AZD0780 to reduce major heart and blood vessel events in people with or at high risk for atherosclerotic cardiovascular disease.

Inclusion Criteria:

* Meets one of the following:

  1. Participants with history of an ASCVD event: Participants ≥ 18 years of age at the time of signing the ICF with a history of MI or ischaemic stroke suspected to be due to atherosclerotic vascular disease ≥ 1 month prior to randomisation (presumed lacunar or cardioembolic strokes are not qualifying events), or revascularisation for symptomatic lower limb PAD any time prior to screening

     Additional risk factors based on the level of the LDL-C and timing of MI or stroke:

     o Participants with an LDL-C ≥ 75 mg/dL (≥ 1.9 mmol/L) need to have at least one of the other additional risk factors (i to viii) below.

     ii) T2DM requiring ongoing medical therapy iii) Age ≥ 65 years v) Previous above ankle amputation due to PAD vi) Previous diagnosis of non-end stage CKD
  2. Participants at increased risk of a first ASCVD event: Male participant ≥ 50 years of age or female participant ≥ 55 years of age at the time of signing the ICF with LDL-C ≥ 100 mg/dL (≥ 2.6 mmol/L), with no prior history of MI, ischaemic stroke due to atherosclerotic disease, or leg revascularisation for symptomatic lower limb PAD, and with diagnostic evidence of at least one of the following disease categories (i, ii, or iii):

  (i) Significant atherosclerotic artery disease (ii) High-risk Type 1 or Type 2 diabetes mellitus with manifestation of at least one of the following end-organ diseases:
  1. Nephropathy - Persistent (≥ 2 readings) microalbuminuria (urine albumin/creatinine ratio ≥ 30 mg/g) and/or persistent eGFR \< 60 mL/min/1.73 m2. At least one reading must come from the medical record within the last 12 months in addition to the reading from screening
  2. Retinopathy - Treated diabetic retinopathy (surgical intervention or injectable therapy) or prior diagnosis made by a relevant healthcare specialist
  3. Neuropathy - Treated neuropathy (medical therapy for pain relief or symptom alleviation) or prior diagnosis made by a relevant healthcare specialist
  4. ABI \< 0.9 or \> 1.4 - confirmed either in study during screening or randomisation, or from the medical record within the last 5 years (iii) Documented atherosclerosis of less significance

     For (ii) and (iii), participants need to have at least one of the additional risk factors below:

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  1. CKD with eGFR x mL/min/1.73 m2
  2. Current tobacco use
  3. Age ≥ 65
  4. T2DM (if included on the less significant atherosclerosis criterion iii)
* Participants should receive a background lipid lowering regimen anticipated to achieve at least a \~50% reduction in LDL-C. Except in cases of intolerance, the regimen should include a high intensity statin therapy or lower intensity statin therapy in combination with an oral agent with proven outcome benefit (eg, ezetimibe and/or bempedoic acid).

Participants must achieve a stable background lipid lowering therapy \> 28 days before screening.

Exclusion criteria:

* Any underlying known disease, or condition including homozygous familial hypercholesterolaemia, or LDL or plasma apheresis within 12 months prior to randomisation, that, in the opinion of the investigator, might interfere with the interpretation of the clinical study results.
* Any revascularisation procedure planned within the next 3 months.
* Available imaging assessment within the last 3 years showing either coronary calcium score of zero, or a coronary computed tomography angiography with no atherosclerosis.
* Calculated eGFR \< 15 mL /min/1.73 m2 at screening.
* Any laboratory values with the following deviations at screening:

  * AST or ALT \> 3 × ULN
  * TBL \> 2 × ULN (except for participants with Gilbert's syndrome where TBL 3 × ULN is acceptable provided direct bilirubin \< 1.5 × ULN)
  * Fasting triglycerides ≥ 400 mg/dL (≥ 4.52 mmol/L).
  * Creatine kinase \> 5 × ULN
  * Urine albumin/creatinine ratio ≥ 500 mg/g
* Uncontrolled T2DM defined as HbA1c ≥ 9.5% at screening.
* Inadequately treated hypothyroidism defined as TSH \> 1.5 × ULN at screening or participants whose thyroid replacement therapy was initiated or modified within the last 3 months prior to screening.
* Use of mipomersen or lomitapide (cholesterol-lowering medications) within 12 months of screening or planned use during the study.
* Use of gemfibrozil within one week prior to the Screening Visit or planned use during the study.
* Use of PCSK9 inhibitors: evolocumab/alirocumab within 12 weeks of the Screening Visit or planned use during the study, or inclisiran within 18 months of the Screening Visit or planned use during the study, or any other approved PCSK9 inhibitor use within 5 half lives prior to the Screening Visit or planned use during the study.