Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in Europe, resulting in 3.9 million deaths every year.1 Low-density lipoprotein cholesterol (LDL-C) plays a pivotal role in the development of atherosclerosis and plaque formation, resulting in impaired blood flow and an elevated risk of cardiovascular (CV) events.2 For this reason, reducing LDL-C levels has become a cornerstone for CVD prevention.3 In fact, a decline of one mmol/L in LDL-C has been associated with a relative risk reduction of up to 23% in major vascular and coronary events, as well as a 10% decrease in total mortality over a 5-year period.4,5 Consequently, the 2019 update of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guidelines recommended more stringent LDL-C targets, i.e. below 70 mg/dL (<1.8 mmol/L) and 55 mg/dL (<1.4 mmol/L) for patients at high and very high CV risk, respectively, together with a minimum 50% reduction in LDL-C levels from baseline.5 To cope such aim, combination therapy (involving statins and non-statin lipid-lowering treatments, LLTs) is highly recommended for these patients.6,7 In statin-naïve patients, combination therapy with ezetimibe and statin has resulted in approximately 15% greater LDL-C reduction compared to statin monotherapy at same doses.5,8 Additionally, this combination has led to more significant LDL-C reductions compared to doubling the statin dose (13–20%) and switching from statin monotherapy to ezetimibe and statin combination therapy (11–15%). Over the past decade, real-world studies using less stringent LDL-C thresholds have consistently demonstrated that many patients, including those at high and very high risk, fail to reach the recommended LDL-C levels.9–13 These studies have also evidenced that LLTs are mainly statin-based monotherapy, and that combination therapy is used by a minority. To date, real-world studies evaluating the impact of 2019 ESC/EAS guidelines on the use of LLTs are scarce.14,15

The SANTORINI was a prospective, multinational, observational study aimed at evaluating the implementation of the 2019 update of the ESC/EAS guidelines in adult patients at high and very high CV risk from 14 European countries between 2020 and 2021.16 Baseline results of 9136 patients revealed that 20.9% of them were not receiving LLTs, 53.6% were treated with LLT monotherapy, and 25.6% were on combination therapy. Out of the 7,210 patients with complete baseline and follow-up LDL-C data, goal attainment increased from 21.2% at baseline to 30.9% at 1-year follow-up.16 LLTs were escalated in one third of patients. The use of monotherapy and combination therapy (n = 9136) also rose (from 53.6% to 57.1%, and from 25.6% to 37.9%, respectively).16

In the present manuscript we present the baseline and 1-year follow-up data on the LLT usage and LDL-C goal attainment in the Spanish subpopulation from SANTORINI (namely SANTORINI Spain) and show the results in perspective with respect to the European cohort without Spanish participants (namely SANTORINI Europe without Spain).

The present results from SANTORINI Spain reveal an increase in LLT use and in the percentage of patients achieving the recommended 2019 ESC/EAS LDL-C targets after 1-year of follow-up. Real-world studies conducted before the publication of the 2019 ESC/EAS guidelines already revealed the suboptimal LDL-C goal attainment in patents at high and very high risk.9–13 At the same time, the studies highlighted that these patients were not receiving the most adequate LLT for reducing their LDL-C levels. In DA VINCI study, carried out between 2017 and 2018, 63% of patients at high risk and 39% at very high risk achieved the 2016 ESC/EAS risk-based goals.12 In addition, the study showed that 84% of LLTs were statin-based monotherapy, whereas 10% was represented by combination therapy. After the 2019 update of the ESC/EAS guidelines only few studies have evaluated the implementation of the more stringent LDL-C thresholds and the usage of LLTs in routine clinical practice.14,15 In Europe, SANTORINI has reported a change in LDL-C attainment from 21.2% at baseline to 30.9% after 1-year of follow-up in the 7210 patients with complete LDL-C data.16 The usage of LLT monotherapy increased from 53.6% to 57.1%, and combination therapy from 25.6% to 37.9%. In fact, a better LDL-C control was reported in patients who were receiving combination therapy. Numerous studies have evidenced the use of combination therapy, both oral (statins, ezetimibe, and bempedoic acid) and subcutaneous (adding PCSK9 inhibitors) for substantially reducing LDL-C, specifically in patients at highest CV risk.6,19–22 In the multicenter, randomized, double-blind, placebo-controlled FOURIER20 and ODYSSEY21 trials, the addition of evolocumab or alirocumab to high-intensity statin therapy decreased the risk for CV events by 15% over approximately two years. In the Treat Stroke to Target study, 2860 patients with a history of ischemic stroke or transient ischemic attack were randomized to achieve an LDL-C level below 70 mg/dL (lower-target group) or between 90 and 110 mg/dL (higher-target group).22 The group with the lower LDL-C goal had a 30% lower risk of experiencing a subsequent MACE. Notably, 40% of patients in the lower LDL-C arm received combination therapy with statin plus ezetimibe. Recent data further show that combination therapy, especially fixed-dose combinations, achieves more effectively lipid targets and CV prevention.23,24 In addition, implementing combination therapies from the early stages, or even from the outset, is suggested to increase the number of patients achieving LDL-C goals, thereby preventing new CV events and improving existing atherosclerotic lesions.6

Basing on evidence, international guidelines recommend the use of combination therapy to achieve the ambitious LDL-C goals. Despite this, as previously mentioned, there is a substantial gap between recommendations and routine clinical practice in the management of dyslipidemias. For instance, a retrospective analysis of the Swiss Secondary Prevention Registry (SwissPR) involving 875 patients with coronary artery disease reported that, following the 2019 ESC/EAS guidelines, only 18% of patients were receiving combination therapy with ezetimibe upon entry into cardiac rehabilitation, and 2% were prescribed with PCSK9 inhibitors.25 Barriers contributing to the gap between guidelines recommendations and routine clinical practice may include those related to the physician (i.e. therapeutic inertia or the misperception of attained LDL-C targets), or to the healthcare system (such as restricted access to combination therapy and/or add-on therapies).26,27 Selecting the most appropriate LLT capable of achieving therapeutic targets from the outset often entails the upfront use of combination therapy, rather than relying on the traditional stepwise approach, which remains endorsed by current dyslipidemia management guidelines.5,28 Initiating therapy based on treatment goals may not only facilitate faster attainment of lipid targets but also minimize the therapeutic inertia.

In our SANTORINI Spain cohort, the increase in LLT usage led to a decrease in LDL-C levels in both patients at high and very high risk. Consequently, the percentage of patients who achieved LLT goals also increased in the same period of time. Interestingly, patients who especially improved the LDL-C control were those who were not receiving LLT at baseline (from 8.6% to 32.4%). In contrast, patients who were receiving LLTs at baseline showed a more modest improvement in LDL-C control, which was observed only in those who changed to combination therapy. Despite of this, in our study, LLT during the 1-year follow-up was unchanged in most of the patients (73.1%). This observation aligns with previous studies, showing that LLT optimization often involves only statin dose escalation.6,7,16 Interestingly, in a Czech study evaluating the adherence of cardiologists to guidelines, authors showed that, in up to 61.5% of the patients at very high CV risk who failed to reach their LDL-C targets, their cardiologists expressed satisfaction with the therapeutic outcomes and chose not to change the treatment.7

When comparing to SANTORINI Europe,16 the overall percentage of patients achieving LDL-C targets after 1-year of follow-up was numerically higher in Spain (34.1% versus 30.4% in Europe). However, in Spain it was lower in patients at high risk (27.3% versus 31.6%) but higher in those at very high risk (37.0% versus 30.0%). The lower achievement of targets in patients at high risk in Spain contrasts with the fact that a greater percentage of patients at high risk in Spain were using combination therapy. This observation could be attributed to a higher percentage of patients included with familial hypercholesterolemia in Spain, 15.4% versus 10.4% in Europe, or possibly due to differences in the CV risk classification between Spain and Europe.16

One limitation of the study may derive from the potential selection bias inherent in observational studies. Participating sites, frequently more experienced, might show a best-case scenario. Additionally, the 50% reduction in LDL-C from baseline was not considered for evaluating the attainment for LDL-C goals. Given the non-interventional nature of the study, no formal hypotheses were tested; thus, conclusions should be cautiously made. Despite these limitations, this is the first prospective study that provides an up-to-date picture of the lipid management and LDL-C goal attainment in patients at highest CV risk in Spain after the 2019 update of the ESC/EAS guidelines. In addition, it presents data on a large cohort of patients with available LDL-C levels from both baseline and 1-year follow-up.

Data of 1-year follow-up from SANTORINI Spain show that the LLT usage increased from baseline, including both monotherapy and combination therapy. Despite recommendations, patients at highest CV risk continue not receiving the most adequate LLT for reducing their LDL-C levels in routine clinical practice. Future dyslipidemia management guidelines should recommend tailoring initial LLT to the magnitude of the LDL-C reduction required, in order to achieve therapeutic goals earlier and reduce therapeutic inertia.

This study was funded by Daiichi Sankyo Europe GmbH, Munich, Germany. Medical writing assistance was provided by Evidenze Health España S.L.U. and funded by Daiichi Sankyo Europe.