Review

Lipoprotein (a) in postmenopausal women: assessment of cardiovascular risk and therapeutic options

Panagiotis Anagnostis 1, Spyridon Karras 1, Irene Lambrinoudaki 2, John C. Stevenson 3, Dimitrios G Goulis 1

1 Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Greece

2 Second Department of Obstetrics and Gynecology, National and Capodestrian University of Athens, Greece

3 National Heart and Lung Institute, Imperial College London, Royal Brompton and Harefield NHS Foundation Trust, London SW3 6NP, UK.

Corresponding author:

Panagiotis Anagnostis, Sarantaporou 10, 54640, Thessaloniki, Greece, phone: 0030 2310 257150, fax: 0030 2310 281179, e-mail: anagnwstis.pan@yahoo.gr.

Disclosures

The authors have no conflict of interest to disclose.

Abstract

Lipoprotein(a) [Lp(a)], a low-density lipoprotein (LDL)-like particle, has been independently associated with increased cardiovascular disease (CVD) risk in various populations, such as postmenopausal women. Past, present and emerging therapies can reduce Lp(a) concentrations to a varying extent. Of these, only hormone therapy (mainly oral estrogens) (HRT) and tibolone have been specifically studied in postmenopausal women and can reduce Lp(a) concentrations by up to 44%, although evidence indicating a concomitant reduction in CVD risk associated with Lp(a) is lacking. As alternative treatments for women who cannot, or will not, take hormonal therapies, niacin and the upcoming proprotein convertase subtilisin / kexin type 9 (PCSK-9) inhibitors are effective in reducing Lp(a) concentrations by up to 30%. Statins have minimal or no effect on Lp(a). However, data for these and other promising Lp(a)-lowering therapies including mipomersen, lomitapide, cholesterol-ester-transfer protein inhibitors and eprotirome are derived from studies in the general, mainly high CVD risk, population, and include only subpopulations of postmenopausal women. Overall, it remains to be proven whether the aforementioned reductions in Lp(a) by these therapeutic options are translated into CVD risk reduction in postmenopausal women.

Keywords: Lipoprotein(a), menopause, postmenopausal women, cardiovascular risk

Review Criteria

· Included data were gathered, selected and analyzed on the basis that they provided the strongest available evidence on the role of lipoprotein (a) [Lp(a)] in menopause-related cardiovascular risk

· The most representative studies on Lp(a)-lowering agents in postmeneopausal women were selected

Message for the clinic

· Lipopoprotein (a) [Lp(a)] may play a role in the increased cardiovascular risk that transition to menopause is associated with.

· Of the available medications, HRT and tibolone may significantly reduce plasma Lp(a) concentrations, as well as, niacin and the newly approved PSCK9 inhibitors may be effective in reducing Lp(a) concentrations.

· Lp(a) may be measured when assessing cardiovascular risk in cases of familial hypercholesterolemia and/or high cardiovascular risk, according to the international guidelines.

1. Introduction

Accumulative body of evidence supports the notion that transition to menopause is associated with increased risk of cardiovascular disease (CVD) [1, 2], mainly attributed to atherogenic lipid profile that converges the male pattern [3, 4]. In particular, an increase in total cholesterol (TC), low-density lipoprotein (LDL) cholesterol (LDL-C), triglycerides (TG), as well as, apolipoprotein B (apoB) concentrations, has been observed in postmenopausal compared with premenopausal women [3, 4]. Moreover, menopause may be also associated with a decrease in high-density lipoprotein cholesterol (HDL-C) [4], mainly due to a reduction in HDL-C subfraction 2 (HDL2-C) [4], although some studies, such as the Framingham Offspring Study did not find any difference in HDL-C concentrations between pre- and postmenopausal women [3]. In addition, an increase in body fat and modification of its distribution to a male pattern (higher trunk fat mass to leg fat mass ratio) have been reported in postmenopausal compared with premenopausal women, contributing to a higher CVD risk [5]. It is not clear if this increased CVD risk (attributed mainly to the differences in plasma lipoproteins) is a result of menopause per se or the ageing process [6].

On the other hand, lipoprotein (a) [Lp(a)] has been recognized as CVD risk factor, independently of other traditional risk factors [7, 8]. The structure of Lp(a) is similar to low-density lipoprotein (LDL). Except for apolipoprotein B100, it contains apolipoprotein (a) [apo(a)], which is non-covalently bound to apoB100 (with a bisulphide bond in a 1:1 molar ratio) [9] (Figure 1). The differences between Lp(a) and LDL with respect to size and electrophoretic mobility are attributed to the high molecular weight of apo(a) [9]. According to apo(a) mobility, at least six different Lp(a) isoforms have been recognized: Lp(a)F, Lp(a)B, Lp(a)S1, Lp(a)S2, Lp(a)S3 and Lp(a)S4. The letters F (fast), S (slow) and B (baseline) refer to the apo(a) mobility in comparison with that of apo B100. In general, there is an inverse association between the molecular weight of apo(a) isoform and serum Lp(a) concentrations [9].

Lp(a) concentrations are genetically determined mainly by the apo(a) gene and are very heterogeneous across individuals and populations. De novo hepatic synthesis, rather than binding to hepatic LDL-receptor, determines serum Lp(a) concentrations [9]. Lp(a) is involved in prothrombotic and atherogenic processes [10]. It is structurally homologous to plasminogen, a key factor of fibrinolysis, although it lacks fibrinolytic activity [11]. The underlying pathogenesis linking Lp(a) with atherosclerotic disease includes the association of its kringle domains with smooth muscle cell proliferation [Kringle-(6-7)], foam cell formation [Kringle (7-8)] and inhibition of angiogenesis [Kringle (9-10)] [12]. Moreover, oxidative compounds, such as oxidized phospholipid (OxPL), non-covalently bound to apoB-100, are also key mediators for the role of Lp(a) in the atherosclerotic process [12]. However, despite the independent association of Lp(a) concentrations with increased prevalence of CVD, few studies have assessed its role in menopause-related CVD risk, seeking for differences between pre- and postmenopausal women [13-19].

The purpose of this narrative review is to present current data on the role of Lp(a) in augmenting CVD risk in postmenopausal women and focus on past, current and emerging therapeutic strategies.

2. Methods

We systematically searched PubMed for English language publications until November 2015 under the following terms: “therapy” OR “treatment” AND [“lipoprotein (a)” OR “Lp(a)”] AND (“postmenopausal women” OR “menopausal women” OR “menopause”). Additionally, we included references from the reviewed articles in order to widen our search.

3. Epidemiological data on Lp(a) as a risk factor for CVD

In general, a continuous and independent association between Lp(a) concentrations and CVD risk exists. One of the largest studies, including 2,047 patients with coronary artery disease (CAD - history of fatal or non-fatal myocardial infarction) and 3,921 control subjects, evaluated the association between Lp(a) concentrations and CAD. Compared with the low Lp(a) concentrations (i.e. < 5 mg/dl), the odds ratio (OR) for CAD was 1.27 [95% confidence interval (CI) 1.11-1.45], 1.39 (95% CI 1.22-1.57) and 1.77 (95% CI 1.57-1.99) for concentrations of 84 mg/dl, 171 mg/dl and 383 mg/dl, respectively. There was only weak or no association between Lp(a) and classical risk factors, such as age, sex, smoking, total cholesterol and blood pressure [20]. A previous meta-analysis of prospective studies showed that individuals with Lp(a) concentrations at the upper third of baseline (~100 mg/dl) had a combined relative risk (RR) of 1.6 (95% CI 1.4-1.8) compared with those having Lp(a) at the lower third (~5 mg/dl). In this study, Lp(a) concentrations were also weakly correlated with traditional CVD risk factors [8]. In a previous retrospective study, patients with Lp(a) concentrations at 206.8 ± 47.1 mg/dl were at 6-fold higher risk of at least one CVD event compared with those with Lp(a) concentrations at 32.2 ± 4.8 mg/l [21]. A recent meta-analysis of case-control and prospective studies showed that Lp(a) is also an independent risk factor for stroke, mainly in patients younger than 55 years. The pooled estimated OR for high compared with low Lp(a) concentrations was 1.41 (95% CI 1.26-1.57) for case-control and 1.29 (95% CI 1.06-1.58) for prospective studies [22].

A consensus statement published in 2010 by the European Atherosclerosis Society (EAS), focusing on the role of Lp(a) as a CVD risk factor, recommends Lp(a) measurement once in patients with premature CVD, familial hypercholesterolaemia (FH), family history of premature CVD and/or elevated Lp(a), recurrent CVD despite optimal lipid-lowering treatment and increased risk of fatal or non-fatal CVD according to the European or US guidelines (≥ 3% and ≥ 10%, respectively). According to this panel, a desirable level of Lp(a) is considered as below the 80th percentile or less than 50 mg/dl [23]. According to the recently published guidelines for the management of dyslipidaemias by the European Society of Cardiology (ESC) and the EAS guidelines, screening for Lp(a) is also recommended for those at 5% 10-year risk of fatal CVD according to the SCORE system [24]. The American Association of Clinical Endocrinologists (AACE) considers screening for Lp(a) as useful in white patients with CAD or in those with unexplained family history of premature CAD [25]. Moreover, recent guidelines in children and adolescents with FH recommend Lp(a) measurement for risk classification, especially in cases of positive family history for premature death from CAD (even in moderate hypercholesterolaemia) [26].

Lp(a) concentrations seem to be two to three times higher in blacks compared with whites and Hispanics [27-29]. Regarding the effect of ethnicity on the association of Lp(a) with CVD risk, there is a continuous correlation, both in blacks [hazard ratio (HR) 1.49; 95% CI 1.09-2.04] and whites (HR 1.22; 95% CI 1.02-1.45). When the level of 50 mg/dl is used as a threshold for determining CVD risk, this may reveal high risk in all races (HR 1.67 for blacks; 1.82 for whites; 2.37 for Hispanics), except for Chinese. Lower thresholds, such as 30 mg/dl identify higher CAD risk only in blacks [30]. Apo(a) gene polymorphisms seem to account in part for these ethnic and racial differences [28].

With respect to sex differences, data from large epidemiological studies, such as the Framingham Offspring Study did not show any significant differences between men and women [18]. However, the association between Lp(a) concentrations and CAD risk was observed only for men, indicating that elevated Lp(a) may be an independent predictor of CAD risk in men [31]. This finding was also confirmed by others [32]. These differences between sexes may be due to the relatively low number of women who developed CAD, suggesting an issue of study power rather a true difference in predictive value. Nevertheless, data from the Women’s Health Study (prospective study, 27,791 apparently healthy women, mean age 54.2 years), showed that women with Lp(a) concentrations ≥ 44 mg/dl were 1.5 times (95% CI 1.21-1.79) more likely to develop CVD events compared with those having Lp(a) ≤ 3.4 mg/dl. This association was independent of traditional CVD risk factors [age, race, diabetes mellitus (DM), blood pressure, total cholesterol, HDL-C], but was stronger in those with LDL-C > 121 mg/dl [33]. Apo(a) isoform size does not seem to contribute to the association between Lp(a) and CVD risk. Methods used for Lp(a) assessment (either turbidimetric or enzyme-linked immunosorbent assays) are independent of apo(a) isoform size, since they utilize capturing (monoclonal) antibodies that do not recognize the kringle-42 domain of apo(a) [31, 33].

Most studies show that Lp(a) concentrations are not affected by age [18, 21], whereas others have found that they increase with age, more markedly in women than men, especially after 50 years of age [34]. Lp(a) follows the distribution of TC concentrations [33], Older studies, such as the Framingham study, did not find association with TC or LDL-C, whereas one study found an inverse association between Lp(a) and TG concentrations in both sexes [18]. Body mass index (BMI), alcohol and smoking do not affect Lp(a) concentrations [18]. Conflicting data exist with regard to the effect of DM on Lp(a) concentrations [21, 31].

Current evidence supports the notion that Lp(a) is a potential independent risk factor for CVD (mainly for myocardial infarction and stroke) in both sexes, is not correlated with traditional CVD risk factors, and should be assessed in patients at high CVD risk, such as those with familial hypercholesterolaemia (FH), as proposed by international societies.

4. Menopause and Lp(a): is there a link?

Most studies have shown that transition to menopause is associated with a more atherogenic lipid profile, which apart from increased TC, LDL-C, apoB and TG, and perhaps low HDL2-C [3, 4] also involves an increase in Lp(a) concentrations [34-36]. This contributes to a potentially higher atherosclerotic risk in post- compared with premenopausal women, independently of other risk factors [18, 21, 34]. Interestingly, in cases of surgical menopause, a significant increase in Lp(a) concentrations is already noticed three months after oophorectomy [36]. However, few studies have directly compared Lp(a) concentrations between pre- and post-menopausal women [13-19]. In the majority of them, postmenopausal women had higher Lp(a) compared with premenopausal [13-17], as well as, with perimenopausal women [13-15]. An increase in Lp(a) concentrations during menopausal transition has also been suggested [13]. In this study, perimenopausal women with 3-6 months of amenorrhoea had higher Lp(a) concentrations than perimenopausal women with menstrual bleeding [13]. Lp(a) concentrations tend to be even higher in postmenopausal women with hypercholesterolaemia compared with pre- or postmenopausal women with normal LDL-C concentrations, indicating the importance of Lp(a) assessment in the former group [16]. In one study, the strongest independent predictor of Lp(a) concentrations was menopausal status in females and waist-to-hip ratio in males [37]. However, it must be emphasized that data for higher Lp(a) concentrations in postmenopausal women than in pre-menopausal women should be appraised with caution, because they derive mainly from studies with a small sample size.

Nevertheless, there are also some comparative studies, which did not show any significant differences in Lp(a) concentrations between pre- and postmenopausal women, despite the fact that postmenopausal had slightly (8%) higher Lp(a) concentrations than pre-menopausal women [18]. In a more recent study in patients with DM, there was no difference between pre- and postmenopausal women with regard to Lp(a) concentrations [19]. In particular, the OR of having serum Lp(a) concentrations > 35 mg/dl was 5.85 in premenopausal and 5.08 in postmenopausal women with DM compared with women without DM, after adjustment for age and BMI [19].

Nonetheless, what is actually more important is whether Lp(a) exerts an independent role in augmenting CVD risk in women after transition to menopause. In a large study, including 2,763 postmenopausal women with CAD aged below 80 years, the HR for those in the second (7.1 - 25.3 mg/dl), third (25.4 - 54.9 mg/dl) and fourth (55 - 236 mg/dl) quartiles of baseline Lp(a) concentrations were 1.01, 1.31 and 1.54 respectively compared with the first quartile (< 7 mg/dl) after multivariate adjustment, illustrating that Lp(a) is an independent risk factor for recurrent CAD in postmenopausal women [38]. In another study, postmenopausal women with angiographically proven CAD had higher Lp(a) concentrations compared with those without vessel-obstruction; in particular, they were two-fold higher in patients with one-vessel obstruction and three-fold higher in the multi-vessel group [39]. However, another study failed to show any association between Lp(a) concentrations and coronary calcium deposits in asymptomatic postmenopausal women [40]. It must be stated that none of these studies included a premenopausal group for comparison.

To summarize, available data show that Lp(a) concentrations might slightly be increased during transition to menopause, although evidence is not robust. Direct comparisons between pre- and postmenopausal women with respect to the effect of Lp(a) in increasing CVD risk are lacking.

5. Therapeutic strategies

Although Lp(a) concentrations are largely genetically determined [i.e. apo(a) isoforms] and lifestyle intervention has no impact on them [24] [controversial studies exist with respect to the effect of exercise on Lp(a)] [41, 42], there are several therapeutic interventions that may decrease them in postmenopausal women, such as hormone replacement therapy (HRT) and tibolone. There are two limitations regarding existing evidence on Lp(a) reduction strategies in postmenopausal women. First, it must be emphasized that data from studies conducted exclusively in postmenopausal women are only available for HRT and tibolone. Data for established and upcoming lipid-lowering agents regarding Lp(a) come from the general population, especially high CVD risk patients. Second, despite the importance of Lp(a) in atherosclerosis and CVD, there is currently no lipid-lowering agent with a proven reduction in CVD risk via a significant reduction in Lp(a) concentrations (Table 1).

5.1. Hormone therapy (HRT)

There is an increasing body of evidence supporting a reduction in Lp(a) concentrations with HRT, ranging between 19.9% and 44% [15, 38, 43-46]. Most of these studies used conjugated equine estrogens (CEE) with medroxyprogesterone (MPA) or dydrogesterone. Patients with high baseline Lp(a) concentrations seem to benefit more compared with those with lower ones [38, 43]. However, some studies did not show any effect of HRT, in particular transdermal estradiol combined with MPA, on Lp(a) concentrations [15, 45]. The superiority of oral over transdermal estrogen on Lp(a) reduction has also been shown in previous comparative studies [15]. A previous meta-analysis (including HRT studies published from 1974 to 2000) showed that the type of estrogen and route of administration affects the magnitude of Lp(a) reduction, being greatest with oral CEE and lesser with transdermal estrogens. In particular, CEE is associated with a reduction of 23.9% (0.625 mg/day) or 24.3% (1.25 mg/day), 2 mg/d of 17β-estradiol by 12.9% and transdermal 17β-estradiol by 6% [47]. The addition of a progestogen seems to augment these reductions (the greatest effect was seen with norethindrone) [47] or has no effect [46]. A more recent meta-analysis showed a mean reduction of 25% (95% CI 17.1-32.9) in Lp(a) concentrations with HRT, with oral agents producing more beneficial results [48]. The reduction in Lp(a) concentrations with HRT seems to be dependent on the estrogen dose, since conventional therapy (2 mg/day of 17β-estradiol) induces greater reductions compared with low-dose (1 mg/d of 17β-estradiol) [46, 49]. An explanation of the effect of HRT on Lp(a) concentrations seems to be the inhibitory effect of estrogen on the apo(a) gene expression [50]. Indeed, kinetic studies have shown a decrease in production rate of apo(a), with no effect on its catabolic rate, after estrogen therapy [51].

In general, a reduction in CAD events attributed to an HRT-associated decrease in Lp(a) concentrations has not been yet demonstrated. Data from the Heart and Estrogen/progestin Replacement Study (HERS), a randomized placebo-controlled trial of secondary prevention including 2,763 postmenopausal women (mean age 66.7 years), showed that HRT (CEE 0.625 mg plus MPA 2.5 mg/day) led to a significant reduction in Lp(a) concentrations by 15 ± 5 mg/dl [38]. Compared with the lowest quartile of Lp(a) concentrations (< 7 mg/dl), women with the highest quartile (> 55 mg/dl) had a 54% increased risk of primary CAD events. The reduction in Lp(a) concentrations was associated with a decreased risk for myocardial infarction (HR 0.46, 95% CI 0.25-0.85), although not for CAD death. Interestingly, subgroup analysis showed that baseline Lp(a) concentrations modified the effect of HRT on CAD risk. In particular, those with Lp(a) at the highest quartile benefited more compared with those at the lowest [HR 0.78 (95% CI 0.52 - 1.18) and 1.49 (95% CI 0.97 - 2.26) respectively] [38]. In this context, HRT may also improve endothelial function and this improvement seems to be partially mediated through the reduction in Lp(a) concentrations [52]. However, it must be underlined that, in the HERS study, only women not on HRT showed an increase in CAD risk with increasing Lp(a) concentrations [38]. This was also confirmed by another study, in which the HR for future CVD in the highest Lp(a) quintile compared with the lowest was 1.8 only in women not on HRT (without any difference in those on HRT), after adjustment for common CVD risk factors [53].

To summarize, current evidence shows a significant, but heterogeneous Lp(a) lowering effect of HRT. Baseline Lp(a) concentrations, estrogen dose, type and route of administration seem to affect Lp(a) reduction, being higher with higher baseline levels (leading perhaps to a greater benefit on CVD risk reduction), with conventional dose and with oral estrogen (greatest with CEE). However, data showing a reduction in CVD events by HRT through reduction in Lp(a) concentrations are lacking.

5.2. Tibolone

Tibolone is a synthetic steroid used for the relief of postmenopausal symptomatology and is characterized by estrogenic, progestogenic and androgenic properties [54]. Its effect on lipid metabolism is consistent with significant reductions in TG and HDL-C concentrations (22% and 25%, respectively) and to a lesser extent reduction in TC (7.4%) [47]. Regarding Lp(a), most studies have showed a significant decrease in its plasma concentrations by tibolone, ranging from to 26% to 48% [44, 55, 56]. The meta-analysis mentioned above showed an overall reduction of 39.2% [47]. A more recent meta-analysis focusing on tibolone and Lp(a), including data from 12 randomized-controlled trials, showed that tibolone treatment was consistent with a significant reduction in Lp(a) concentrations in postmenopausal women irrespective of the dose or duration of treatment (mean reduction: 25.28%, 95% CI 36.50-14.06). In detail, tibolone at the usual dose of 2.5 mg/day was associated with a 29% mean reduction in Lp(a) concentrations, whereas the respective mean reduction with doses of < 2.5 mg/day was 17%. Regarding the duration, treatment of ≥ 24 months or < 24 months led to comparable decreases in Lp(a) concentrations (26.8% and 23.1%, respectively) [57]. Others have shown a much lower (-5%) [58] or no reduction [59, 60] in Lp(a) plasma concentrations with tibolone therapy. The reduction may be seen by the second week of treatment [49]. The observed differences in Lp(a) reduction may be attributed to the different baseline Lp(a) concentrations and to the fact that most of these studies were not randomized.

In general, tibolone seems to induce a greater reduction in Lp(a) in comparison with HRT when transdermal estrogen (50 μg/d) is used [45, 61] and similar [58] or greater reduction when oral estrogen is used (0.625 mg/d of CEE or 2 mg of 17β-estradiol) [44, 45, 61]. The exact mechanisms for tibolone-induced reductions in Lp(a) have not been clarified. It can be speculated that tibolone acts via the estrogen response element of the Lp(a) gene, reducing the hepatic output of apo(a) [62]. A direct role via its androgenic properties (independently of its estrogenic effect) can also be proposed, since experimental studies have shown that testosterone also decreases apo(a) gene expression [63].

Tibolone causes a significant reduction in Lp(a) concentrations in postmenopausal women regardless of the dose or duration of treatment, although its detrimental effect on HDL-C should also be taken into account. No data exist with regard to CVD risk reduction with tibolone.

5.3. Niacin

Niacin, administered either as monotherapy or as add-on therapy to statins, can cause decreases in Lp(a) concentrations of 7 - 40% (20 - 26% on average), in a dose-dependent manner (1 - 3 g/day), in addition to its other effect on lipid parameters, mainly on HDL-C and TG [23, 64-68]. The magnitude of Lp(a) reduction seems to depend on its baseline levels, being greater with higher concentrations [68]. A reduction of even 88% in a case of markedly elevated Lp(a) has even been reported [69]. Apo(a) phenotype seems to determine the response to niacin (being higher in cases of low-molecular weight phenotype) [64], although others did not show that apo(a) genotype affects niacin’s Lp(a) lowering effect [67]. No differences between sexes regarding the effect of niacin on Lp(a) have been reported. The exact mechanism of Lp(a) reduction by niacin is not known. Inhibition of free fatty acid mobilization from adipose tissues, which attenuates hepatic synthesis of apoB, degradation of apoB-containing lipoproteins and inhibition of diacylglycerol acyltransferase-2, a key enzyme for TG synthesis, constitute some of the potential mechanisms of Lp(a) reduction by niacin [70]. Studies on apo(a) kinetics have shown both a decrease in apo(a) production and catabolic rates [71, 72].

A meta-analysis of randomized controlled trials [73] showed that niacin treatment is associated with a significant reduction in major coronary events (relative odds reduction: 25%, 95% CI 13-35), stroke (26%, 95% CI 8-41) and any cardiovascular events (27%, 95% CI 15-37). It should be noted that this meta-analysis included studies of secondary prevention, which were conducted before statin therapy became the standard care. Based on the results of the aforementioned meta-analysis, the EAS expert panel recommends niacin at doses of 1-3 g/day as the preferable therapy in patients with elevated Lp(a) concentrations [23]. The AACE guidelines also recommend it as first-line therapy in patients with elevated Lp(a), but they admit that the clinical benefit of this strategy has not been proven yet [25].

Nevertheless, two hallmark studies were published recently, the Atherosclerosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) [74] and the Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) studies [75], which failed to demonstrate any significant clinical benefit with the addition of niacin (1-2 g/day) to LDL-C lowering therapy. Both of them included high CVD risk patients, who had already achieved the LDL-C target of < 70 mg/dl with optimal statin dose, but had low HDL-C concentrations. In addition, the adverse effects associated with niacin use, such as skin, gastrointestinal and musculoskeletal ones, as well as, DM, are quite common and lead patients to suspend therapy. Niacin, as an extended-release form is co-administered with laropriprant, a selective prostaglandin D2 receptor antagonist, in order to reduce skin reactions (i.e. flushing) [75]. Despite the null-effect on the reduction of CVD risk, niacin led to a decrease in Lp(a) concentrations by 21% in the AIM-HIGH study [76]. There are no reported data regarding this parameter in the HPS2-THRIVE study. It must be underlined that after the publication of the AIM-HIGH and HPS2-THRIVE studies, the European Medicine Agency (EMA) has withdrawn niacin from the market [77].

Based on the available evidence, niacin may significantly reduce Lp(a) concentrations in postmenopausal women, although data come from studies in the general population and its clinical benefit with respect to CVD risk reduction has yet to be proven.

5.4. Statins

In general, statins have minimal or no lowering effect on Lp(a) concentrations [78-80]. This seems to be dose-dependent, since in one study in patients with FH, atorvastatin 10 mg caused a 6% reduction in Lp(a) concentrations [78], whereas, in another study, a 22% reduction was observed with atorvastatin 80 mg and 18.8% with simvastatin 40 mg [79]. Data from the Scandinavian Simvastatin Survival Study (4S), a double-blind, randomized placebo-controlled trial, which compared the effect of simvastatin therapy on mortality and morbidity in patients with CAD, showed that baseline Lp(a) concentrations predicted survival and major coronary events. In particular, the reduction in deaths was more pronounced in patients with Lp(a) concentrations at the highest compared with the lowest quartile [81]. Experts in the field of dyslipidaemias recommend reduction of LDL-C to the lowest attainable value with statins, in patients with Lp(a) >30 mg/dl and high CVD risk and, in cases with inadequate response, niacin or LDL-apheresis is suggested [82].

Furthermore, analysis of data from the AIM-HIGH study also showed that Lp(a) concentrations predicted CVD events in patients both on simvastatin and on simvastatin plus niacin combination therapy [66]. Post-hoc analysis of the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which evaluated the effect of rosuvastatin therapy in asymptomatic individuals with LDL-C < 130 mg/dl but with high-sensitivity C-reactive protein (hsCRP) concentrations ≥ 2 mg/l, showed similar results with AIM-HIGH regarding Lp(a). In particular, despite the null effect of rosuvastatin on Lp(a), both baseline and on-statin Lp(a) concentrations determined residual CVD risk irrespective of LDL-C. The adjusted HR for incident CVD was 1.18 (95% CI 1.03-1.34) per 1 standard deviation (SD) increment in natural logarithm of Lp(a) concentrations (corresponding to 2.5-fold increment). However, the magnitude CVD risk reduction was comparable in participants with both high or low Lp(a) concentrations. In this study, females, comprised the 33% of the cohort (mean age 66 years) and had higher baseline Lp(a) concentrations than males [29].

Therefore, it can be concluded that, although statins do not exert any considerable effect on Lp(a) concentrations, they may decrease Lp(a)-associated CVD risk especially in high risk population. In other words, Lp(a) assessment may help identifying high-risk individuals, such as those with FH, who could benefit from aggressive therapy. This may also be extended to postmenopausal women. However, it must be noted that others did not confirm the contribution of Lp(a) in the regression of atherosclerosis in statin-treated patients with FH [79, 83].

5.5. Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors

PCSK-9 is an enzyme which plays a significant role in lipid metabolism as it reduces hepatic LDL-C uptake by enhancing endosomal and lysosomal degradation of the LDL receptor. Early studies have shown that loss-of-function genotypes are characterized by low LDL-C concentrations and low incidence of CAD, whereas gain-of-function mutations in PCSK9 lead to a high LDL-C level and premature atherosclerosis [84]. Two human monoclonal antibodies to PCSK-9, alirocumab and evolocumab, have been developed for reducing LDL-C in patients insufficiently managed by, or intolerant to, current therapies. Data from phase II and III randomized studies show that these agents cause marked reduction in LDL-C concentrations (mean reduction compared with placebo: 62%) [85, 86]. There was a significant reduction in the rate of major CVD events (death from CAD, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke or unstable angina) by 47 - 48%, at 78 weeks of therapy [85, 86]. These agents were generally well-tolerated, with their adverse effects limited to minor skin reactions [85, 86].

Apart from their considerable effect on LDL-C concentrations, current data also support a reduction in Lp(a) with these agents. In a more detailed way, alirocumab administered subcutaneously every two weeks at the dose of 150 mg induced a 30% reduction in Lp(a) concentrations in patients with hypercholesterolaemia inadequately controlled with conventional lipid-lowering therapy. Patients with higher baseline concentrations demonstrated greater absolute reductions. Mean age of the participants was 58 ± 10 years, 54% of which were women. There was a weak correlation between reductions in Lp(a) and the magnitude of LDL-C reduction (Spearman r = 0.22) [87]. On the other hand, evolocumab, the other PCSK-9 inhibitor, can cause a dose-related reduction in Lp(a) concentrations when administered to high CVD risk patients inadequately controlled with statins or to statin intolerant patients. In particular, analysis of data from 1,359 patients in four phase II trials showed the mean percentage in Lp(a) concentration reduction with 70, 105 and 140 mg every two weeks was 13.8%, 25.2% and 29.5%, respectively. The respective percentages with 4-weekly doses of 280 mg, 350 mg and 420 mg were 18.7%, 21.3% and 24.5% [88].

Although these studies were not confined to postmenopausal women, evidence shows that Lp(a) reductions are independent of age and sex. Moreover, concomitant use of statins is associated with greater reductions [88]. Notably, a recent study has shown that PCSK-9 concentrations are higher in postmenopausal than premenopausal women, irrespectively of the estrogen status [89]. However, it is not known if the upcoming reduction in CVD risk by PCSK-9 inhibitors may be partly and independently attributed to their Lp(a) lowering effect. Both PCSK-9 inhibitors have been approved by the FDA [90, 91] and the EMA [92, 93] for lowering LDL-C in subjects with homozygous or heterozygous FH or in high-risk secondary-prevention patients, who are inadequately treated with statins.

6. Promising therapies

6.1. Mipomersen

Mipomersen is an antisense oligonucleotide, which can decrease apoB synthesis by inhibition of messenger ribonucleic acid (mRNA) translation [94]. In clinical phase III trials in high CVD risk patients, mainly those with homozygous or severe heterozygous FH inadequately controlled with other agents, mipomersen weekly administered at a dose of 200 mg has been associated with a mean reduction in Lp(a) concentrations by 26.4%, along with its beneficial effect on the other lipid parameters (mean reduction in LDL-C by 33.1%, non-HDL-C by 31.7% and apoB by 33.3%) [94, 95]. The mean change in Lp(a) concentrations is modestly correlated with apoB (r = 0.43; p < 0.001) and LDL-C (r = 0.36; p < 0.001), respectively. [95]. However, mipomersen has been associated with increased risk of adverse effects such as injection-site reactions, flu-like symptoms and alanine aminotransferase elevations (the percentage of patients with more than three-fold the upper limit of normal was 10-15% in phase II and III trials, with an OR of 11.21) [94, 96]. In one study, the distribution of patients according to sex was almost equal and their age was 55-60 years. Thus, data can also be applied to postmenopausal women [96].

6.2. Lomitapide

Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor. MTP, which is found in the endoplasmic reticulum of hepatocytes and enterocytes, regulates the formation of the apoB-containing lipoproteins both in the liver and the intestine [97]. Its efficacy in reducing LDL-C has been mainly tested in patients with homozygous FH. At a median dose of 40 (5-60) mg/day, lomitapide can cause reductions in LDL-C concentrations up to 50%. Aminotransferase elevation (more than three-fold the upper limit of normal has been reported in 34%) and liver steatosis are the most common side effects, which may limit its use [98]. With respect to Lp(a), lomitapide can cause reductions of 17-19% both in patients with homozygous FH [98] and at high CVD risk [99], although this effect in the former study was seen at 26-56 weeks of therapy, but was not sustained at 78 weeks of therapy [98]. The age of the participants in the latter study was 55-57 years, with an equal distribution between sexes [99].

6.3. Cholesterol-ester-transfer protein (CETP)-inhibitors

These agents were first developed to increase HDL-C, but they can also decrease very-low density lipoprotein cholesterol (VLDL-C) and LDL-C concentrations [100]. The first CETP-inhibitor tested in clinical trials in patients at high CVD risk was torcetrapib, which resulted in an increased risk of CVD events and mortality of any cause [101], whereas dalcetrapib in the same population did not have any effect on CVD events, despite the marked increase in HDL-C [102]. New CETP-inhibitors, anacetrapib and evacetrapib have been developed which can increase HDL-C concentrations by 129-151% and decrease LDL-C by 36-41% and Lp(a) by 17%. Their efficacy on CVD risk reduction has not yet been proven [100]. Recently, the responsible company for evacetrapib announced the discontinuation of the drug, due to “insufficient efficacy” [103]. The main mechanism of Lp(a) reduction by these agents may be the decreased flux of cholesterol from HDL-C into apoB-containing lipoproteins [100]. Another mechanism may be the decreased hepatic PCSK9 expression and increased LDL receptor protein content [104].

6.4. Eprotirome

Eprotirome is a liver-selective thyroid hormone receptor agonist, which, after binding to the triiodothyronine receptor β isoform, mimics the lipid-lowering effect of thyroid hormones causing an up-regulation of the LDL receptors. Eprotirome has been tested in short-term clinical trials in patients with FH either as monotherapy or as add-on therapy to statins. In these trials, eprotirome reduced LDL-C by 12%, 23% and 32% at a dose of 50, 100 or 200 μg/day, with similar reductions in non-HDL-C and apoB [105, 106]. The achieved reduction in Lp(a) concentrations was 27-43% (with 25-100 μg/day), being greater with higher baseline levels. A dose-dependent increase in sex-hormone binding globulin and mild and reversible increases in serum alanine aminotransferase concentrations are the most common adverse effects (increase more than three times the upper limit of normal are rare: 2% to 8.6%) [105, 106].

To summarize, modest reductions in Lp(a) concentrations can be achieved by the aforementioned novel therapies, although studies are of small sample size. No study with these promising agents has been yet conducted in postmenopausal women. Moreover, the clinical benefit with regard to CVD risk reduction has not been shown at the moment.

6.5. Lp(a) apheresis

In cases of high Lp(a) inadequately controlled with available therapeutic options and high CVD risk, Lp(a) apheresis is a quite effective method, which seems also to reduce CVD events [107, 108]. In general, lipoprotein apheresis is recommended for patients with homozygous FH and heterozygous FH with CVD refractory to lipid-lowering drug therapy or statin-intolerant FH patients [109]. Weekly or bi-weekly lipoprotein apheresis selectively removes apoB-containing lipoproteins (sparing HDL-C) and can achieve LDL-C and Lp(a) reductions of 50-75% [107].

7. Conclusions

Lp(a), which has been considered as an independent risk factor for CVD in the general population, may also play a role in the increased CVD risk that transition to menopause is associated with. Of the available medications, only HRT and tibolone have been studied exclusively in postmenopausal women and may significantly reduce plasma Lp(a) concentrations. Data from lipid lowering agents, such as niacin and statins, emerge from studies in the general population. Among the medications approved for the reduction of CVD risk, statins have no or very modest effects on Lp(a) and only the newly approved PSCK9 inhibitors may be effective in reducing Lp(a) concentrations. Promising Lp(a)-lowering therapies, such as mipomersen, lomitapide, CETP inhibitors and eprotirome, may be useful, especially in cases of FH. It must be emphasized that there are no studies to date that clearly prove that lowering Lp(a) concentrations is translated into a reduction in CVD risk. Thus, a general recommendation for measuring Lp(a) concentrations in all postmenopausal women cannot be justified by current data. However, it is prudent to include Lp(a) when assessing CVD risk in cases of FH and/or high CVD risk, according to the international guidelines.

References

1. Colditz GA, Willett WC, Stampfer MJ, et al. Menopause and the risk of coronary heart disease in women. N Engl J Med 1987; 316: 1105-1110.

2. Kannel WB, Hjortland MC, McNamara PM, et al. Menopause and risk of cardiovascular disease: the Framingham study. Ann Intern Med 1976; 85: 447-452.

3. Schaefer EJ, Lamon-Fava S, Cohn SD, et al. Effects of age, sex, and menopausal status on plasma low density lipoprotein cholesterol and apolipoprotein B levels in the Framingham Offspring Study. J Lipid Res 1994; 35: 779-792.

4. Anagnostis P, Stevenson JC, Crook D, et al. Effects of menopause, sex and age on lipids and high-density lipoprotein cholesterol subfractions. Maturitas. 2015;81:62-68.

5. Park JK, Lim YH, Kim KS, et al. Body fat distribution after menopause and cardiovascular disease risk factors: Korean National Health and Nutrition Examination Survey 2010. J Womens Health (Larchmt) 2013; 22: 587-594.

6. Løkkegaard E, Jovanovic Z, Heitmann BL, et al. The association between early menopause and risk of ischaemic heart disease: influence of Hormone Therapy. Maturitas 2006; 53: 226-233.

7. Emerging Risk Factors Collaboration, Erqou S, Kaptoge S, Perry PL, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009; 302: 412-423.

8. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies. Circulation 2000; 102:1082-5.

9. Maranhão RC, Carvalho PO, Strunz CC, Pileggi F. Lipoprotein (a): Structure, Pathophysiology and Clinical Implications. Arq Bras Cardiol 2014; 103:76-84.

10. Yazici M, Demircan S, Durna K, Sahin M. Lipoprotein(a) levels in patients with unstable angina and their relationship with atherothrombosis and myocardial damage. Int J Clin Pract 2005; 59: 150-155.

11. McLean JW, Tomlinson JE, Kuang WJ, et al. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature 1987; 330: 132-137.

12. Cai A, Li L, Zhang Y, Mo Y, Mai W, Zhou Y. Lipoprotein(a): a promising marker for residual cardiovascular risk assessment. Dis Markers 2013; 35: 551-559.

13. Kim CJ, Kim TH, Ryu WS, Ryoo UH. Influence of menopause on high density lipoprotein-cholesterol and lipids. J Korean Med Sci 2000; 15: 380-386.

14. Berg G, Mesch V, Boero L, et al. Lipid and lipoprotein profile in menopausal transition. Effects of hormones, age and fat distribution. Horm Metab Res 2004; 36: 215-220.

15. Ushioda M, Makita K, Takamatsu K, Horiguchi F, Aoki D. Serum lipoprotein(a) dynamics before/after menopause and long-term effects of hormone replacement therapy on lipoprotein(a) levels in middle-aged and older Japanese women. Horm Metab Res 2006; 38: 581-6.

16. Sanada M, Higashi Y, Nakagawa K, et al. Comparison of forearm endothelial function between premenopausal and postmenopausal women with or without hypercholesterolemia. Maturitas 2003; 44: 307-15.

17. Abbey M, Owen A, Suzakawa M, Roach P, Nestel PJ. Effects of menopause and hormone replacement therapy on plasma lipids, lipoproteins and LDL-receptor activity. Maturitas 1999; 33: 259-69.

18. Jenner JL, Ordovas JM, Lamon-Fava S, et al. Effects of age, sex, and menopausal status on plasma lipoprotein(a) levels. The Framingham Offspring Study. Circulation 1993; 87: 1135-41.

19. Nakhjavani M, Morteza A, Esteghamati A, et al. Serum lipoprotein(a) levels are greater in female than male patients with type-2 diabetes. Lipids 2011; 46: 349-56.

20. Bennet A, Di AE, Erqou S, et al. Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data. Arch Intern Med 2008; 168: 598-608.

21. Tselmin S, Julius U, Müller G, Fischer S, Bornstein SR. Cardiovascular events in patients with increased lipoprotein (a) - retrospective data analysis in an outpatient department of lipid disorders. Atheroscler Suppl 2009; 10: 79-84.

22. Nave AH, Lange KS, Leonards CO, et al. Lipoprotein (a) as a risk factor for ischemic stroke: A meta-analysis. Atherosclerosis 2015; 242: 496-503

23. Nordestgaard BG, Chapman MJ, Ray K, Borén J, Andreotti F, Watts GF, et al; European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010; 31: 2844-2853.

24. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS)Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, et al; Eur Heart J 2016 Aug 27. pii: ehw272. [Epub ahead of print]

25. Jellinger PS, Smith DA, Mehta AE, Ganda O, Handelsman Y, Rodbard HW, et al; AACE Task Force for Management of Dyslipidemia and Prevention of Atherosclerosis. American Association of Clinical Endocrinologists' Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis. Endocr Pract 2012; 18 Suppl 1:1-78.

26. Gidding SS, Watts GF, Chapman MJ, et al; European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J 2015; 36: 2425-2437.

27. Marcovina SM, Albers JJ, Jacobs DR Jr, et al. Lipoprotein[a] concentrations and apolipoprotein[a] phenotypes in Caucasians and African Americans. The CARDIA study. Arterioscler Thromb 1993; 13: 1037-1045.

28. Deo RC, Wilson JG, Xing C, et al. Single-nucleotide polymorphisms in LPA explain most of the ancestry-specific variation in Lp(a) levels in African Americans. PLoS One 2011; 6: e14581.

29. Khera AV, Everett BM, Caulfield MP, et al. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). Circulation 2014; 129: 635-642.

30. Guan W, Cao J, Steffen BT, et al. Race is a key variable in assigning lipoprotein(a) cutoff values for coronary heart disease risk assessment: the Multi-Ethnic Study of Atherosclerosis. Arterioscler Thromb Vasc Biol 2015; 35: 996-1001.

31. Lamon-Fava S, Marcovina SM, Albers JJ, et al. Lipoprotein(a) levels, apo(a) isoform size, and coronary heart disease risk in the Framingham Offspring Study. J Lipid Res 2011; 52:1181-7.

32. Wild SH, Fortmann SP, Marcovina SM. A prospective case-control study of lipoprotein(a) levels and apo(a) size and risk of coronary heart disease in Stanford Five-City Project participants. Arterioscler Thromb Vasc Biol 1997; 17:239-45.

33. Suk Danik J, Rifai N, Buring JE, et al. Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women. JAMA 2006; 296: 1363-1370.

34. Yamamoto A, Horibe H, Mabuchi H, et al. Analysis of serum lipid levels in Japanese men and women according to body mass index. Increase in risk of atherosclerosis in postmenopausal women. Research Group on Serum Lipid Survey 1990 in Japan. Atherosclerosis 1999; 143: 55-73.

35. Li Z, McNamara JR, Fruchart JC, et al. Effects of sex and menopausal status on plasma lipoprotein subspecies and particle sizes. J Lipid Res 1996; 37: 1886-1896.

36. Bruschi F, Meschia M, Soma M, et al. Lipoprotein(a) and other lipids after oophorectomy and estrogen replacement therapy. Obstet Gynecol 1996; 88: 950-954.

37. Slunga L, Asplund K, Johnson O, Dahlén GH. Lipoprotein (a) in a randomly selected 25-64 year old population: the Northern Sweden Monica Study. J Clin Epidemiol 1993; 46: 617-624.

38. Shlipak MG, Simon JA, Vittinghoff E, et al. Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause. JAMA 2000; 283: 1845-1852.

39. Sposito AC, Mansur AP, Maranhão RC, et al. Triglyceride and lipoprotein (a) are markers of coronary artery disease severity among postmenopausal women. Maturitas 2001; 39: 203-208.

40. Nishino M, Malloy MJ, Naya-Vigne J, et al. Lack of association of lipoprotein(a) levels with coronary calcium deposits in asymptomatic postmenopausal women. J Am Coll Cardiol 2000; 35: 314-20.

41. Lobo RA, Notelovitz M, Bernstein L, et al. Lp(a) lipoprotein: relationship to cardiovascular disease risk factors, exercise, and estrogen.

Am J Obstet Gynecol 1992; 166:1182-90.

42. Hamasaki H, Kawashima Y, Tamada Y, et al. Correction: Associations of Low-Intensity Resistance Training with Body Composition and Lipid Profile in Obese Patients with Type 2 Diabetes. PLoS One 2015; 10: e0137154.

43. Bayrak A, Aldemir DA, Bayrak T, et al. The effect of hormone replacement therapy on the levels of serum lipids, apolipoprotein AI, apolipoprotein B and lipoprotein (a) in Turkish postmenopausal women. Arch Gynecol Obstet 2006; 274: 289-329.

44. Christodoulakos GE, Lambrinoudaki IV, Panoulis CP, et al. Effect of hormone replacement therapy, tibolone and raloxifene on serum lipids, apolipoprotein A1, apolipoprotein B and lipoprotein(a) in Greek postmenopausal women. Gynecol Endocrinol 2004; 18: 244-57.

45. Perrone G, Capri O, Galoppi P, et al. Effects of either tibolone or continuous combined transdermal estradiol with medroxyprogesterone acetate on coagulatory factors and lipoprotein(a) in menopause. Gynecol Obstet Invest 2009; 68: 33-39.

46. Stevenson JC, Rioux JE, Komer L, et al. 1 and 2 mg 17β-estradiol combined with sequential dydrogesterone have similar effects on the serum lipid profile of postmenopausal women. Climacteric 2005; 8: 352-359.

47. Godsland IF. Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a) concentrations: analysis of studies published from 1974-2000. Fertil Steril 2001; 75: 898-915.

48. Salpeter SR, Walsh JM, Ormiston TM, et al. Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes Metab 2006; 8: 538-554.

49. Eilertsen AL, Sandvik L, Steinsvik B, Sandset PM. Differential impact of conventional-dose and low-dose postmenopausal hormone therapy, tibolone and raloxifene on C-reactive protein and other inflammatory markers. J Thromb Haemost 2008; 6: 928-934.

50. Boffelli D, Zajchowski DA, Yang Z, et al. Estrogen modulation of apolipoprotein(a) expression. Identification of a regulatory element. J Biol Chem 1999; 274: 15569-15574.

51. Su W, Campos H, Judge H, et al. Metabolism of Apo(a) and ApoB100 of lipoprotein(a) in women: effect of postmenopausal estrogen replacement. J Clin Endocrinol Metab 1998; 83: 3267-76.

52. Ossewaarde ME, Bots ML, van der Schouw YT, et al. Does the beneficial effect of HRT on endothelial function depend on lipid changes. Maturitas 2003; 45: 47-54.

53. Suk Danik J, Rifai N, Buring JE, et al. Lipoprotein(a), hormone replacement therapy, and risk of future cardiovascular events. J Am Coll Cardiol 2008; 52: 124-131.

54. Modelska K, Cummings S. Tibolone for postmenopausal women: systematic review of randomized trials. J Clin Endocrinol Metab 2002; 87:16-23.

55. Rymer J, Crook D, Sidhu M, et al. Effects of tibolone on serum concentrations of lipoprotein(a) in postmenopausal women. Acta Endocrinol (Copenh) 1993; 128: 259-62.

56. Haenggi W, Riesen W, Birkhaeuser MH. Postmenopausal hormone replacement therapy with Tibolone decreases serum lipoprotein(a). Eur J Clin Chem Clin Biochem 1993; 31: 645-650.

57. Kotani K, Sahebkar A, Serban C, et al; Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. Tibolone decreases Lipoprotein(a) levels in postmenopausal women: A systematic review and meta-analysis of 12 studies with 1009 patients. Atherosclerosis 2015; 242: 87-96.

58. Dören M, Rübig A, Coelingh Bennink HJ, et al. Resistance of pelvic arteries and plasma lipids in postmenopausal women: comparative study of tibolone and continuous combined estradiol and norethindrone acetate replacement therapy. Am J Obstet Gynecol 2000; 183: 575-582.

59. Lloyd G, McGing E, Cooper A, et al. A randomised placebo controlled trial of the effects of tibolone on blood pressure and lipids in hypertensive women. J Hum Hypertens 2000; 14: 99-104.

60. Bjarnason NH, Bjarnason K, Haarbo J, et al. Tibolone: influence on markers of cardiovascular disease. J Clin Endocrinol Metab 1997; 82: 1752-1756.

61. Hänggi W, Lippuner K, Riesen W, Jaeger P, Birkhäuser MH. Long-term influence of different postmenopausal hormone replacement regimens on serum lipids and lipoprotein(a): a randomised study. Br J Obstet Gynaecol 1997; 104: 708-717.

62. Hoover-Plow J, Huang M. Lipoprotein(a) metabolism: potential sites for therapeutic targets. Metabolism 2013; 62: 479-491.

63. Frazer KA, Narla G, Zhang JL, et al. The apolipoprotein(a) gene is regulated by sex hormones and acute-phase inducers in YAC transgenic mice. Nature Genetics 1995; 9: 424-431.

64. Artemeva NV, Safarova MS, Ezhov MV, et al. Lowering of lipoprotein(a) level under niacin treatment is dependent on apolipoprotein(a) phenotype. Atheroscler Suppl 2015; 18: 53-58.

65. Kei A, Liberopoulos E, Tellis K, et al. Effect of hypolipidemic treatment on emerging risk factors in mixed dyslipidemia: a randomized pilot trial. Eur J Clin Invest 2013; 43: 698-707.

66. Albers JJ, Slee A, O'Brien KD, et al. Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes). J Am Coll Cardiol 2013; 62: 1575-1579.

67. Cenarro A, Puzo J, Ferrando J, et al. Effect of Nicotinic acid/Laropiprant in the lipoprotein(a) concentration with regard to baseline lipoprotein(a) concentration and LPA genotype. Metabolism 2014; 63: 365-71.

68. Helmbold AF, Slim JN, Morgan J, et al. The Effects of Extended Release Niacin in Combination with Omega 3 Fatty Acid Supplements in the Treatment of Elevated Lipoprotein (a). Cholesterol 2010; 2010: 306147.

69. Li M, Saeedi R, Rabkin SW, et al. Dramatic lowering of very high Lp(a) in response to niacin. J Clin Lipidol 2014; 8: 448-450.

70. Kamanna VS, Kashyap ML. Mechanism of action of niacin. Am J Cardiol 2008; 101: 20B-26B.

71. Croyal M, Ouguerram K, Passard M, et al. Effects of Extended-Release Nicotinic Acid on Apolipoprotein (a) Kinetics in Hypertriglyceridemic Patients. Arterioscler Thromb Vasc Biol 2015; 35: 2042-2047.

72. Ooi EM, Watts GF, Chan DC, et al. Effects of Extended-Release Niacin on the Postprandial Metabolism of Lp(a) and ApoB-100-Containing Lipoproteins in Statin-Treated Men With Type 2 Diabetes Mellitus. Arterioscler Thromb Vasc Biol 2015; 35: 2686-2693.

73. Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis 2010; 210: 353-361.

74. Boden WE, Probstfield JL, Anderson T, et al; AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011; 365: 2255-2267.

75. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013; 34: 1279-1291.

76. Albers JJ, Slee A, O'Brien KD, , et al. Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes). J Am Coll Cardiol 2013; 62: 1575-9.

77. Niacin/Laropiprant Products to Be Withdrawn in EU Next Week. Medscape. Jan 18, 2013. http://www.medscape.com/viewarticle/777870.

78. Gonbert S, Malinsky S, Sposito AC, et al. Atorvastatin lowers lipoprotein(a) but not apolipoprotein(a) fragment levels in hypercholesterolemic subjects at high cardiovascular risk. Atherosclerosis 2002; 164: 305-311.

79. van Wissen S, Smilde TJ, Trip MD, et al. Long term statin treatment reduces lipoprotein(a) concentrations in heterozygous familial hypercholesterolaemia. Heart 2003; 89: 893-6.

80. Broncel M, Marczyk I, Chojnowska-Jezierska J, et al. The comparison of simvastatin and atorvastatin effects on hemostatic parameters in patients with hyperlipidemia type II. Pol Merkur Lekarski 2005; 18: 380-384.

81. Berg K, Dahlén G, Christophersen B, et al. Lp(a) lipoprotein level predicts survival and major coronary events in the Scandinavian Simvastatin Survival Study. Clin Genet 1997; 52: 254-261.

82. Jacobson TA. Lipoprotein(a), cardiovascular disease, and contemporary management. Mayo Clin Proc 2013; 88: 1294-1311.

83. Bos S, Duvekot MH, Touw-Blommesteijn AC, et al. Lipoprotein (a) levels are not associated with carotid plaques and carotid intima media thickness in statin-treated patients with familial hypercholesterolemia. Atherosclerosis 2015; 242: 226-229.

84. Urban D, Pöss J, Böhm M, et al. Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. J Am Coll Cardiol 2013; 62: 1401-1408.

85. Robinson JG, Farnier M, Krempf M, et al; ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372: 1489-1499.

86. Sabatine MS, Giugliano RP, Wiviott SD, et al; Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372: 1500-1509.

87. Gaudet D, Kereiakes DJ, McKenney JM, et al. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Am J Cardiol 2014; 114: 711-715.

88. Raal FJ, Giugliano RP, Sabatine MS, et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol 2014; 63:1278-88.

89. Guo W, Fu J, Chen X, et al. The effects of estrogen on serum level and hepatocyte expression of PCSK9. Metabolism 2015; 64: 554-560.

90. Approve PCSK9 Inhibitor Evolocumab, FDA Panel Recommends. Medscape. June 10, 2015. http://www.medscape.com/viewarticle/846236

91. FDA Approves New LDL-Lowering Agent Alirocumab (Praluent). Medscape. July 10, 2015. http://www.medscape.com/viewarticle/848535

92. EU Approves PCSK9 Inhibitor Evolocumab (Repatha). July 21, 2015. http://www.medscape.com/viewarticle/848370

93. EMA Committee Backs Approval of PCSK9 Inhibitor Alirocumab (Praluent) July 24, 2015. http://www.medscape.com/viewarticle/848595

94. Ricotta DN, Frishman W. Mipomersen: a safe and effective antisense therapy adjunct to statins in patients with hypercholesterolemia. Cardiol Rev 2012; 20: 90-95.

95. Santos RD, Raal FJ, Catapano AL, et al. Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 phase III trials. Arterioscler Thromb Vasc Biol 2015; 35: 689-699.

96. Li N, Li Q, Tian XQ, et al. Mipomersen is a promising therapy in the management of hypercholesterolemia: a meta-analysis of randomized controlled trials. Am J Cardiovasc Drugs 2014; 14: 367-376.

97. Calandra S, Tarugi P, Speedy HE, et al. Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk. J Lipid Res 2011; 52: 1885-926.

98. Cuchel M, Meagher EA, du Toit Theron H, et al; Phase 3 HoFH Lomitapide Study investigators. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013; 381: 40-46.

99. Samaha FF, McKenney J, Bloedon LT, et al. Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat Clin Pract Cardiovasc Med 2008; 5: 497-505.

100. Bochem AE, Kuivenhoven JA, Stroes ES. The promise of cholesteryl ester transfer protein (CETP) inhibition in the treatment of cardiovascular disease. Curr Pharm Des 2013; 19: 3143-3149.

101. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357: 2109-2122.

102. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012; 367: 2089-99.

103. Lilly Pulls Plug on Its CETP Inhibitor Evacetrapib. October 12. 2015. http://www.medscape.com/viewarticle/852516

104. Van der Tuin SJ, Kühnast S, Berbée JF, et al. Anacetrapib reduces (V)LDL-cholesterol by inhibition of CETP activity and reduction of plasma PCSK9. J Lipid Res 2015; 56: 2085-2093.

105. Sjouke B, Langslet G, Ceska R, et al. Eprotirome in patients with familial hypercholesterolaemia (the AKKA trial): a randomised, double-blind, placebo-controlled phase 3 study. Lancet Diabetes Endocrinol 2014; 2: 455-463.

106. Ladenson PW, Kristensen JD, Ridgway EC, et al. Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med 2010; 362: 906-916.

107. Sampietro T, Sbrana F, Bigazzi F, et al. The incidence of cardiovascular events is largely reduced in patients with maximally tolerated drug therapy and lipoprotein apheresis. A single-center experience. Atheroscler Suppl 2015; 18: 268-272.

108. Archontakis S, Pottle A, Hakim N, et al. LDL-apheresis: indications and clinical experience in a tertiary cardiac centre. Int J Clin Pract 2007; 61: 1834-1842.

109. Nordestgaard BG, Chapman MJ, Humphries SE, et al; European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013; 34: 3478-3490a.

Conflict of interest statement

The authors declare that they have no conflict of interest to disclose.

1

Figure 1. Diagrammatic structure of Lp(a).