Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, accounting for approximately 20.5 million deaths in 2021.1 Ischemic heart disease and stroke together represent the vast majority of these deaths, comprising around 85% of all CVD-related mortality.1 In Portugal, CVD is likewise the primary cause of death, responsible for 26.5% of all fatalities in 2022.2 That year, ischemic heart disease accounted for 5.5% of total deaths, while cerebrovascular disease contributed to 7.7%.2

Dyslipidemia is a major modifiable risk factor for atherosclerotic CVD (ASCVD), particularly in relation to myocardial infarction (MI), ischemic stroke, and peripheral arterial disease.3–5 Extensive evidence from epidemiological studies and Mendelian randomization analyses has established a causal role for low-density lipoprotein cholesterol (LDL-C) in the development of atherosclerotic plaque and the occurrence of subsequent cardiovascular (CV) events.6 Consistent findings from randomized controlled trials have demonstrated that reducing LDL-C levels safely lowers the risk of CV events.7,8 A landmark meta-analysis showed that each 1 mmol/L reduction in LDL-C with statin therapy, sustained over five years, results in a 21% relative reduction in major vascular events – regardless of sex, baseline LDL-C concentration, or history of vascular disease.9 Furthermore, LDL-C lowering with non-statin therapies – including ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and bempedoic acid – has been shown to confer comparable CV risk reduction per mmol/L decrease in LDL-C, reinforcing the principle that “lower is better” for LDL-C.7,10,11

Lowering LDL-C is a cornerstone of therapy in patients at high or very high risk for ASCVD, as well as in those with established ASCVD.12 The 2019 guidelines from the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) recommend a ≥50% reduction in LDL-C from baseline, with target levels of <70 mg/dL for high-risk individuals and <55 mg/dL for those at very high risk, including patients with documented ASCVD.12 Importantly, emerging evidence highlights that the duration of LDL-C lowering is as critical – if not more so – than the absolute LDL-C level achieved or the intensity of LDL-C reduction, emphasizing the long-term benefit of sustained lipid control.13

Despite strong evidence and clear guideline recommendations, real-world data consistently show low rates of LDL-C goal attainment. The EUROpean Action on Secondary and Primary Prevention by Intervention to Reduce Events (EUROASPIRE) V survey assessed lipid control among 7824 patients with coronary heart disease (CHD) across 27 countries and found that although nearly half were receiving high-intensity lipid-lowering therapy (LLT), only 32.3% of men and 23.1% of women achieved LDL-C levels below 70 mg/dL – the recommended target for very high-risk individuals at the time of the study.14 Similarly, the EU-wiDe cross-sectionAl obserVatIoNal study of lipid-modifying therapy use in seCondary and prImary care (DA VINCI) study, a cross-sectional observational analysis of 5888 patients from 18 countries receiving LLT, which was high-intensity in 38% of patients, reported that just 33% met the 2019 ESC/EAS LDL-C targets overall, with only 18% of very high-risk patients achieving the <55 mg/dL threshold.15 The Treatment of high and very high riSk dyslipidemic pAtients for the preveNTion of cardiOvasculaR events in Europe–a multInatioNal observatIonal (SANTORINI) study, which included 9136 high- and very high-risk patients from 14 European countries, further highlighted this gap.16 At baseline, 44% of patients were on high-intensity LLT, increasing to 60% at one year.17,18 Despite treatment intensification in approximately one-third of participants, only 25.5% of patients receiving monotherapy and 39.4% of those on combination LLT reached their LDL-C targets after one year.18

The SANTORINI study is the first large-scale European observational study conducted after the release of the 2019 ESC/EAS guidelines, designed to evaluate real-world patterns in the use of LLT and its effectiveness in managing LDL-C levels in high- and very high-risk patients.16 In this analysis, we focus on the cohort of patients enrolled in Portugal.

The aims of this analysis were to describe patient characteristics, assess patterns of LLT use, and evaluate the extent to which LDL-C targets – defined by the 2019 ESC/EAS dyslipidemia management guidelines – are being achieved in routine clinical practice.

In the Portuguese cohort of the largest European observational study investigating LLT use and LDL-C goal attainment, conducted after the publication of the 2019 ESC/EAS guidelines for the management of dyslipidemia, we observed minor changes in mean LDL-C levels in both high- and very high-risk patients over one year of longitudinal follow-up, despite a reduction in the number of patients not taking any LLT and an increase in the proportion of patients taking a combination of a statin and ezetimibe. Over the same period, LDL-C goal attainment declined in both high-risk and very high-risk patients, to a degree that exceeded what would be anticipated based on the change in mean LDL-C levels alone.

These findings differ markedly from those observed in the patient cohort from the other 13 countries participating in the SANTORINI study, where mean LDL-C levels decreased by 17 mg/dL and the proportion of patients achieving LDL-C goals increased 1.47-fold over one year. Although a greater proportion of patients in Portugal were at goal at baseline compared to the other countries (30.4% vs. 21.1%), this trend reversed at one-year follow-up, with more patients outside Portugal achieving LDL-C targets.

Several factors may have contributed to the observed discrepancies between the Portuguese cohort and the patient populations from other participating countries. First, the mean baseline LDL-C level was lower in the Portuguese cohort (81.0 mg/dL) compared to the group of patients from the other participating countries (93.7 mg/dL). This difference may, in part, be explained by a lower proportion of patients not receiving any LLT and a higher proportion receiving combination LLT in the Portuguese cohort at baseline. Second, the Portuguese cohort included fewer patients with investigator-reported ASCVD (60.7% vs. 77.6%) and fewer classified as being at very high CV risk (56.4% vs. 71.4%) compared to patients from the other participating countries. Consequently, due to this more favorable risk profile and the lower mean baseline LDL-C level, patients in the Portuguese cohort were, a priori, more likely to be closer to or already at the recommended LDL-C target at baseline. In fact, a higher proportion of Portuguese patients had already achieved the LDL-C goal at baseline compared with all other patients. For the same reasons, the need for LLT intensification was lower in Portugal, which may partly explain the lower rate of LLT escalation observed between baseline and one-year follow-up in the Portuguese cohort compared to that of the other countries (12.8% vs. 26.3%). Third, although combination LLT was more frequently used at one-year follow-up in Portugal compared to other countries (50.4% vs. 37.8%), a notable proportion of patients in the latter group (6.7%) received a PCSK9 inhibitor in combination with at least one other LLT, whereas no patients in the Portuguese cohort were treated with a PCSK9 inhibitor. The potent LDL-C–lowering effect of PCSK9 inhibitors, especially when used in combination regimens, may have contributed to the higher proportion of LDL-C goal attainment at one-year follow-up in patients from other countries compared with those from Portugal (31.0% vs. 22.6%). The absence of PCSK9 inhibitor use in the Portuguese cohort may reflect the lower proportion of patients with investigator-reported ASCVD at baseline, as current guidelines provide weaker recommendations for PCSK9 inhibitor use in primary prevention settings compared with secondary prevention.12 Fourth, although LLT de-escalation was infrequent overall, it occurred more often in Portugal compared to other countries (6.0% vs. 2.2%). This difference may have further contributed to the lower proportion of patients achieving LDL-C goals at one-year follow-up in the Portuguese cohort. Moreover, despite the lower mean LDL-C level at baseline in the Portuguese group, the combination of more frequent LLT de-escalation and less frequent therapy escalation may help explain the higher mean LDL-C level observed at follow-up in this cohort compared to patients from the other participating countries.

Another notable observation in the Portuguese cohort is the disproportionately large reduction in the proportion of patients at LDL-C goal from baseline to one-year follow-up (30.4% to 22.6%), despite only a minimal increase in mean LDL-C levels during this period (81.0–81.6 mg/dL). This finding suggests that many patients who were at LDL-C goal at baseline had LDL-C levels close to the upper limit of the guideline-recommended targets (55 mg/dL for very high-risk and 70 mg/dL for high-risk individuals). As such, even a slight increase in LDL-C levels may have been sufficient to shift a substantial proportion of these patients out of goal range.

The comparison between the Portuguese cohort and patients from other countries underscores two key practical points. First, patients in the Portuguese cohort were more frequently on LLT at baseline, particularly combination therapy, which corresponded with a higher rate of LDL-C goal achievement. This observation is consistent with prior research19 and the overall findings of the SANTORINI study,18 supporting the superior efficacy of combination LLT over statin monotherapy in reaching LDL-C targets. Consequently, many experts recommend shifting clinical practice toward initiating high-intensity combination LLT rather than relying solely on high-intensity statin monotherapy to better mitigate residual CV risk associated with inadequate LDL-C management.20 Second, during the one-year follow-up period, LLT was escalated in only 12.8% of patients in Portugal, compared with 26.3% in the other countries. This indicates a higher prevalence of therapeutic inertia in the Portuguese cohort, with a ratio of LLT intensification to non-intensification of 1:6.7, vs. 1:2.8 in the other group. Strategies proven to reduce therapeutic inertia and improve LDL-C control include multidisciplinary, team-based collaborative care.21 These approaches can help address common barriers, such as limited physician time, by involving other healthcare professionals – including nurses and pharmacists – in patient education regarding medication intensification, adherence, and side effect management. However, current implementation research has limitations, including predominantly single-center studies, methodological weaknesses, and insufficient evaluation of innovative tools like artificial intelligence. Therefore, further high-quality implementation research is needed to identify effective, sustainable interventions to optimize lipid management in the long term.

The rate of LDL-C goal attainment in the Portuguese cohort of the SANTORINI study compares favorably with prior studies conducted in Portugal, including DYSIS-Portugal,22 DISGEN,23 Portuguese cohort of patients with CHD in EUROASPIRE V,24 LATINO,25 PORTRAIT-DYS,26 and LATINO-ACS.27 Nevertheless, mean LDL-C levels at one-year follow-up remained substantially above guideline-recommended thresholds: 90.1 mg/dL in high-risk patients and 75.2 mg/dL in very high-risk patients – approximately 20 mg/dL above their respective targets. Based on the well-established relationship between LDL-C levels and CV outcomes, this 20 mg/dL excess corresponds to an estimated 10% increase in relative risk of major vascular events over five years, representing a missed opportunity to prevent avoidable and potentially life-threatening events. A 22% reduction in mean LDL-C would be needed to achieve the 70 mg/dL target in high-risk patients, and a 27% reduction would be required to reach the 55 mg/dL goal in very high-risk patients. Clinical studies have demonstrated that adding bempedoic acid to maximally tolerated statin therapy can reduce LDL-C levels by 17–23% in patients at high or very high CV risk.28 Notably, no patients in the Portuguese cohort received bempedoic acid during the study period. Incorporating this therapy into treatment strategies may help a substantial proportion of patients not at goal to achieve guideline-recommended LDL-C levels.

Several limitations of this study must be acknowledged. First, although recruitment was conducted across multiple sites by physicians from various specialties and broad inclusion criteria were applied, the relatively small sample size may limit both the internal and external validity of the findings. To address this, 95% confidence intervals have been provided for the proportions of patients achieving LDL-C targets. Second, as sites involved in clinical research often differ systematically from those that do not participate, the results may reflect a best-case scenario and may not be fully generalizable to routine clinical practice. Third, CV risk may have been underestimated in some patients classified as very high risk. It remains unclear whether this potential misclassification led to physicians targeting an LDL-C goal of 70 mg/dL rather than the recommended 55 mg/dL, which could have artificially inflated the observed rate of LDL-C goal attainment. Fourth, the definition of LDL-C goal attainment was based solely on absolute risk-based thresholds (70 mg/dL and 55 mg/dL), without considering the additional guideline-recommended criterion of at least a 50% reduction from baseline levels. Finally, given the observational, non-interventional, and cross-sectional design of the study, medication adherence was neither systematically assessed nor supported through targeted interventions, limiting insight into real-world treatment effectiveness.

In summary, the Portuguese cohort of the SANTORINI study reveals both meaningful progress and ongoing challenges in real-world dyslipidemia management following the 2019 ESC/EAS guidelines. At baseline, the greater use of combination LLT with statins and ezetimibe, coupled with reduced reliance on statin monotherapy, was associated with superior LDL-C goal attainment compared to other European cohorts. However, over the one-year follow-up period, LDL-C goal achievement declined among both high- and very high-risk patients, diverging from the improvements observed in other participating countries. This unfavorable trend likely reflects suboptimal treatment intensification, limited integration of adjunctive therapies such as PCSK9 inhibitors and bempedoic acid, and persistent clinical inertia. These findings underscore the urgent need to optimize guideline-concordant lipid management in Portugal by expanding access to potent combination LLT and implementing comprehensive strategies to address therapeutic inertia. Enhancing LDL-C control in high- and very high-risk patients represents a pivotal opportunity to reduce preventable CV events and improve long-term clinical outcomes.

SANTORINI was funded by Daiichi Sankyo Europe GmbH, Munich, Germany. The funder had a role in the study design, data collection, data analysis, and interpretation. Moreover, the funder provided medical writing support in accordance with Good Publication Practice.

Carlos Aguiar has received payments for speaker services, consultancy, and research activities from the following entities: Abbott, Abbvie, Amgen, Alnylam, AstraZeneca, Bayer, BiAL, Boehringer Ingelheim, Daiichi Sankyo, Ferrer, Gilead, GSK, Lilly, Novartis, Novo Nordisk, Pfizer, Sanofi, Servier, Takeda, Tecnimede. Patrício Aguiar received grants/research support from Takeda, and honoraria from Takeda, Alexion, Alnylam, Sanofi, Amicus, Biomarin, Ultragenyx, Chiesi, MSD, Bayer, Daiichi Sankyo, Viartris, Menarini, Novartis, Amgen, and GSK. P.M. has received payments for speaker services, consultancy, and research activities from Daiichi Sankyo. Fausto Pinto reports receiving personal fees from Boehringer Ingelheim, Daichi Sankyo, Novartis, Servier, Vifor, and Zydus and serving on advisory boards for Daiichi Sankyo, Medtronic, Novartis, Servier, and CSL Vifor. Pedro von Hafe has received speaker fees from Boehringer Ingelheim, Astra Zeneca, Daichi Sankyo, and Novartis. Carla Teixeira and Jorge Ruivo are employees of Daiichi Sankyo. Alberico Catapano, in the last three years, has received honoraria, lecture fees or research grants from Aegerion, Akcea Therapeutics, Amarin, Amgen, Amryt Pharma, AstraZeneca, Daiichi Sankyo, Esperion, Ionis Pharmaceutical, Medscape Education, Menarini, Merck, Mylan, Novartis, Novo Nordisk, PeerVoice, Pfizer, Recordati, Regeneron, Sanofi, The Corpus, and Viatris. Kausik Ray reports unrestricted research grants (last three years) from Imperial College London, Amarin, Amgen, Sanofi, Regeneron, Daiichi Sankyo, and Ultragenix; Consulting fees from Novartis, Daiichi Sankyo, Kowa, Esperion, Novo Nordisk, MSD, Lilly, Silence Therapeutics, AZ, New Amsterdam Pharma, Bayer, Beren Therapeutics, CLEERLY, EMENDOBIO, SCRIBE, CRISPR, VAXXINITY, Amarin, Regeneron, Ultragenix, for serving as a member of the SC or EC of clinical trials and roles as PI, NLI, attending advisory boards; lecture fees from Novartis, BI, AZ, Novo Nordisk, Viatris, Amarin, Sanofi, Amgen, Esperion, Daiichi Sankyo, Macleod Pharma for CME and non-CME symposia at international meetings; stock options from New Amsterdam Pharma, SCRIBE and PEMI31. João Sequeira Duarte, Victor Gil, Jorge Mimoso, Fernando Pinto, and João Raposo report no conflicts of interest.