Introduction

The overall prevalence of hypercholesterolemia in the Spanish adult population has been estimated between 34% and 50% in recent studies [1–3]. The importance of this high prevalence is due to the association of high levels of serum cholesterol with cardiovascular disease (CVD), which has been well established [4, 5]. For instance, the occurrence of CV events in patients with familial hypercholesterolemia has been highlighted, with a prevalence of premature CVD (before 55 years of age in men and before 65 years of age in women) of 10%, in contrast to less than 3% in relatives without familial hypercholesterolemia [6].

The therapeutic arsenal available for hypercholesterolemia includes the standard treatment based on lifestyle and dietary modification strategies, and lipid-lowering medications, mainly statins [7]. Other existing treatments for controlling low-density lipoprotein cholesterol (LDLc) levels are ezetimibe (added to statins in primary hypercholesterolemia and homozygous familial hypercholesterolemia or as a monotherapy in cases of statin intolerance or if they are contraindicated), fibrates and bile-acid sequestrants. In addition, newly developed lipid-lowering drugs (monoclonal antibodies proprotein convertase subtilisin/kexin type 9 inhibitor) have been recently approved by the Food and Drug Administration and European Medicines Agency. Lipid-lowering treatments (LLT) are efficacious in reducing LDLc levels and reducing the burden of major CV events as well as CV mortality, even among populations without known CVD [8, 9]. Consequently, recent European Clinical Practice Guidelines have established LDLc targets accordingly to individual’s CV risk [7]: LDLc levels <100 mg/dl for patients without CVD, but with diabetes mellitus (DM) or with high CV risk based on a Systematic COronary Risk Evaluation (SCORE) risk assessment >5 (Primary prevention hereinafter), and <70 mg/dl for patients with overt CVD, i.e., those who have suffered a previous CV event (Secondary prevention). However, according to the results published in a multinational study conducted between 2006 and 2007, despite the use of LLT, a significant proportion of patients did not attain target levels of LDLc [10], which means they still have a significant CV residual risk. Understanding the contemporary magnitude of this condition is of importance to plan additional interventions to reach LDLc targets and to reduce the burden of the related CV events and deaths. Thus, the objectives of the present research were to review the published evidence addressing the prevalence of hypercholesterolemia, the usual clinical management of lipid profile, and the attained control of LDLc levels in patients with high CV risk from Spain.

Methods

A systematic review of the literature was conducted in accordance with the accepted standards [11] and with a research question defined with reference to Patients, Interventions, Comparisons, Outcomes, and Study design (PICOS) (please see Table S1 in the supplementary material for details). The search was run on the second week of October 2014 (from 6th to 10th) in Medline and two Spanish electronic databases: Biblioteca Virtual de la Salud (BVS) and Medes. The search strategies included both controlled and free terms in both English and Spanish languages. The search strategies executed in each electronic public-access libraries are presented in Table S2 in the supplementary material.

The information gathered was manually cross-checked using the relevant references given in the publications included. To select the studies, titles and abstracts were first examined. After this, full text of selected manuscripts was reviewed. The selection criteria for publications were as follows:

Inclusion Criteria

Studies carried out in Spain and focused on lipid levels of patients belonging to one of the following groups: (a) heterozygous familial hypercholesterolemia (HeFH); (b) overt CVD including acute coronary syndrome (ACS), chronic coronary heart disease (CHD), ischemic stroke (IS) and peripheral arterial disease (PAD); (c) DM; or (d) high CV risk. ACS was defined as acute myocardial infarction or unstable angina in the last 12 months. Chronic CHD refers to patients with ACS occurred longer than 12 months, or with stable angina or revascularization. Regarding CV risk, a SCORE risk assessment >5 (tables for countries with low CV risk) or equivalent was considered. Furthermore, according to the objectives described before, the studies had to include information on one of the following results: (a) prevalence of hypercholesterolemia; (b) rates of pharmacological treatment or (c) control of LDLc levels.

Exclusion Criteria

Manuscripts were discarded if any of the following conditions applied: (a) carried out outside Spain; (b) studies that did not include original patient data (i.e., reviews, editorials or letters); (c) studies that did not include human data; (d) studies with pediatric populations or (e) case reports.

Compliance with Ethics Guidelines

This article is based on previously conducted studies, and does not involve any new studies of human or animal subjects performed by any of the authors.

Results

A total of 1362 publications were retrieved from PubMed, 537 from the BVS and 560 from Medes (512 were duplicates so an initial pool of 1947 original manuscripts were identified for title and abstract review). Following the selection process, the full text of 264 manuscripts was reviewed, of which a total of 120 original papers were finally considered (Fig. 1).

Fig. 1
figure 1

Flow diagram showing the selection process of the included articles. BVS Biblioteca Virtual de la Salud

Full size image

HeFH

In the study using data from the electronic database of the Spanish Familial Hypercholesterolemia Longitudinal Cohort Study (SAFEHEART) [12], 84% of the HeFH patients were receiving LLT at the time of inclusion (97% index cases and 78% HeFH relatives). 95% of treated patients received statins, 58% as monotherapy and 31% in combination, mostly with ezetimibe. Meanwhile, in another observational study [13] which included 241 patients with HeFH and 286 with combined familial hypercholesterolemia, 100% received LLT during a monitoring period of 1 year. Patients took an average of 1.5 lipid-lowering drugs (94% statins and 33% ezetimibe).

Despite the high proportion of patients undergoing a LLT in both studies [12, 13], between 72% and 96%, approximately, did not reach a target LDLc below 100 mg/dl and only 45% reduced LDLc levels by >50% (Table 1).

Table 1 Lipid-lowering treatments and LDL cholesterol targets in Heterozygous familial hypercholesterolemia
Full size table

Hypercholesterolemia in Secondary Prevention

ACS

In studies carried out among patients with ACS the prevalence of hypercholesterolemia was highly variable ranging from 45% to 80% [15–31]. The proportion of ACS patients undergoing LLT ranged between 33% and 90%, but control levels were poor with only 14% of patients with LDLc levels <70 mg/dl and 56% meeting the target of LDLc <100 mg/dl [26] (Table 2; Fig. 2).

Table 2 Lipid-lowering treatments and LDL cholesterol targets in secondary prevention
Full size table
Fig. 2
figure 2

Control in secondary prevention. LDLc low-density lipoprotein cholesterol, DM diabetes mellitus, BMI body mass index

Full size image

CHD

The prevalence of hypercholesterolemia in patients with chronic CHD was more uniform than that found in patients with ACS, according to the information collected, ranging from 64% to 74% [32–38, 44–46]. More than 80% of patients were receiving LLT, statins accounting for 95% of them [37]. Again, despite the high proportion of treatment, only between 26% and 55% of patients had LDLc levels <100 mg/dl (Table 2).

IS

The prevalence of hypercholesterolemia in patients with IS ranged from 40% to 70% [39–41, 47–60]. The proportion of treated patients was lower than that found in ACS or CHD patients. Upon discharge from hospital following an IS episode, between 38% and 76% of patients were receiving LLT [39, 40, 49]. In addition, one observational study with 203 patients admitted for medium- to long-term stays in one hospital between 2009 and 2010 found that only 20% of the total number of post-event patients received the dosage recommended by current guidelines [54].

With regards to attained cholesterol levels, 3 studies were found [39–41], reporting figures on LDLc control of <100 mg/dl between 25% and 33%. In two additional studies [54, 61] in which targets were set at Total Cholesterol (TC) < 175 mg/dl, control rates were between 43% and 77% (Table 2; Fig. 2).

PAD

A very limited number of studies were identified for this particular subgroup [42, 62–64]. In these studies, the clinical diagnosis of PAD was based on an ankle-brachial index <0.9. A prevalence of hypercholesterolemia between 60% and 80% was reported. With regard to treatment applied and results achieved, between 46% and 79% of patients received LLT. However, only 30% of them achieved a target LDLc <100 mg/dl (Table 2; Fig. 2).

Hypercholesterolemia in Primary Prevention

DM

In accordance with a previous diagnosis or the use of LLT, data indicated that between 50% and 84% of DM patients would present with hypercholesterolemia [44, 57, 65–68].

Regarding the rates of LLT usage (Table 3; Fig. 3), between 45% and 90% of DM patients were using a LLT [26, 69, 70]. With respect to the lipid control achieved in this population, rates ranged from 40% to 50% in DM patients with no CVD history (LDLc goal <100 mg/dl), to only 15% in DM patients with a history of CVD (LDLc goal <70 mg/dl).

Table 3 Lipid-lowering treatments and LDL cholesterol targets in primary prevention: diabetes mellitus
Full size table
Fig. 3
figure 3

Control in primary prevention: diabetes mellitus. LDLc low-density lipoprotein cholesterol, DM diabetes mellitus

Full size image

Patients with High CV Risk

Within this group of special interest in the prevention of CVD, between 30% and 60% had a specific diagnosis of hypercholesterolemia, based on a TC >200 mg/dl or previous treatment [1, 3, 76–78].

LLT was used in 50% to 60% of these patients [1], while control rates ranged from 35% to 65%, considering a LDLc target of <100 mg/dl [1, 72, 73]. Table 4 and Fig. 4 summarize these data.

Table 4 Lipid-lowering treatments and LDL cholesterol targets in primary prevention: high cardiovascular risk patients
Full size table
Fig. 4
figure 4

Control in primary prevention: high or very high risk patients. LDLc low-density lipoprotein cholesterol, DM diabetes mellitus, CVD cardiovascular disease

Full size image

Discussion

It has been shown that hypercholesterolemia is significantly present among patients with an increased vascular risk and those who have already suffered a CV event: 50–84% of patients with DM [44, 57, 67, 68, 74], 30–50% of high risk patient [1, 3, 76–78], and between 35% and above 80% in those with overt CVD, depending on the type of event [15–41, 44–60]. The association of this condition with the risk of CV events [9, 83] makes it all the more necessary to endorse the interventions aimed at managing the modifiable risk factors (diet and exercise), to prescribe a LLT accordingly to individual’s CV risk [7], and also to plan an adequate monitoring of the pharmacological therapies implemented to maximize their benefit. There are many examples of this relationship in our country: hypercholesterolemia doubled the risk of an ischemic disease [84, 85], and would be the cause of 22% of all coronary events. The risk increased significantly among patients who did not have their lipid values controlled, while among those diagnosed with controlled hypercholesterolemia and, who are undergoing a lipid-lowering treatment, the increased risk of ischemic heart disease was not statistically significant [84].

Due, in large part, to the information above, the use of lipid-lowering drugs in Spain has increased from 18.9 defined daily doses (DDD) per 1000 inhabitants per day (DDD/1000 inhabitants/day) in the year 2000 to 102.6 DDD/1000 inhabitants/day in the year 2012, an increase of 442% [86]. Statins are the most commonly used drugs (91.7 DDD/1000 inhabitants/day in 2012) representing 89.3% of all LLT, but also fibrates, bile-acid sequestrants, ezetimibe, and omega 3 fatty acids contributed during 2012 to LLT use [86]. The increase in the use of LLT can be justified by their ability to reduce the risk of CV events, and the associated burden of disease.

Although treatments available have led to an improvement in the clinical situation and prognosis of these cases, it is clear that there is a lot of effort still to be made until LDLc targets defined by current European guidelines [7] can be reached by most of patients. In all of the groups analyzed, an important number could still be found with total cholesterol and LDLc levels above the acceptable threshold. For example, among diabetics, only between 15% (in case of those with previous CVD) and 40–50% (in those without CVD) attained recommended levels of lipids in the blood [26, 69–71], and the situation is not better in secondary prevention or among patients with HeFH. This picture, which is similar to other western countries [87–89], highlights the need to continue maximizing the control of lipids in the blood and to minimize therapeutic inertia. Regarding this, in one recent study with CHD patients, therapeutic inertia was estimated to be as high as 73% [33].

It should be noted, as the main limitation of the present work, how difficult it is to make a more exact approximation of the estimations presented in this manuscript. This is due in great part to the sheer heterogeneity of the criteria used in the various studies in defining hypercholesterolemia, CV risk, ACS or CHD. In addition, one other relevant aspect to consider is the nature of the studies included. They are mainly cross-sectional investigations and with a wide range of different sampling procedures and sample sizes. Even more, many studies are based on the analysis of individuals coming from the same national databases or registries. Considering these important constraints, a more analytic approach as meta-analysis might be applied at least with those studies following comparable clinical criteria to have a more accurate estimation of disease prevalence and control in each of the groups of interest, and to highlight the significance of the heterogeneity found between studies. Despite this, an important strength of the present manuscript is that all the relevant studies carried out in Spain and published in peer review journals have been systematically identify and reviewed to facilitate a global but comprehensive report of this condition in our country.

Conclusions

There is an elevated prevalence of hypercholesterolemia in Spain among those selected groups with a high CV risk. Although LLT is present in an elevated proportion, controls rates of lipid levels need to be improved both in primary and secondary prevention.