Background: The 2019 joint ESC/EAS guidelines specify lower low-density lipoprotein cholesterol (LDL-C) goals that are based on outcome evidence but require greater use of combination therapies to achieve. Access to PCSK9 inhibitors, the efficacy of ezetimibe, and statin-associated muscle symptoms may be barriers in achieving LDL-C goals.

Purpose: To estimate the number of patients with high or very high cardiovascular risk reaching their LDL-C goal with the addition of oral bempedoic acid (BA) after ezetimibe in the treatment pathway, using a simulation model in a real-world cohort of German patients.

Methods: SANTORINI (NCT04271280) is an observational study of European patients with high or very high cardiovascular risk. Patients in Germany receiving any known lipid-lowering therapy and with baseline LDL-C data were eligible for this analysis. For patients whose LDL-C exceeded their risk-based goal and who were not receiving a PCSK9 inhibitor at baseline, a two-step intensification of lipid-lowering therapy with ezetimibe first and BA second was simulated using probabilistic distributions reflecting their efficacy in clinical trials through a Monte Carlo simulation with 10,000 iterations.

Results: Patients in Germany eligible for the analysis (N = 1,458) had a mean age of 66.3 years and a mean baseline LDL-C of 86.6 mg/dL (Table 1). Most patients (78%, n = 1,132) were at very high risk, with 22% (n = 326) at high risk; 15% (n = 214) were at LDL-C goal, 95% (n = 1,381) were on statins, 26% (n = 376) were on ezetimibe, and 5% (n = 74) were on a PCSK9 inhibitor (Table 1). Of 1,200 patients who entered the treatment simulation, 921 were not receiving ezetimibe at baseline. Following the simulation of ezetimibe treatment, 26% (236/921) were predicted to achieve their risk-based goal. The remaining patients not at goal after ezetimibe (964 patients in total) were assigned BA treatment in the simulation, which was predicted to result in a further 33% of patients reaching their LDL-C goal (n = 323/964). Overall, the number of patients at goal in the cohort of 1,458 patients would be expected to increase from 15% (n=214) at baseline to 31% (n=450) and 53% (n=773) after addition of ezetimibe and BA, sequentially (Figure 1). The mean LDL-C for the whole cohort would be expected to fall through this pathway from 86.6 mg/dL at baseline to 72.7 mg/dL and 62.9 mg/dL, respectively.

Conclusion: Real-world evidence from the SANTORINI cohort in Germany showed low LDL-C goal attainment. Sequential oral combination therapy with statin, ezetimibe, and BA could increase LDL-C goal attainment by more than three times (from 15% at baseline to 53%).

Table 1.           Baseline Characteristics of the SANTORINI Simulation Cohort

Figure 1.        Patient LDL-C Distribution at Baseline and After the Lipid-Lowering Therapy Intensification (Two-Step, Ezetimibe First and BA Second) Simulation