Lipoprotein(a) and Metabolic Syndrome

Evidence for an Inverse Association in a Pooled Cross-Sectional Analysis of the Berlin Aging Study II (BASE-II) and the Study of Health in Pomerania (SHIP-0)

Background: An inverse association between lipoprotein(a) (Lp[a]) and type 2 diabetes mellitus is well documented. However, data on the association of the metabolic syndrome (MetS) with Lp(a) are sparse.

Methods: Cross-sectional data for MetS and Lp(a) were available for 5743 BASE-II and SHIP-0 participants (48.7% men; age 58 [20–85] years) (BASE, Berlin Aging Study; SHIP, Study of Health in Pomerania). The association of MetS and its components with Lp(a) was analyzed by means of median regression adjusted for age, sex, and study. Associations were evaluated for the total population as well as stratified by sex and menopausal status.

Results: Overall, 27.6% (n = 1573) of the participants in the two studies had MetS and 22.5% (n = 1291) were premenopausal women. There was an inverse association between MetS and Lp(a) in the whole study sample (β = −11.9, 95% confidence interval [−21.3; −2.6]) as well as in men (β = −16.5 [−28.6; −4.3]). Participants with MetS (whole study sample) had 11.9 mmol/L lower Lp(a). Analogous results were found in postmenopausal women (β = −25.4 [−46.0; −4.8]). In premenopausal women with MetS, Lp(a) levels were higher by 39.1 mg/L on average [12.3; 65.9]) than in premenopausal women without MetS.

Conclusion: Hormonal aspects and menopausal alterations seem to affect the association between MetS and Lp(a), as the expected inverse association was not present in premenopausal women.

Cardiovascular disease (CVD) has been the most common cause of death in Germany for many years (1). In both the primary and secondary prevention of CVD, risk-adapted control of low density lipoprotein cholesterol (LDL-C) represents a central therapeutic approach (2). Lipoproteins are physiologically important for the transport of cholesterol in the blood. However, there is broad scientific consensus that lowering LDL-C reduces the risk of CVD, especially in secondary prevention strategies (3).

Lipoprotein(a) [Lp(a)] is also thought to have a prominent role in the progression of CVD. Lp(a) consists essentially of an LDL-C that is bonded with a protein, apolipoprotein(a). Up to 20% of the general population have high levels of Lp(a) and thus may have an elevated risk of atherothrombosis. Mechanisms such as impaired fibrinolysis, increasing cholesterol deposition in arterial walls and inflammatory processes on the vascular walls play a role (4, 5).

In contrast to LDL-C, which can usually be controlled by means of medication, there is still no drug treatment option for lowering Lp(a). To date, in patients with elevated Lp(a) the focus is on controlling LDL-C and other cardiovascular risk factors. Promising studies on antisense drugs targeting LPA gene expression are well under way (6). There are few pathophysiological mechanisms affecting Lp(a) concentrations in the human body. Hormonal changes and insulin resistance can modulate the genetically determined Lp(a) production in the liver (5). These parameters also play a major role in the development of the metabolic syndrome (MetS), which is highly prevalent in the general population (7, 8).

Against this background, the present data analysis concerns itself with the association between MetS and Lp(a), with a particular focus on menopausal status in women. To this end, data from two large population studies, the Berlin Aging Study II (BASE-II) and the Study of Health in Pomerania 0 (SHIP-0), were evaluated.

Previous studies have already explored the effects of Lp(a) on cardiovascular and metabolic health (5, 9) and revealed an inverse association between Lp(a) and type 2 diabetes mellitus (T2D) (10, 11). In contrast to the association with T2D, there has been little research into the association between MetS and Lp(a) (11, 12, 13, 14, 15), which is surprising given that the pathogenesis of MetS and type 2 diabetes mellitus overlaps in some respects. Moreover, the association between Lp(a) and MetS has not yet been investigated in a relatively healthy elderly population, and most of the studies that have been carried out have not taken account of menopausal status.

Since therapeutic approaches to lowering Lp(a) are close to approval, it is crucial to understand the complex relationship between metabolic changes and the influence of hormonal changes on Lp(a) in order to be able to classify the possible consequences of such a therapy in specific subpopulations.

Methods

Study populations

The BASE-II study was designed to investigate factors associated with a “healthy” or “unhealthy” aging process. The BASE-II study population consists of 1600 elderly people living independently in the community (60–84 years old) and a control group of about 600 younger subjects (20–36 years old) from the greater metropolitan area of Berlin (16, 17, 18), all of whom gave written informed consent. The ethics committee of the Charité—University Medical Center Berlin approved the study (approval number EA2/029/09).

SHIP-0 is a population-based cohort study in West Pomerania. During the period 1997–2001, a total random sample of 6265 subjects was drawn from the target population (20–79 years old), of whom 4308 participated in the first examination (response rate 68.8%). The study design, protocols, and sampling methods have been described in detail elsewhere (19). All participants gave written informed consent, and the study was approved by the ethics committee of the University of Greifswald.

Definition of type 2 diabetes and metabolic syndrome

A detailed comparison for both study cohorts with respect to the definition of MetS is given in eTables 1 and 2. In BASE-II an oral glucose tolerance test (OGTT) was performed in participants without previously known diabetes and T2D was defined on the basis of the following criteria:

eTable 1

Association between metabolic syndrome and lipoprotein(a) in SHIP-0 stratified by sex and menopause

eTable 2

Association between metabolic syndrome and lipoprotein(a) in BASE-II stratified by sex and menopause

• A history of T2D or diabetes-specific medication
• Fasting glucose (after ≥ 8 h fasting) ≥ 126 mg/dl
• OGTT glucose ≥ 200 mg/dl (120 min after glucose load; if available)
• Hemoglobin A_1c (HbA_1c) ≥ 6.5% according to the ESC criteria 2013 (20).

In SHIP-0 T2D was defined by self-reported diabetes in the medical interview or intake of anti-diabetics (ATC code A10).

MetS was defined using a modification of the approach suggested by Alberti et al. 2009 (21, 22) as a combination of three out of five parameters:

• Insulin resistance: > 5.6 mmol/L fasting glucose (BASE-II) or > 8.0 mmol/L non-fasting glucose (SHIP-0) or known T2D/known medication
• Abdominal obesity: waist circumference > 94 cm (male) or > 80 cm (female)
• Low HDL-C: < 1.03 mmol/L (male) or < 1.3 mmol/L (female)
• High triglycerides: > 1.7 mmol/L fasting triglycerides (BASE-II) or > 2.3 mmol/L non-fasting triglycerides (SHIP-0) or lipid-lowering medication
• High blood pressure: > 130/85 mmHg or known hypertension/known medication

The pre-/postmenopausal status was assessed using standardized questionnaires. The clinical chemistry tests and and statistical methods are shown in the eBox.

eBox

Measurements

Results

Description of the study population

Complete cross-sectional data for MetS and Lp(a) were available for 5743 participants (1987 from BASE-II and 3756 from SHIP-0) (Table 1). The BASE-II participants were older than those of SHIP-0, while the Lp(a) concentrations were comparable in BASE-II (100 mg/L; interquartile range [IQR] 40–290; p = 0.871) and SHIP-0 (94 mg/L; IQR 43–263). Compared with to SHIP-0 participants, BASE-II participants had lower concentrations of LDL-C, triglycerides, C-reactive protein, and glucose, but on average higher concentrations of HDL-C and HbA_1c.

Table 1

Basic characteristics of the BASE-II and SHIP-0 study populations

Across the entire study population, the prevalence of MetS was 27.6% (n = 1573; 29.8% in BASE-II, n = 593, and 26.4% in SHIP-0, n = 980). The prevalence of T2D was comparable in BASE-II (6.8%; n = 135) and in SHIP-0 (7.3%; n = 276). Nicotine consumption was reported for 14.5% of participants in BASE-II, much lower than the 30.5% in SHIP-0. Moreover, 43.8% of women in the two study cohorts stated that they were premenopausal (n = 1291) (Table 1).

Multivariable regression results

Regression models adjusted for age, sex, and study were calculated to analyze the association of MetS and its components with Lp(a) (Table 2). In the pooled sample, the mean Lp(a) level was 11.9 mg/L lower in persons with MetS than in those without MetS. Moreover, participants with high serum triglyceride or glucose levels showed lower Lp(a) concentrations than participants with lower triglyceride or glucose levels (Figures 1 and 2). On the other hand, there was a positive association of total cholesterol and LDL cholesterol with Lp(a).

Figure 1

Association between triglycerides and lipoprotein(a), stratified by sex and menopause

Figure 2

Association between glucose and lipoprotein(a), stratified by sex and menopause

Table 2

Association between metabolic syndrome and lipoprotein(a) stratified by sex and menopause

Lp(a) levels were lower in men with MetS than in men without MetS. Male participants with higher triglyceride or glucose levels, body mass index or waist circumference had higher Lp(a) levels. HDL- C levels were positively associated with Lp(a) levels in men.

Postmenopausal women with MetS had a 25.4 mg/L lower mean Lp(a) level than postmenopausal women without MetS, whereas premenopausal women showed a positive association between MetS and Lp(a). In premenopausal but not in postmenopausal women, there were positive associations of body mass index and waist circumference with Lp(a).

Discussion

In this analysis of two large German population-based cohort studies BASE-II and SHIP-0 (n = 5743), we found an inverse association between the presence of MetS and Lp(a). The mean Lp(a) level was 11.9 mg/L lower in probands with MetS. However, subgroup analysis revealed that this inverse association was found only in men (median Lp(a) level 16.5 mg/L lower in those with MetS) and postmenopausal women (median Lp(a) level 25.4 mg/L lower with MetS), while in premenopausal women a positive association was evident (mean Lp(a) level 39.1 mg/L higher with MetS).

Few studies to date have analyzed the association between MetS and Lp(a). To our knowledge, none of these studies examined a relatively healthy study population and considered menopausal status in women. These previous investigations came to conflicting results. In a large Asian cohort, the authors reported an inverse association between Lp(a) concentrations and MetS (14, 23). These results are in line with the majority of other studies in various populations (11, 14, 15, 24, 25). However, there are also a few studies suggesting no association (13, 26) or even a positive association between Lp(a) and MetS. Notably, studies showing a positive association between Lp(a) and MetS did not differentiate according to menopausal status and studied predominantly premenopausal women. A positive MetS/Lp(a) association results may be favored by younger age, premenopausal status, or varying severity of the components of MetS (12, 27, 28, 29). Thus we see these results as also being in line with our findings.

The concept of the MetS is based on a complex interplay among metabolic, inflammatory, and endocrine alterations, whereby insulin resistance, in particular, is viewed as the most important pathophysiological mechanism. Patients with MetS have a 5 times higher lifetime risk of developing T2D (21, 30). Although we recently (31) found no association between Lp(a) and serum insulin levels, insulin probably plays a role in modulating hepatic Lp(a) synthesis (32).

The evidence relating to Lp(a) is still limited, and the mechanism driving the production of Lp(a) remains under discussion (5). Lp(a) improves wound healing due to binding to the membrane receptors of macrophages and platelets. However, negative effects of Lp(a) in the context of arteriosclerosis and progression of cardiovascular diseases have also been clearly demonstrated (5, 33). Besides the possible role of T2D and insulin in modulating hepatic Lp(a) synthesis, there are a few other mechanisms that affect both MetS and Lp(a); in particular, a role is played by hormonal changes. Estrogen and progesterone production decrease in the postmenopause. Estrogen reduces cardiovascular risk through the modulation of blood lipids in premenopausal women (4, 34). These lipids are part of the definition of MetS. Moreover, estrogen leads to reduced insulin resistance and lowers the risk of obesity—two essential parameters of MetS (7, 34). Gentile et al. found an inverse association between Lp(a) and MetS in menopausal women (n = 222) (24). However, pre- and postmenopausal status were not differentiated. This is a new consideration in this area. It seems plausible that in the current analysis there was an inverse association between MetS and Lp(a) in postmenopausal women and men, in which groups the influence of estrogen plays a subordinate role. Furthermore, previous studies have demonstrated that estrogen lowers the Lp(a) levels in healthy postmenopausal women (35, 36). Recent research suggests that estrogen induces increased hepatic uptake of Lp(a) via the LDL receptor (8), thus paving the way for modulation of Lp(a) production (37, 38).

Limitations

The present study is subject to certain limitations. Given the cross-sectional design of the BASE-II and SHIP-0 dataset, conclusions regarding causalities cannot be drawn. Moreover, BASE-II is a convenience sample, and the participants are on average healthier than the general population. Nevertheless, the prevalence of MetS in this population was high. There are also obvious differences between the BASE-II dataset and the SHIP-0 dataset. Although there is a certain similarity with respect to the prevalence of T2D, owing to the study design BASE-II participants were on average older than those of SHIP-0 and fewer premenopausal women were included. Although we controlled the regression models for “study,” differences may arise from investigating differing populations. For the present analysis, Alberti et al.’s (21) definition of MetS was used; however, various definitions for MetS have been proposed by professional societies in recent years. It cannot be excluded that using a different definition would change the results. Furthermore, in SHIP-0 non-fasting values for glucose and triglycerides were used. In SHIP-0 adapted cut-off values were used (22), so a certain inaccuracy cannot be ruled out. However, results were comparable in the two study populations examined. In addition, in BASE-II and SHIP-0 questionnaires were used to gather anamnestic information on hypertension, menopause, and diabetes; this may lead to under- or overestimation of the results. Moreover, some aspects could not be extensively explored. Lp(a) is affected by inflammation and acute illness such as myocardial infarction. Although regression models were controlled for C-reactive protein, it cannot be assumed with certainty that all factors that influence Lp(a) and MetS were fully taken into account.

Conclusion

In summary, this study suggests an association between MetS and Lp(a) through various mechanisms. With regard to the development of specific drugs for Lp(a) lowering, the question arises as to which patients could benefit from such treatment. Studies suggest that patients with Lp(a) and small apolipoprotein(a) size are particularly at risk for the development of cardiovascular disease (CVD) (39). In a recent study of high-risk patients, Vonbank et al. found no additional CVD risk due to Lp(a) in probands with MetS (15). The study included mainly men and elderly probands. On the one hand, therefore, it must be taken into account which apo(a) isoform is present in the case of an Lp(a) increase. On the other hand, MetS seems to exert an effect on Lp(a) that might modify its atherogenicity. These considerations show clearly that both the impact of MetS on Lp(a) isoforms and the aspect of hormonal influences in this context must be further investigated in order to identify patients eligible for Lp(a) modification. Both a better understanding of the role of the specific mechanism in the liver and genetic studies could yield more insight into the relationship between MetS and Lp(a). The consideration of hormonal aspects, in particular the postmenopausal change in estrogens, seems important if our knowledge of the association between MetS and Lp(a) is to be enhanced.

Acknowledgments
The BASE-II research project was supported by the German Federal Ministry of Education and Research (BMBF) under grant numbers #16SV5536K, #16SV5537, #16SV5538, and #16SV5837 and by the Max Planck Institute for Human Development (MPIHD), Berlin, Germany.

The Study of Health in Pomerania (SHIP) is part of the BMBF-funded Community Medicine Research Network (CMR) of the University Medical Center Greifswald (grant numbers 01ZZ96030 and 01ZZ0701).

This study was carried out in collaboration with the German Center for Cardiovascular Research (DZHK) and the German Center for Diabetes Research (DZD), which are funded by the BMBF.

Data availability
For data protection reasons, the data are available only upon request. External scientists may apply to the steering committee of BASE-II for data access (requests to Ludmila Müller, scientific coordinator, at [e-mail]).

Data from SHIP are available from the University Medical Center Greifswald, Germany but restrictions apply to the use of these data, which were used under license for the current study and thus are not publicly available. Data are, however, available upon reasonable request at https://www.fvcm.med.uni-greifswald.de/dd_service/data_use_intro.php and with permission of the Community Medicine Research Network of the University Medical Center Greifswald.

Conflict of interest statement
Dr. Buchmann has received payments for educational events
from Novartis.

Prof. Santos has received payments as a consultant for Novartis. He has received remuneration for lectures from Amgen, Novartis, Sanofi, Ache, and GETZ Pharma.

Prof. Steinhagen-Thiessen has received payments as a consultant for Novartis and Daiichi-Sankyo. She has received remuneration for lectures from Novartis, Pfizer, Sanofi, Amgen, Daiichi-Sankyo, Synlab, Amarin, and Fresenius.

The remaining authors declare that no conflict of interest exists.

Manuscript submitted on 25 August  2021, revised version accepted on 17 February 2022

References

Corresponding author
Dr. med. Nikolaus Buchmann
Abteilung für Kardiologie, Charité – Universitätsmedizin Berlin
(Campus Benjamin Franklin)
Hindenburgdamm 30, 12203 Berlin, Germany

Cite this as:
Buchmann N, Ittermann T, Demuth I, Markus MRP, Völzke H, Dörr M, Friedrich N, Lerch MM, Santos RD, Schipf S, Steinhagen-Thiessen E: Lipoprotein(a) and metabolic syndrome—evidence for an inverse association in a pooled cross-sectional analysis of the Berlin Aging Study II (BASE-II) and the Study of Health in Pomerania (SHIP-0). Dtsch Arztebl Int 2022; 119: 270–6. DOI: 10.3238/arztebl.m2022.0153

►Supplementary material

eBox, eTables:
www.aerzteblatt-international.de/m2022.0153

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