Lipoprotein(a) (Lp(a)) is increasingly important as an independent risk factor for cardiovascular disease. Numerous studies have shown that elevated Lp(a) levels are associated with higher rates of coronary heart disease, stroke, peripheral arterial disease and aortic valve stenosis. This includes patients with pre-existing cardiovascular disease. A linear risk for myocardial infarction and increasing Lp(a) levels was found, without a threshold effect [1, 2, 3, 4, 5]. Various pathophysiological relationships are responsible for this. Lp(a) consists not only of LDL-Cholesterol (LDL-C) particles, from which highly inflammatory oxidized LDL-C is formed after entry into the vessel wall, but also of apoliprotein(a) (apo(a)), which among other things also acts highly inflammatory and also antifibrinolytic through the inhibition of plasminogen activation. Thus, it promotes arterial thrombosis and venous thrombosis [6, 7, 8]. However, there is a lack of therapeutic options for prevention. Lifestyle modifications such as diet or physical activity do not significantly affect Lp(a) levels [9]. There is currently no approved medication for the treatment of elevated Lp(a) levels, although there are Proproteinkonvertase Subtilisin Kexin Typ 9 (PSCK9) inhibitors that can lower Lp(a) levels. Thus, a specific therapy currently exists only with lipid apheresis, which can effectively lower Lp(a) and significantly reduce the risk of cardiovascular events [10, 11]. However, lipid apheresis is essentially used only for secondary prevention. In Germany, treatment with lipid apheresis is approved only in cases of progressive cardiovascular disease despite optimal of the usual secondary prevention therapy and even then only for lipoprotein(a) levels above 60 mg/dL or 120 nmol/L.

However, patients with and without preexisting cardiovascular disease with elevated Lp(a) levels for whom apheresis is not an option are increasingly being presented for therapeutic intervention. In the absence of drug therapies, it is probably essential for this patient group to efficiently control traditional cardiovascular risk factors to minimize risk. It is also an open question whether individuals with elevated Lp(a) levels are also more likely to have other risk factors and whether they should be treated even more intensively.

The aims of this evaluation of the ELITE (Ernährung, Lebensstil und individuelle Information zur Verhinderung von Herzinfarkt, Schlaganfall und Demenz; german for: Nutrition, Lifestyle and Individual Information for the Prevention of Heart Attack, Stroke and Dementia) study were to present the frequency of elevated Lp(a) levels and to investigate the care situation and control of other risk factors in a rural population in northwestern Germany.

All participants received detailed individual and written education about their cardiovascular risk factors and their treatment. In the further follow-up of 5 years, it will be examined how persons with elevated Lp(a) implement these recommendations compared with persons with normal Lp(a) levels and how frequently cardiovascular events occur.

A detailed description, methods, and basic results have already been published [12, 13]. ELITE is a prospective interventional cohort study. Information about Cardiovascular risk factors (CVRF), mild cognitive impairment, psychosocial factors and Nutritional habits was prospectively collected. These CVRFs should be improved through targeted individualized prevention suggestions. The objective is to improve the health status of the participants and to identify the reasons for the lack of implementation of the prevention recommendations. The study included 4602 participants older than 16 years. Participation was called for via newspapers, sports clubs, companies or hospitals. Exclusion criteria were age under 16 years, lack of a declaration of consent, and obvious difficulties in tracking the participant. The aims of this particular evaluation were to present the frequency of elevated Lp(a) levels and to investigate the control of other risk factors in a rural population in northwestern Germany.

Table 1 shows the baseline data of the cohort divided into 3 groups (Lp(a) 75 nmol/L, Lp(a) 75–120 nmol/L, Lp(a) $>$120 nmol/L). The group with normal Lp(a) was clearly the largest, although almost 20% had elevated Lp(a) values. The groups compared with each other were homogeneous with no significant differences in sex or age. Lipid therapy was significantly more common in the Lp(a) group with values $>$120 nmol/L.

The prevalence of cardiovascular risk factors has been compared among the 3 groups in Tables 2 and 3. In Table 2, the results on BP are presented in detail. The overall prevalence did not vary significantly in the different groups (58.7%, 57.8% and 61%).

First, the difference between normotensive participants (all participants with BP values 140/90 mmHg) and all hypertensive participants was analyzed. Here, there were no significant differences in frequency between the Lp(a) groups.

Then, all hypertensives (all participants with high BP and/or antihypertensive medication and/or history of hypertension) were analyzed in more detail and divided into drug-treated hypertensives (“treated hypertensives”) and drug-untreated hypertensives (“untreated hypertensives”). Again, there were no significant differences in the Lp(a) groups. Finally, the group of treated hypertensives was again divided into well-controlled hypertensives (treated controlled hypertensives, i.e., with drug therapy and blood pressure 140/90 mmHg) and poorly controlled hypertensives (“treated uncontrolled hypertensives”, i.e., with drug therapy and BP $\ge$140/90 mmHg). Interestingly, “treated uncontrolled hypertensives” have significantly more often high Lp(a) values $>$120 nmol/L than the “treated controlled hypertensives”. This is also reflected in the mean Lp(a) values (Table 2). Here, the mean values of Lp(a) in the different BP groups were compared with the normotensives. Only the treated uncontrolled hypertensives group had significantly higher mean Lp(a) values compared with normotensives.

Table 3 shows the other risk factors in the Lp(a) groups. Only LDL-C differs significantly between the groups in each case. The “soft” risk factors like depression and stress also showed no significant difference.

Nevertheless, there are significant differences in the number of cardiovascular risk factors per participant in the 3 Lp(a) groups (Table 4). 2 other risk factors were found significantly more frequently in the Lp(a) $>$120/nmol/L group, whereas no other risk factors were less frequent in this group than in the Lp(a) 75 nmol/L and Lp(a) 75–120 nmol/L groups.

This is not reflected in a different ESC risk of a cardiovascular event in 10 years. Here, there are no significant differences in the groups (p = 0.325). The laboratory values in Table 5 showed no significant differences except for LDL-C and total cholesterol.

In this Northwest German Cohort Study, the frequency of elevated Lp(a) and the correlation of Lp(a) levels with other CVRF were investigated. No frequency studies have previously been performed for this region.

The frequency of elevated Lp(a) was 19.8% with no significant differences between women and men. Among them, 7.7% were above the normal value of 75 nmol/L and 12.1% were above 120 nmol/L. From this value, patients with progressive atherosclerosis can apply for apheresis treatment in Germany. Thus, the frequency is within the previously published range [14, 17]. For Europe, North America and Australia, elevated values above 50 mg/dL or above 125 nmol/L are reported in 20%, in Africa even in 30%, in China in 10% [18, 19, 20].

The question of this work was whether other cardiovascular risk factors are also more frequent in individuals with elevated Lp(a) than with normal Lp(a) levels.

In summary, there was no significant difference in the prevalence of other CVRF such as arterial hypertension, Smoking, HDL- cholesterol triglycerides, uric acid, and diabetes mellitus. Also, physical activity, brain dysfunction, depressive symptoms, psychological stress, or age were not different in the three Lp(a) groups. Only LDL-C was significantly more prescriptions of statins in the group with the despite, which was largely due to the methodical co-recording and measurement of the LDL-C fraction in lipoprotein(a). The number of participants treated with statins was also significantly higher in this group, so that the difference in LDL-C was originally even higher. As expected, the group with Lp(a) levels above 120 nmol/L was significantly more likely to have a positive family history of coronary heart disease.

A common clinical question is how to proceed in patients with elevated Lp(a) and not yet manifest cardiovascular disease, especially with a positive family history. Previous guidelines recommend Lp(a) measurements in defined patient groups [21, 22].

An isolated assessment of cardiovascular risk only by means of high Lp(a) and the subsequent setting of individual thresholds for LDL-C is not yet mentioned in the guidelines. Lp(a) should currently only be used as a decision aid in patients between moderate and high risk of cardiovascular events [21]. It is problematic that even when the ESC score is used for risk assessment, the attributive risk of Lp(a) elevation is not detected. Thus, currently, in the absence of drug therapy, the logical consequence remains to optimally adjust all other risk factors.

Therefore, the frequency of other cardiovascular risk factors was evaluated in this study. This is of particular importance, because in this study participants with Lp(a) had significantly more frequent two risk factors - especially in the group with Lp(a) $>$120 nmol/L. In particular, the question arises as to the clinical significance and therapeutic consequence of elevated LDL-C in conjunction with elevated Lp(a). Overall, it must be assumed that patients with Lp(a) $>$120 nmol/L are at moderate to high cardiovascular risk and thus, according to guidelines, should achieve an LDL-C target value of at least below 100 mg/dL (or even 70 mg/dL). However, this classification has to be put up for discussion, because the guidelines on dyslipidaemia do not consider Lp(a) for risk assessment. The LDL-C mean value of this group in our study is 139.22 mg/dL. A controlled LDL-C is essential for this risk group. Nevertheless, in our survey only 14% of the participants in this group were in the target range of below 100 mg/dL, while almost 59.4% were above 130 mg/dL. Only 13.6% in the Lp(a) $>$120 nmol/L were receiving lipid lowering therapy. The Jupiter Trial or the AIM-High Trial confirm a continued increased cardiovascular risk despite controlled LDL-C, although potentially lower than uncontrolled LDL-C [23, 24]. A meta-analysis by Tsimikas et al. [25] provides evidence for a significant increase in Lp(a) by statins . Up for debate is whether this elevation partially explains the residual cardiovascular risk with statin therapy. It has been shown that increased Lp(a) leads to a linear increase in cardiovascular risk even with statin therapy [26].

In addition to LDL-C, all other CVRFs must of course be adjusted [27]. There is impressive evidence that the cardiovascular risk of elevated Lp(a) further increases in the presence of additional CVRF [28, 29, 30]. Saeed et al. [28] found a significantly increased risk of cardiovascular events over 15 years when diabetes or prediabetes was present. Smoking also significantly increased the risk [29, 30]. Hypertension, as one of the major CVRFs, was not adequately controlled in all 3 groups. In the “high-risk” group Lp(a) $>$120 nmol/L, only 17.7% of all hypertensive patients were controlled (140/90 mmHg). While the mean Lp(a) values of untreated hypertensives and treated controlled hypertensives did not differ significantly from normotensives, treated uncontrolled hypertensives showed significantly increased Lp(a) values. Thus, the most prognostically unfavorable hypertensive group showed the highest Lp(a) values.

The significance and cause are unclear. Also, these results need to be confirmed. One could discuss that the high BP levels in combination with high Lp(a) might have led to inflammation with endothelial damage. It may also be speculated that mechanisms such as fibrinolysis inhibition contributed to this. The compliance of patients with a lot of different medication could also be a problem in this group.

Overall, the strict cessation of further classical CVRF is of paramount importance. Nevertheless, this study shows that the recommendations of professional societies are not currently implemented in the general population.

This analysis shows that recognition of the hazardous nature of elevated Lp(a) does not lead to better adjusted traditional cardiovascular risk factors. As a consequence, high-risk patients may need to be much better educated and monitored with respect to their individual cardiovascular risk profile. In ELITE, participants are revisited annually and detailed individual prevention recommendations are made. Evaluation of follow-up data at 1 year and endpoints at 5 years will show whether intensive written recommendations can help to better control cardiovascular risk factors in patients with high Lp(a).

BS, JS, ASh, ASc and SL drafted the manuscript, BV was responsible for the statistical evaluation and described the statistical analyses, AE, MK and HH advised on the design of the study and improved the manuscript of this paper. BS, JS and SL designed the ELITE study. The decision to submit the manuscript for publication was made jointly by all authors, who also guarantee the completeness and correctness of the data and the study conduct.

All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of University of Göttingen (approval number: 34/6/14).

We would like to express our gratitude to all those who helped us during the writing of this manuscript.

This research received no external funding.

The study is supported personally or financially by numerous regional and national companies and institutions (in alphabetical order): AOK – Die Gesundheitskasse für Niedersachsen, Sevelter Str. 40, 49661 Cloppenburg B. Braun Melsungen AG, Carl-Braun-Straße 1, 34212 Melsungen Big Dutchman International GmbH, Auf der Lage 2,49377 Vechta-Calveslage, Bilfinger EMS GmbH, 49661 Cloppenburg Biochem Zusatzstoffe Handels- und Produktionsges. mbH, Küstermeyerstr. 16, 49393 Lohne Böckmann Fahrzeugwerk GmbH, Siehefeld 5, 49688 Lastrup Brand Qualitätsfleisch GmbH & Co.KG, Brandstr. 21,49393 Lohne, DiNo 1 GmbH, Mühlenstr. 10, 49661 Cloppenburg, Elektro Koopmann GmbH, Zum Brook 19 – 21, 49661 Cloppenburg, Fleming & Wendeln GmbH & Co. KG, Auf’m Halskamp 12, 49681 Garrel, Gemüsebau Mählmann, Im Siehenfelde 13, 49692 Cappeln Hans und Marlies Stock-Stiftung, Köln, c/o DSZ, Bark- hovenallee 1, 45239 Essen, Heidemark GmbH, Lether Gewerbestr. 2, 26197 Ahlhorn Jungpflanzen Lüske, Josef, Kirchstr. 29, 49685 Höltinghausen Moorgut Katrzfehn von Kameke GmbH & Co. KG, Kartz-von- Kameke-Allee 7, 26219 Bösel, Paul Lüske GmbH, Mercedes, Emsteker Str. 95, 49661 Cloppenburg, Sanofi-Aventis Deutschland GmbH, Potsdamer Str. 8a, 10785 Berlin Servier Deutschland GmbH, Elsenheimerstr. 53, 80687 München, Sieverding Heizungs- und Sanitärtechnik GmbH, Tenstedter Str. 40, 49692 Cappeln, St.-Josefs Hospital Cloppenburg gGmbH, Krankenhausstr. 13, 49661 Cloppenburg, Stevens Truthahn-Delikatessen GmbH, Vahrener Weg 1,49696 Molbergen, Weigel, Werner, Teichstr. 13, 49661 Cloppenburg Wernsing Feinkost GmbH, Kartoffelweg 1, 49632 Addrup. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.