Overview
Drug-drug interactions often limit statin optimization in a population of patients prescribed cytochrome P3A4 inhibitors, which include immunosuppressive agents, protease inhibitors, and antifungals. These patients frequently have autoimmune conditions or rheumatologic disorders that require complex drug regimens and are often on low-dose statin therapy or no statin at all, resulting in suboptimal LDL levels despite increased cardiovascular (CV) risk.
There is an unmet clinical need to improve LDL levels in this vulnerable patient population, which faces increased CV risk due to underlying conditions that also contribute to polypharmacy and multiple drug-drug interactions. This study is a randomized, open-label trial evaluating subcutaneous inclisiran plus standard of care for LDL-C lowering in high-risk primary prevention patients with multiple comorbidities (e.g., Type II diabetes, liver disease, chronic kidney disease, autoimmune disease, solid-organ transplant) who are taking five or more medications in which drug-drug interactions prevent optimization of statin therapy.
Description
This is an investigator-initiated, single-site, open-label, randomized trial. The investigators will enroll up to 100 high-risk primary prevention patients with at least one comorbidity and an indication for additional lipid control (such as Type II diabetes with A1c ≤ 8.5%, subclinical atherosclerosis, or ASCVD risk of 7.5% or greater). Patients will be randomized 1:1 to the inclisiran arm (n ≥ 50) with standard of care or standard of care alone (n ≥ 50).
The study will consist of five study visits (screening, baseline, 3 months, 9 months, and 12 months). Patients in the inclisiran arm will receive a subcutaneous injection of inclisiran 284 mg for three doses (baseline, 3 months, and 9 months following randomization) as add-on therapy. LDL-C (the primary endpoint) along with other biomarkers will be measured at screening, baseline (inclisiran dose #1), 3 months (inclisiran dose #2), 9 months (inclisiran dose #3), and 12 months (labs only). Patients will also undergo medical history and medication review at each visit. Surveys will be completed at each visit during the study period.
Patients in the control arm (standard of care) will continue with their current lipid-lowering therapy. No adjustments will be made to lipid-lowering therapy during the course of the study. Participants will be aware of the group to which they have been randomized.
The primary objective is to determine the efficacy of inclisiran for LDL-C lowering in high-risk primary prevention patients with multiple comorbidities (e.g., Type II diabetes, autoimmune disease, liver disease, chronic kidney disease, solid-organ transplant) who are taking five or more medications in which drug-drug interactions prevent optimization of statin therapy.
Eligibility
Inclusion Criteria:
- Provision of signed and dated informed consent form.
- Stated willingness to comply with all study procedures and availability for the duration of the study, including potential randomization to injections.
- Age >18 and <85 years and able to provide self-consent.
- Taking five or more prescription drugs at the time of enrollment, of any type.
- Meets at least one of the following criteria:
- Elevated 10-year ASCVD risk score ≥7.5% (based on the ACC/AHA ASCVD Risk Estimator Plus tool).
- Evidence of subclinical atherosclerosis including:
Calcification in any vascular bed, including coronary arteries and aorta. Calcification of cardiac valves. Breast calcification. Carotid plaque that is not hemodynamically significant.
- Type II diabetes on a stable medical regimen with HbA1c <8.5%. Per American Diabetes Association guidelines, patients with Type II diabetes aged 40-75 years should be on a moderate-intensity statin.
Patients with documented partial or complete statin intolerance are eligible for enrollment.
- On maximally tolerated statin therapy (which can be no statin for patients with
documented intolerance) and have suboptimal LDL levels:
- For patients with Type II diabetes: LDL >70 mg/dL or non-HDL >120 mg/dL.
- For other patients: LDL >90 mg/dL or non-HDL >120 mg/dL.
- Willing to adhere to the randomized study regimen, including subcutaneous injection
of inclisiran.
- Agreement to adhere to lifestyle considerations (see Section 5.3) throughout the study duration.
Exclusion Criteria:
- Prior or current use of inclisiran.
- Known hypersensitivity or allergy to inclisiran or its components.
- Active liver disease or unexplained persistent elevations in liver enzymes (ALT or AST >3x upper limit of normal).
- History of rhabdomyolysis or severe muscle-related statin intolerance.
- Uncontrolled diabetes (HbA1c >8.5%).
- Active malignancy requiring systemic therapy.
- Recent major cardiovascular event (myocardial infarction, stroke, or hospitalization for unstable angina) within the past 3 months.
- History of organ transplant other than solid-organ transplant.
- Pregnancy or breastfeeding.
- Any condition that, in the opinion of the investigator, would make participation unsafe or interfere with study procedures.