LDL cholesterol (LDL-C) is a modifiable risk factor causally related to atherosclerotic cardiovascular disease (ASCVD) [1, 2]. Strong evidence from clinical trials supports the cardiovascular benefits of lowering LDL-C by statins, cholesterol absorption inhibitors (e.g. ezetimibe), and PCSK9 inhibitors [1]. Major international guidelines therefore recommend lowering of LDL-C to risk-dependent goals to reduce ASCVD risk [3, 4]. However, these treatment targets are only achieved in a minority of patients. Registries such as the EUROASPIRE V survey in 27 European countries report that an LDL-C below 70 mg/dL is achieved in less than a third of very-high-risk patients [5, 6]. Current treatment goals recommended by the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) for these patients are even lower (< 55 mg/dL) [4]. Statins are recommended as first-line therapy to reduce LDL-C. However, in patients with high baseline LDL-C or in patients that cannot tolerate high statin doses, e.g., because of muscle symptoms [7], statin monotherapy may not be sufficient to attain the LDL-C target. This underlines the need for additional non-statin lipid-lowering therapies (LLT) such as ezetimibe [8].

Data on trends in the prescription of oral non-statin LLT may inform real-world utilization of these drugs and help identify opportunities to improve the low rates of LDL-C target attainment. This includes the use of fixed-dose combinations (FDC). In patients with hypertension, FDC have been shown to improve medication adherence and blood pressure control [9, 10]. FDC are therefore recommended by the current ESC guidelines on the treatment of hypertension [11]. However, the available data on FDC for the treatment of dyslipidaemia are sparse.

The main objectives of this study were to analyse (1) prescription trends of oral non-statin LLT in Germany, (2) trends in the prescription of statin/ezetimibe combinations as FDC or separate pill combinations (SPC), and (3) LDL-C reductions achieved with statin/ezetimibe combinations, comparing FDC and SPC in a large cohort of patients at very-high cardiovascular risk.

In this analysis of 311,242 German outpatients at very-high risk of ASCVD, prescriptions for high-potency statins increased from 2013 to 2018. Prescriptions for non-statin LLT remained stable over the study period, with an increase in ezetimibe prescriptions balanced by a decrease in fibrates prescriptions among GPs and a decrease in prescriptions for other non-statin LLTs among cardiologists. The most frequently prescribed and increasingly utilized non-statin LLT was ezetimibe. An important and novel finding is that LDL-C reduction was significantly greater when statin and ezetimibe were prescribed as fixed dose combination (FDC) compared with separate pill combinations (SPC). Our study shows the potential of lipid-lowering combination therapy and suggests that, similar to current recommendations for anti-hypertensive treatment, FDC prescription should be preferred over SPC.

The current ESC/EAS guidelines for the management of dyslipidaemias [4] introduced an LDL-C target of 55 mg/dL for very-high-risk patients. While statins remain the cornerstone of lipid lowering in patients at very-high cardiovascular risk, current LDL-C treatment targets will not be reached in many patients receiving statin monotherapy, and additional non-statin LLT is needed [18]. Our study confirms the effectiveness of ezetimibe in lowering LDL-C in a real-world setting. The observed relative LDL-C reductions are comparable to those seen in the IMPROVE-IT trial [19]. Our data therefore support the use of combination LLT as an important strategy to improve LDL-C target attainment in the ASCVD population.

Another important and novel finding is the larger proportional and absolute LDL-C reduction observed in patients receiving statin/ezetimibe FDC as compared to SPC, resulting in a higher percentage of patients achieving LDL-C target. In hypertension, a reduction in the number of tablets prescribed is associated with better medication adherence and blood pressure control [10]. An analysis from an Australian health dataset found no association between statin/ezetimibe FDC and medication possession ratio; however, this study did not assess cholesterol effects [20]. In contrast, in the treatment of hypertension, there are several studies showing improved medication adherence under FDC treatment compared to SPC [9, 10]. Moreover, higher adherence is associated with lower LDL-C levels [21, 22], and adherence to lipid-lowering and blood pressure-lowering therapies is strongly correlated [22]. While our study cannot prove the underlying cause of improved LDL-C lowering with FDC, the aforementioned data suggest better medication adherence is a likely explanation. However, it is relevant to note that, following the addition of ezetimibe to statins and despite the additional decrease in LDL-C, few patients with very-high cardiovascular risk achieved the recommended LDL-C levels. Our data suggest that, in addition to ezetimibe, many patients with very-high cardiovascular risk will require the addition of high-potency therapies such as PCSK9 inhibitors to bring LDL-C levels below the recommended targets.

Our results highlight the importance of medication adherence for chronic conditions, which has been associated with mediators of ASCVD such as LDL-C or blood pressure, and also with mortality [23‐25]. Considering the same amount of drug is considerably more efficacious when provided as FDC, our findings highlight the importance of strategies to support medication adherence. In this respect, it appears beneficial to introduce novel non-statin oral LLT as FDC formulations [26]. Identification of patients at risk of low adherence, such as patients with depression, may inform prescription choices [22] and measures to improve medication adherence should gain more attention [27].

Our study has limitations. We do not have data on medication adherence which would strengthen our conclusion. Furthermore, the reasons why physicians prescribed FDC or SPC cannot be derived from the data, potential certain confounding related to the prescribing individuals is possible and could only be excluded by a randomized trial. Strengths of our study are the inclusion of a very large and representative cohort and the long observation period. Another strength of the dataset is the longitudinal follow-up of LDL-C that allows for inferences on changes in parameters due to changes in medication.

In conclusion, we provide definitive information regarding trends in LLT prescriptions in Germany from 2013 to 2018. Prescriptions for high-intensity statins and ezetimibe increased over time. Ezetimibe added to statin therapy effectively reduced LDL-C and increased the proportion of patients with controlled LDL-C, with FDC treatment being more effective than SPC. These data identify practical strategies to improve LDL-C goal achievement for ASCVD prevention. However, a high proportion of patients remain with uncontrolled LDL-C despite the combination of oral LLT.