The Effects of Evolocumab in Patients With Diabetes and Atherosclerotic Vascular Disease

Exclusion Criteria

• •Personal or family history of hereditary muscular disorders;
• •NYHA III or IV heart failure, or last know left ventricular ejection fraction (LVEF) \<30%;
• •Uncontrolled serious cardiac arrhythmia defined as recurrent and highly symptomatic ventricular tachycardia, atrial fibrillation with rapid ventricular response, or supraventricular tachycardia that are not controlled by medications, in the past 6 weeks prior to randomization;
• •Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery graft (CABG) or stroke within 3 months prior to randomization;
• •Planned cardiac surgery or revascularization;
• •Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) \<30mL/min/1.73m2 at screening;
• •Type 1 diabetes, poorly controlled type 2 diabetes (HbA1c \>10%), newly diagnosed type 2 diabetes (within 6 months of randomization), or laboratory evidence of diabetes during screening (fasting serum glucose ≥126mg/dL \[7.0mmol/L\] or HbA1c ≥6.5% without prior diagnosis of diabetes;
• •Uncontrolled hypertension, defined as sitting systolic blood pressure (SBP) \>160mmHg or diastolic BP (DBP) \>100mmHg;
• •Subject who has taken a cholesterol easter transfer protein (CETP) inhibitor in the last 12 months prior to LDL-c screening, such as: anacetrapib, dalcetrapib or evacetrapib;
• •Treatment in the last 3 months prior to LDL-c screening with any of the following drugs: systemic cyclosporine, systemic steroids (e.g. IV, intramuscular \[IM\], or PO) (Note: hormone replacement therapy is permitted), vitamin A derivatives and retinol derivatives for the treatment of dermatologic conditions (e.g. Accutane); (Note: vitamin A in a multivitamin preparation is permitted). Topical retinol prescription and non-prescription derivatives or creams are permitted;
• •Uncontrolled hypothyroidism or hyperthyroidism as defined by thyroid stimulating hormone (TSH) \<1.0 time the lower limit of normal or \>1.5 times the ULN, respectively, at screening. Potential subjects with TSH \<1.0 time the lower limit of normal due to thyroid replacement therapy is not considered an exclusion;
• •Active liver disease or hepatic dysfunction, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>3 times the ULN as determined by central laboratory analysis at screening;
• •Known active infection or major hematologic, renal metabolic, gastrointestinal or endocrine dysfunction in the judgment of the investigator;
• •Diagnosis of deep vein thrombosis or pulmonary embolism within 3 months prior to randomization;
• •Unreliability as a study participant based on the investigator's (or designee's) knowledge of the subject (e.g. alcohol or other drug abuse);
• •Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational agent(s);
• •Female subject who has either (1) not used at least 1 highly effective method of contraception for at least 1 month prior to screening or (2) is not willing to use such a method during treatment and for an additional 15 weeks after the end of treatment, unless the subject is sterilized or postmenopausal;
• •Subject who is pregnant or breast feeding, or planning to become pregnant during treatment and/ or within 15 weeks after the end of treatment;
• •Use of PCSK9 inhibitor within 10 weeks from screening;
• •Subject who has any kind of disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or to comply with all required study procedures;
• •Malignancy except non-melanoma skin cancers, cervical or breast ductal carcinoma in situ within the last 5 years;
• •Subject who has known sensitivity to any of the products or components to be administered during dosing;
• •Subject who is likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator's knowledge;
• •History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the principal investigator would pose a risk to subject or interfere with the study evaluation, procedures or completion;
• •Blood donation 4 weeks prior to screening, or stated intention to donate blood or blood products during the period of the study or within one month following completion of the study;
• •Subjects who have participated in other studies within 30 days prior to screening, or have five times the plasma half-life (if known) of the investigational drug, whichever is longer;
• •BMI\>40kg/m2.