Table 1 Main features of included trials
First Author, year (Study acronym) | Country | Study Duration, weeks | Primary outcome | Main Inclusion criteria | Main Exclusion criteria | Background statin therapy | Population | Patients, n | Age | Diabetes (%) | Baseline LDL-C | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
Ray 2019, (CLEAR HARMONY) [13] | UK | 52 | Safety (Incidence of adverse events) | Fasting LDL > 70 mg/dl despite maximum tolerated LLT | Use of gemfibrozil or simvastatin at doses greater than 40 mg per day | Maximally tolerated statin therapy | ASCVD and/or FH | BA | 1448 | 65.8 ± 9.1 | 28.6 | 103.6 ± 29.1 |
Control | 742 | 66.8 ± 8.6 | 28.6 | 102.3 ± 30.0 | ||||||||
Ballantyne 2019 [21] | US | 12 | Efficacy (LDL reduction at week 12) | Fasting LDL-cholesterol > 100 mg/dL (ASCVD and/or FH) or > 130 mg/dL (multiple CVD risk factors) despite maximum tolerated statin therapy | Fasting TG ≥ 500 mg/dl BMI ≥ 40 kg/m2, recent cardiovascular or cerebrovascular event or procedure | Maximally tolerated statin therapy | ASCVD, and/or FH and/ or multiple CVD risk factors | BA + EZE | 108 | 63.0 ± 10.0 | 45.4 | 152.0 ± 39.0 |
Control | 55 | 65.6 ± 0.7 | 43.6 | 153.0 ± 42.0 | ||||||||
Ballantyne 2019 [21] | US | 12 | Efficacy (LDL reduction at week 12) | Fasting LDL-cholesterol > 100 mg/dL (ASCVD and/or FH) or > 130 mg/dL (multiple CVD risk factors) | Fasting TG ≥ 500 mg/dl, BMI ≥ 40 kg/m2, recent cardiovascular or cerebrovascular event or procedure | Maximally tolerated statin therapy | ASCVD, and/or FH and/or multiple CVD risk factors | BA | 110 | 65.2 ± 9.5 | 56.4 | 147.0 ± 36.0 |
Control | 55 | 65.6 ± 10.7 | 43.6 | 153.0 ± 42.0 | ||||||||
Goldberg 2019, [12] (CLEAR WISDOM) | US and Europe | 52 | Efficacy (LDL reduction at week 12) | Fasting LDL > 100 mg/dl despite maximum tolerated LLT | Fasting TG ≥ 500 mg/dL, BMI ≥ 50, eGFR < 30 mL/min/1.73 m2, recent CHD event, or clinically significant disease | Maximally tolerated statin therapy | ASCVD and/or FH | BA | 522 | 64.1 ± 8.8 | 29.7 | 119.4 ± 37.7 |
Control | 257 | 64.7 ± 8.7 | 31.5% | 122.4 ± 38.3 | ||||||||
Lalwani 2019 [22] | US | 4 | Efficacy (LDL reduction at day 29) | Fasting LDL > 100 mg/dl (patients with high-intensity statin therapy), > 115 mg/dl (moderate/low-intensity statin therapy) | Recent or current ASCVD, statin intolerance | High intensity statin therapy | Hypercholesterolemic | BA | 41 | 58 ± 10 | NA | 71 ± 19 |
Control | 23 | 58 ± 8 | NA | 86 ± 26 | ||||||||
Ballantyne 2016 [23] | US | 12 | Efficacy (LDL reduction at week 12) | Fasting LDL-C levels from 115 to 220 mg/dl and a fasting triglyceride level of 400 mg/dl after washout of lipid-regulating agents | History of clinically ASCVD within 12 months of screening | Maximally tolerated statin therapy | Hypercholesterolemic | BA | 45 | 57 ± 10 | 142 | |
Control | 45 | 56 ± 10 | 131 | |||||||||
Laufs 2019 [11] (CLEAR Serenity) | US and Canada | 24 | Efficacy (LDL reduction at week 12) | Fasting LDL- ≥ 130 mg/dL (primary prevention) or ≥ 100 mg/dL (secondary prevention and/or FH) | Total fasting TG ≥ 500 mg/dL, eGFR < 30 mL/min/1.73 m2 BMI ≥ 50 kg/m2, recent cardiovascular events or procedure | Lipid lowering agents other than statins and/or very low intensity statin therapy | Statin intolerant patients | BA | 234 | 65.2 ± 9.7 | 26.9 | 158.5 ± 40.4 |
Control | 111 | 65.1 ± 9.2 | 23.4% | 155.6 ± 38.8 | ||||||||
Ballantyne 2018 [14] | US and Canada | 12 | Efficacy (LDL reduction at week 12) | Statin intolerant patients, requiring additional LDL-C lowering | Clinically significant cardiovascular or cerebrovascular disease; history of coronary or peripheral revascularization | Low intensity or none | Hypercolesterolemic | BA | 181 | 63.7 | 5 | 129,8 |
Control | 88 | 63.8 | 6 | 123 | ||||||||
Bays 2021 [24] | US | 12 | Efficacy (LDL reduction at week 12) | Type 2 diabetes mellitus (HbA1c > 7%) and LDL-cholesterol > 70 mg/dl | BMI > 40 kg/m2, documented ASCVD, fasting triglyceride > 400 mg/dL, type 1 diabetes, significant hepatic, renal or hematologic disorder, active malignancy | None (5 weeks washout period) | T2DM and Hypercholesterolemia | BA | 60 | 61.4 ± 9.1 | 100 | 145.1 ± 31.5 |
Control | 119 | 61.3 ± 8.4 | 100 | 141.3 ± 27.2 | ||||||||
Rubino 2020 [20] | US | 6 | Efficacy (LDL reduction at week 6) | Fasting LDL-C 130–189 mg/dL | Cardiovascular disease; (BMI) > 50 kg/m2; fasting triglycerides > 400 mg/dL; history of type 1 or type 2 diabetes or f; uncontrolled hypothyroidism; liver, renal or gastrointestinal disorder | None (6 weeks washout period) | Hypercolesterolemic | BA | 43 | 61.2 | N/A | 154.3 |
Control | 23 | 61.2 | N/A | 155.9 | ||||||||
Rubino 2021 [21] | US | 8 | Efficacy (LDL reduction at 2 month) | Fasting LDL-C levels ≥ 160 mg/dL (without any other lipid lowering agent) and LDL-C levels ≥ 70 mg/dL on PCSK9i | FH, fasting triglyceride levels ≥ 500 mg/dL diabetes, CVD, PAD, uncontrolled hypertension and/or, hypothyroidism, renal, liver, gastroenterological or hematologic disorder | None | Hypercolesterolemic | BA | 28 | 62.0 | 0 | 102.1 |
Control | 30 | 58.4 | 0 | 104.1 | ||||||||
Nissen 2023 [16] (CLEAR Outcomes) | 32 countries | 162,4 | Efficacy (MACE incidence) | Statin intolerant patients with increased cardiovascular risk (primary or secondary prevention) with fasting LDL-C levels ≥ 100 mg/dl | Fasting triglycerides ≥ 500 mg/dl, recent acute ASCVD, uncontrolled hypertension, uncontrolled diabetes, hypothyroidism, renal/liver/gastroenterological/hematologic/oncologic disorder | None or very low dose | Statin intolerant patients with ASCVD or at high risk for ASCVD | BA | 6992 | 65.5 | 45% | 139 ± 34.9 |
Control | 6978 | 65.5 | 46.3% | 139 ± 35.2 | ||||||||