Abstract Background Combination lipid-lowering therapies (LLT) are likely needed to achieve the 2019 ESC/EAS low-density lipoprotein cholesterol (LDL-C) targets. The potential clinical utility of combining the three available oral medications - statins, ezetimibe, and bempedoic acid (BA) - has not been characterized in larger real-world populations. Purpose To estimate LDL-C goal attainment and the predicted 10-year cardiovascular (CV) risk reduction in a European cohort of high- and very-high-risk patients not at LDL-C goal, by simulating the potential impact of an optimized triple oral LLT pathway. Methods SANTORINI is an observational study of European patients at high or very high CV risk. Patients were eligible for the simulation of treatment optimization if they were not at LDL-C goal without LLT or despite receiving statins and/or ezetimibe. Patients receiving a PCSK9 inhibitor, BA, or oral LLT without statins were excluded. A Monte Carlo simulation (10,000 iterations) modelled a three-step LLT intensification pathway: statin optimization, consisting of initiation (atorvastatin 40mg) or up-titration (to atorvastatin 40mg, if not already on higher or equivalent statin intensity or on combination therapy with ezetimibe), ezetimibe addition, and BA addition if LDL-C remained above goal after each optimization step. The expected reduction in LDL-C and predicted 10-year CV risk reduction were assessed. Results Among 6,323 eligible patients (mean age 65.5 years, baseline LDL-C 104.5 mg/dL), 92.1% were at very high CV risk, with 29.3% receiving no LLT, 53.2% on statin monotherapy, and 17.5% on statin + ezetimibe (Table). Following treatment optimization, all patients received statins, 87.6% received statin + ezetimibe, and 60.9% received statins + ezetimibe + BA (Figure). The proportion of patients at LDL-C goal increased from 0% at baseline to 12.4% (n=781) after statin optimization (consisting of 8.8% (n=555) after initiation and 3.6% (n=226) after up-titration), 39.1% (n=2,473) after ezetimibe addition, and 61.8% (n=3,906) after BA addition. Mean LDL-C levels declined from 104.5 mg/dL at baseline to 82.1 mg/dL, 68.2 mg/dL, and 59.8 mg/dL, respectively. The predicted relative risk reduction in major CV events (as defined by the CTTC) in the simulation cohort was 11.8% after statin optimization, 18.7% after ezetimibe addition, and 22.6% after BA addition, equating to predicted absolute risk reductions of 3.7%, 5.7%, and 6.8%, respectively, from a baseline 10-year risk of 29.8%. Conclusions Real-world data from the large contemporary SANTORINI cohort suggest that stepwise optimized oral combination therapy with statins, ezetimibe, and BA could enable six in ten patients to achieve LDL-C goals, with predicted meaningful long-term CV risk reduction compared with statins alone.
Katzmann et al. (Sat,) studied this question.