Study to understand if inclisiran is better than a placebo at lowering LDL-cholesterol,is safe and can have an impact on patient quality of life, when given along with other lipid lowering medications.

Prior treatment

• Participants on more than one other lipid-lowering drug on top of statin at screening visit.
• Previous (within 90 days of screening), current or planned treatment with a monoclonal antibody (mAb) directed towards PCSK9 (e.g. evolocumab, alirocumab) at screening or baseline visit.
• Previous exposure to inclisiran or any other non-mAb PCSK9 targeted therapy, either as an investigational or marketed drug within 2 years prior to screening or baseline visit.
• Previous, current or planned treatment with LDL-apheresis at screening or baseline visit.
• Acute coronary syndrome, ischemic stroke or TIA, coronary revascularization or peripheral arterial revascularization procedure or amputation due to atherosclerotic disease < 3 months prior to the screening or baseline visit.

Other illness

• Heart failure New York Heart Association (NYHA) class IV at screening or baseline visit

Lab values

• Liver and CK: (a) Active liver disease defined as any current infectious, neoplastic, or metabolic pathology of the liver or (b) unexplained alanine aminotransferase (ALT), aspartate aminotransferase (AST) elevation >3x ULN, or total bilirubin elevation > 2x ULN (except for participants with Gilbert's syndrome), or (c) creatine kinase (CK) >5x ULN at screening or baseline visit.
• Participant with severe renal impairment defined by eGFR <30 mL/min/1.73m2 as calculated by the Modification in Diet in Renal Disease (MDRD) formula at screening or baseline visit.

Other

• Pregnant or nursing (lactating) women at screening or baseline visit.
• Women of child-bearing potential, unless they are using highly effective methods of contraception during dosing of study treatment.
• Participants with a known intolerance to rosuvastatin at screening or baseline visit.

• Male or female participants ≥18 years of age.
• Very high risk participants with at least one of the following: • Documented Atherosclerotic cardiovascular disease (ASCVD) i Acute coronary syndrome: Unstable angina or myocardial infarction. ii Stable angina. iii Coronary revascularization. iv Unequivocally documented ASCVD upon prior imaging. v Stroke and TIA. vi Peripheral artery disease (PAD). • Diabetes mellitus (DM) with target organ damage (defined as microalbuminuria, retinopathy, or neuropathy), or at least ≥ 3 major risk factors, or early onset of Type 1 DM of long duration (> 20 years). • A calculated SCORE2 ≥ 7.5% for age <50 years; SCORE2 ≥10% for age 50-69 years; SCORE2-OP ≥15% for age ≥70 years to estimate 10-year risk of fatal and non-fatal cardiovascular disease (CVD). • Pre-existing diagnosis of heterozygous familial hypercholesterolemia (HeFH) with ASCVD or with another major risk factor. High risk participants with at least one of the following: • Markedly elevated single risk factors, in particular total cholesterol >310 mg/dL, LDL-C > 190 mg/dL, or blood pressure ≥ 180/110 mmHg • Pre-existing diagnosis of HeFH without other major risk factors. • Diabetes Mellitus (DM) without target organ damage (defined as microalbuminuria, retinopathy, or neuropathy), with DM duration ≥ 10 years or other additional risk factor. • Moderate chronic kidney disease (eGFR 30-59 mL/min/1.73m2). • A calculated SCORE2 2.5 to <7.5% for age < 50 years, SCORE2 5 to < 10% for age 50-69 years; SCORE2-OP 7.5 to < 15% for age ≥70 years to estimate 10-year risk of fatal and non-fatal CVD as defined by the cardiovascular risk categories in the 2019 ESC/EAS guideline (Mach et al 2020).
• LDL-C levels: • in participants with very high cardiovascular risk: serum LDL-C ≥55 mg/dL. • in participants with high cardiovascular risk: serum LDL-C ≥70 mg/dL
• Participant on a stable dose of a statin for ≥ 30 days at screening.
• Participants on the individual MTD of statin for ≥ 30 days at baseline.
• Fasting triglyceride < 400 mg/dL at screening and baseline.