Lp(a) levels in the intermediate risk category (75-125 nmol/L), remeasuring Lp(a) may be warranted after menopause. 32 The American Heart Association and EAS recommend additional CV monitoring for women reaching menopausal age; 17 , 84 the 2022 EAS statement incorporates Lp(a) measurement into this strategy for women with borderline premenopausal Lp(a) levels of 75 to 125 nmol/L to better stratify those at increased CVD risk and allow for timely intervention for treating modifiable risk factors. 17 Moreover, monitoring of Lp(a) levels in pregnant women may offer an early opportunity to identify individuals at an increased risk of APOs and implement preventive strategies, and young women with a history of APOs or PCOS may be considered candidates for Lp(a) testing. 47 If initial Lp(a) testing is performed during pregnancy and the level is noted to be elevated (>125 nmol/L), practitioners may consider repeat Lp(a) testing postpartum to identify the patient’s baseline Lp(a) level. 85 Although Lp(a) measurement reproducibility in commercial laboratories has improved substantially, and most contemporary assays show good correlation with reference methods, clinically relevant interassay variability persists, with reported differences ranging from 3% to 69% across individual samples. 86 , 87 This assay variability has important implications for clinical practice, particularly for risk stratification and longitudinal monitoring in individuals whose Lp(a) levels are in the intermediate risk range as outlined previously. Nevertheless, most modern assays demonstrate good correlation with reference methods, 86 and Lp(a) testing is strongly encouraged to facilitate risk stratification.

As women undergo menopause, the cardioprotective functions of estrogen are lost, leading to increases in total cholesterol, LDL-C, and triglyceride levels and a decrease in high-density lipoprotein cholesterol. 64 Premature (occurring before 40 years of age) and early (occurring between ages 40-45 years) menopause, both natural and surgical, have been shown to increase the relative risk of incident ASCVD and major CV events compared with similarly aged women who have not experienced premature menopause. 34 , 65 , 66 Female sex hormones are major modulators of lipoprotein metabolism, and both endogenous and exogenous estrogens appear to modulate plasma Lp(a) levels. 67 Estrogen is an established negative regulator of the gene encoding apo(a) ( LPA ). 68 Significant increases in Lp(a) levels have been observed in postmenopausal women from diverse ethnic groups, which may be due to the associated decline in estrogen ( Figure 2 ), 3 , 18 , 36 , 69 such that the overall prevalence of elevated Lp(a) increases in women aged >50 years compared with younger age groups. 3 In an analysis of 70,000 participants in the Copenhagen General Population Study, Lp(a) levels were, on average, 18% higher in women aged 50 to 59 years compared with those aged <50 years; in a subanalysis of women with premenopausal and postmenopausal Lp(a) measurements, levels were 27% higher postmenopause. 3 Figure 2 Changes in Lp(a) Levels in Women in Response to Changes in Estrogen How Lp(a) levels change in women due to fluctuating estrogen levels at different life stages and in response to exogenous factors. HRT = hormone replacement therapy; SERM = selective estrogen receptor modulator; other abbreviation as in Figure 1 . Changes in Lp(a) Levels in Women in Response to Changes in Estrogen How Lp(a) levels change in women due to fluctuating estrogen levels at different life stages and in response to exogenous factors. HRT = hormone replacement therapy; SERM = selective estrogen receptor modulator; other abbreviation as in Figure 1 . Identifying discrete roles for menopause and aging on the modulation of Lp(a) levels has proven difficult. 18 A 2023 meta-analysis concluded that Lp(a) levels are significantly increased following menopause but that the effect of aging cannot be excluded. 18 However, in the Copenhagen General Population Study, only women experienced a significant increase in Lp(a) levels after the age of 50 years, but males did not, suggesting other factors beyond aging alone. 3 The impact of bilateral oophorectomy (surgical menopause) on Lp(a) levels offers valuable insight. Lp(a) levels significantly increase immediately following this procedure, with levels reduced to presurgical levels following initiation of estrogen hormone replacement therapy (HRT). 70 , 71 In several studies that reported no change in Lp(a) levels following bilateral oophorectomy, the induction of HRT could have masked the impact of endogenous estrogen deficiency on Lp(a). 72 , 73 Similarly, due to the inclusion of Lp(a) measurements from women who initiated HRT following oophorectomy, Anagnostis et al 18 concluded that bilateral oophorectomy does not affect Lp(a) levels, which is in contrast to 2 of the 3 studies reporting significantly increased Lp(a) levels following the procedure. 70 , 71 , 72 Considerable evidence supports a role for exogenous estrogen, such as oral contraceptives, HRT, and selective estrogen receptor modulators, in the fluctuation of Lp(a) levels ( Figure 2 ). 18 , 74 , 75 Evidence from 24 randomized controlled trials demonstrated that HRT significantly reduced Lp(a) levels in postmenopausal women (mean relative difference: −‍20.4%) compared with those not receiving HRT. 76 A 2015 meta-analysis of 12 studies investigating the effect of the oral selective estrogen receptor modulator tibolone on Lp(a) levels in postmenopausal women reported a dose-dependent 25% reduction in circulating Lp(a) following treatment. 74 Estrogen-based oral contraceptives are also associated with decreases in Lp(a) levels 75 and may have a net benefit in reducing the incidence of CVD events. 77 Few studies have been conducted in transgender women receiving estrogen therapy (and in transgender men receiving testosterone therapy) to examine the impact of gender-affirming hormone therapy on Lp(a) levels. 78 Several analyses highlight a reduced correlation between Lp(a) levels and CV outcomes in women aged >50 years. 10 , 79 In a Japanese population undergoing coronary angiography, elevated Lp(a) was a risk factor for premature CHD in both men and women aged <55 years, and in men but not women aged 55 to 65 years. 79 In contrast, many studies point to CV risk in postmenopausal women with elevated Lp(a) levels. 14 , 43 , 80 Simony et al 3 demonstrated that the morbidity and mortality risk associated with elevated Lp(a) is similar in women and men aged >50 years. In an analysis of postmenopausal women with hypercholesterolemia from the WHS and the WHI Observational Study, the risk of a 10-year first CVD event was 89% higher when Lp(a) level was >50 mg/dL (∼125 nmol/L) vs a reference group with Lp(a) <10 mg/dL. 43 Finally, in a study by Yan et al 80 including 783 postmenopausal women with a first episode of angina-like chest pain, Lp(a) was found to be an independent risk factor for predicting the presence and severity of new-onset CHD. HRT use in postmenopausal women may confound the CV risk associated with elevated Lp(a). Furthermore, the question of whether HRT can reduce the CVD risk associated with elevated Lp(a) is controversial. The Heart and Estrogen/Progestin Replacement Study assessed the effects of HRT on the reduction of Lp(a) levels and CHD events in 2,763 postmenopausal women. The authors concluded that Lp(a) was an independent risk factor for recurrent CHD and that HRT lowered Lp(a) levels. 14 Reductions in Lp(a) level greater than –8.8 mg/dL significantly lowered the risk of CHD events compared with women who had smaller reductions in Lp(a). 14 An analysis of 27,736 women from the WHS found that among women not receiving HRT, elevated Lp(a) was significantly associated with CVD risk, whereas among women receiving HRT, there was no statistically significant association with risk. 13 In contrast, in the UK Biobank cohort, the opposite relationship was seen, with the risk of CHD associated with elevated Lp(a) being greater among HRT users compared with nonusers ( P = 0.04). 81 Differences in patterns of HRT use over time may contribute to contrasting results between studies. It is important to note that the use of HRT for the sole purpose of management of Lp(a) is not recommended by the National Lipid Association (NLA). 32 Although estrogen therapy can lower Lp(a) levels, the prothrombotic and proinflammatory effects of HRT may outweigh any benefits.

Although CV outcome trials of Lp(a)-targeted therapies, including pelacarsen, olpasiran, and lepodisiran, are underway, 88 approved pharmacological therapies for specifically and effectively lowering Lp(a) are not yet available. Nevertheless, elevated Lp(a) is actionable now, as strategies can be undertaken to reduce overall CVD risk. 89 Although elevated Lp(a) is present in 20% to 30% of the global population, 6 the majority of CVD events are preceded by suboptimal control of traditional risk factors, 90 underscoring the need for a holistic approach to CVD prevention. Guidelines recommend early, intensive management of modifiable risk factors such as smoking, diet, hypertension, diabetes, and LDL-C levels. 29 , 33 , 34 There are currently no sex-specific recommendations for lipid or Lp(a) management; therefore, patient education is needed to raise awareness of CVD risk factors in women, 2 including elevated Lp(a). A multidisciplinary approach to CVD management in women is essential to help lower CVD-associated morbidity and mortality. 91 For instance, cardio-obstetrics involves collaboration between several disciplines, including cardiology, obstetrics/gynecology, maternal-fetal medicine, anesthesiology, and pharmacy, with the aim of optimizing maternal CVD outcomes. 91 In practice, gynecologists and obstetricians are at the forefront of patient management during pregnancy, delivery, and/or menopause, while primary care physicians are often the first point of contact and should be aware of CVD prevention strategies, particularly during menopause and after delivery. 92 Although a baseline lipid panel before pregnancy may be beneficial to identify women with severe lipid disorders, specific guidance for testing Lp(a) levels in women is limited. Ongoing communication between specialties is an important component of a holistic risk mitigation strategy. In line with this, a Delphi consensus panel of experts spanning cardiology, gynecology and obstetrics, and primary care, reported recommendations that may improve CVD management in women, including specific CVD risk follow-up in women with preterm labor, pre-eclampsia, and/or gestational hypertension. 92

More work is needed to determine the role of elevated Lp(a) levels in women’s reproductive and CV health. Potentially confounding factors such as race and ethnicity, apo(a) isoform distribution, reproductive age, and the use of HRT are not adequately characterized, or considered, in current research. 16 , 18 , 52 , 53 , 67 The authors provide a call to action on areas that require attention and areas for future research, which are summarized in the Central Illustration . Sex-specific, nongenetic influences on Lp(a) levels challenge the recommendation that one single lifetime measurement of Lp(a) is adequate in women; 16 , 17 , 18 however, evidence-based guidance on the management of increases in Lp(a) levels postmenopause is lacking. Although Lp(a) elevations above those considered to be normal during pregnancy are associated with APOs, data are conflicting, with little research into the underlying pathologic mechanisms. Nevertheless, it is crucial that the risks associated with elevated Lp(a) levels in women are appropriately recognized by health care professionals to ensure the effective management of CVD risk and optimal CVD prevention in clinical practice.

Medical writing support was provided by BOLDSCIENCE Ltd and was funded by 10.13039/100008272 Novartis Pharmaceuticals Corporation . This manuscript was developed in accordance with Good Publication Practice (GPP 2022) guidelines. The authors had full control of the content and made the final decision on all aspects of this publication. Dr Michos has received fees for consulting/advisory boards for Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Edwards Lifesciences, Esperion Therapeutics, Ionis Pharmaceuticals, Lilly, Medtronic, Merck & Co, NewAmsterdam Pharma, Novartis Pharmaceuticals Corporation, Novo Nordisk, and Pfizer. Dr Saucier has received fees for consulting/speaker’s bureau for Amgen and Novartis Pharmaceuticals Corporation. Dr. Mehran has received institutional research payments from Abbott, Affluent Medical, Alleviant Medical, Amgen, AstraZeneca, BAIM, Beth Israel Deaconess Medical Center, Boston Scientific, Bristol Myers Squibb, CardiaWave, CERC, Chiesi, Concept Medical, Daiichi Sankyo, Duke, Faraday, Idorsia, Janssen, MedAlliance, Medscape, Mediasphere, Medtelligence, Medtronic, Novartis, OrbusNeich, Pi-Cardia, Protembis, RM Global Bioaccess Fund Management, Sanofi, and Zoll; personal fees from Affluent Medical, Boehringer Ingelheim, Chiesi USA, Cordis, Daiichi Sankyo, Esperion Science/Innovative Biopharma, Gaffney Events, Educational Trust, Global Clinical Trial Partners, Ltd., IQVIA, Medscape/WebMD Global, Novo Nordisk, PeerView Institute for Medical Education, TERUMO Europe N.V., Radcliffe; equity <1% in: Elixir Medical, Stel, and ControlRad (spouse); no fees from SCAI (Women in Innovations Committee Member), Faculty CRF, and Women as One; honorarium from AMA - JAMA Cardiology (Associate Editor) and ACC (BOT Member, SC Member CTR Program). Dr Koschinsky has received fees for consulting/advisory boards for Eli Lilly and Novartis Pharmaceuticals Corporation and research contracts with Abcentra, Amgen, and Eli Lilly.