Background: Current ESC/EAS guidelines for the treatment of dyslipidemias recommend more aggressive targets for low-density lipoprotein cholesterol (LDL-C) in patients at high cardiovascular (CV) risk and in patients with familial hypercholesterolemia (FH). Standard lipid-lowering treatment (LLT) is often inadequate to achieve these targets, particularly in patients with high baseline LDL-C and/or statin intolerance. In these “difficult-to-treat” patients specifically referred to our specialized lipid outpatient clinic we analyzed achievement of LDL-C targets with oral combination LLT (consisting of statin, and/or bempedoic acid and ezetimibe) in comparison to PCSK9-inhibitor (PCSK9i) treatment. 

Methods: Since 2017, 1062 patients were referred to our outpatient lipid clinic and were followed repeatedly. Of these, 996 at very high (n=824) or high (n=172) CV risk were treated according to current ESC/EAS guidelines to reach LDL-C targets <55 and <70 mg/dl, respectively. The reduction in LDL-C and the number of patients reaching the LDL-C treatment target were investigated by comparing baseline data with the most recent values. 

Results:  Patients (n=583 men, n=413 women, mean age 56±14 yrs.) had LDL-C levels of 199±76 mg/dL on average at first presentation; 40.7% reported statin intolerance, limiting their ability to tolerate a dosage necessary to achieve LDL-C targets. After at least 3 follow-up visits (n=416) 189 (45.4%) received oral combination LLT therapy, 185 (44.5%) received PCSKi in combination with oral LLT (when oral LLT was insufficient) and 42 (10.1%) received PCSK9i monotherapy. LDL-C was reduced by 60±17% (-113±62 mg/dL) using oral combination LLT, by 73±20% (-170±84 mg/dL) using PSCK9i plus oral LLT (p<0.0001), compared to 59±24% (-115±59 mg/dL) with PCSK9i only. Based on the 2019 ESC/EAS guidelines the percentage of patients achieving LDL reduction ≥50% from baseline was 80.0% (oral LLT), 90.2% (PCSK9i plus oral LLT), and 73.8% (PCSK9i mono). Achievement of ESC targets was 57.2% (oral LLT), 65.8% (PCSK9i plus oral LLT), and 51.2% (PCSK9i mono).

Conclusions: More than half “difficult-to-treat” high risk patients referred to a specialized lipid clinic because of high baseline LDL-C values, FH, and/or statin intolerance achieve LDL-C targets with oral combination lipid lowering therapy. The remaining are candidates for PCSK9i therapy and, thus, another considerable proportion (~two-thirds) can be successful treated on this way. However, closely monitoring with several follow-up visits and treatment modifications are necessesary to reach this goal.