This is a randomized placebo-controlled study in treated and suppressed HIV-infected individuals aged ≥40 years with either known CVD or 1 CVD risk factor to study the effect of Bempedoic acid (BA) on safety, arterial inflammation as assessed by FDG-PET/CT, lipids, inflammation, immune activation, cardiometabolic indices, and non-calcified plaque (NCP) in the coronary arteries (assessed by coronary CT angiography, CCTA). This trial will be enrolled at UCSF and UCLA. Collaborators at Massachusetts General Hospital (MGH) will serve as the core facility for imaging.
Persons living with HIV infection (PLWH) have a 2-fold higher risk of myocardial infarction and are twice as likely to develop cardiovascular disease accounting for a significant global burden of disease. While the mechanism underlying this excess risk remains poorly understood, studies demonstrate that atherosclerosis in the setting of HIV is distinct and characterized by heightened arterial inflammation as assessed by FDG-PET/CT. HIV and antiretroviral medication can worsen cardiometabolic parameters. Thus a therapeutic strategy that can lower lipids, inflammation, and improve glycemic parameters may be even more advantageous in HIV. Bempedoic acid (BA, an inhibitor of ATP citrate lyase), is safely tolerated, significantly lowers LDL-C and inflammatory markers (on top of statin therapy), and is FDA approved for individuals with heterozygous familial hypercholesterolemia or with established ASCVD who require additional LDL-C lowering. Additionally, BA has a protective effect on glycemic parameters and may reduce adiposity. Given the key role of lipids and inflammation in atherosclerosis in HIV, the purpose of this proof-of-concept mechanistic trial is to evaluate the impact of BA on the biology of HIV-associated atherosclerosis. This is a randomized placebo controlled study of effectively treated PLWH aged 40 years and older with either known CVD or 1 CVD risk factor to study the effect of BA on arterial inflammation (assessed by FDG-PET/CT), lipid levels, biomarkers of inflammatory/immune activation, cardiometabolic indices, and non-calcified plaque in the coronary arteries (assessed by CCTA). This multicenter trial will include PLWH enrolled at UCSF and UCLA. Long term collaborators at MGH will serve as the core facility for the imaging end-points. There are three specific aims for the: Cholesterol and inflammation Lowering via BEmpedoic Acid, an ACL-inhibiting Regimen in HIV Trial (CLEAR HIV Trial): Aim 1: To determine whether BA can safely reduce arterial inflammation including carotid plaque as assessed by FDG-PET/CT; Aim 2: To determine whether BA improves cardiometabolic measures (lipid, inflammatory, glycemic and adipose parameters) among PLWH. Exploratory objectives will be to assess BA's effect (vs. placebo) on glycemic as well as adipose tissue measures (HbA1c, HOMA IR, and adipose tissue volumes); Aim 3: To evaluate the impact of BA on non-calcified coronary plaque volume as measured by coronary CT angiography (CCTA).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
121
Bempedoic Acid is an oral first-in-class small molecular adenosine triphosphate (ATP)-citrate lyase (ACL) inhibitor which lowers LDL-C by inhibition of cholesterol synthesis in the liver. ACL is an enzyme upstream of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase in the cholesterol biosynthesis pathway. Inhibition of ACL by bempedoyl-CoA results in decreased cholesterol synthesis in the liver and lowers LDL-C in blood via upregulation of LDL receptors and concomitant suppression of hepatic fatty acid biosynthesis. BA has been studied in \>4300 individuals and is currently being studied in \>14,000 individuals in CLEAR Outcomes (NCT02993406).
Placebo
UCLA Center for Clinical AIDS Research and Education (CARE)
Los Angeles, California, United States
RECRUITINGSan Francisco General Hospital
San Francisco, California, United States
RECRUITINGUT Health Houston
Houston, Texas, United States
RECRUITINGFDG PET/CT Endpoint
Change in Target-to-background ratio from baseline to follow-up study at 52 weeks. The main arterial endpoint is the most diseased segment of the index vessel. These findings will be correlated to measurements in the secondary endpoint.
Time frame: Baseline and Week 52
Total Cholesterol Endpoint
Change in total cholesterol will be assessed from baseline to week 24 and week 52.
Time frame: Baseline, Week 24 and Week 52
HDL Endpoint
Change in HDL will be assessed from baseline to week 24 and week 52.
Time frame: Baseline, Week 24 and Week 52
LDL Endpoint
Change in LDL will be assessed from baseline to week 24 and week 52.
Time frame: Baseline, Week 24 and Week 52
Triglycerides Endpoint
Change in triglycerides will be assessed from baseline to week 24 and week 52.
Time frame: Baseline, Week 24 and Week 52
Apolipoprotein B Endpoint
Change in apolipoprotein B will be assessed from baseline to week 24 and week 52.
Time frame: Baseline, Week 24 and Week 52
Hb A1c Endpoint
Change in HbA1c from baseline to week 24 and week 52.
Time frame: Baseline, Week 24 and Week 52
Fasting glucose Endpoint
Change in fasting glucose measurements from baseline to week 24 and week 52.
Time frame: Baseline, Week 24 and Week 52
Insulin Endpoint
Change in insulin measurements from baseline to week 24 and week 52.
Time frame: Baseline, Week 24 and Week 52
homeostatic Model Assessment for Insulin Resistance (HOMA-IR) Endpoints
The change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), a calculation based on insulin and glucose, will also be assessed from baseline to week 24 and 52. The equation simplifies to \[HOMA-IR = fasting insulin \*fasting glucose /22.5\] where fasting plasma insulin is measured in (µIU/mL) and fasting plasma glucose is measured in (mmol/L). Values below 1.0 are generally considered optimal.
Time frame: Baseline, Week 24 and Week 52
Adipose Volume Endpoint
Change in adipose tissue volumes will be assessed by FDG PET/CT (as measured in primary outcome) from baseline to week 52.
Time frame: Baseline and Week 52
hsCRP Endpoint
Change in hsCRP from baseline to follow-up at weeks 24 and 52.
Time frame: Baseline, Week 24 and Week 52
IL-1B Endpoint
Change in IL-1B from baseline to follow-up at weeks 24 and 52.
Time frame: Baseline, Week 24 and Week 52
IL-18 Endpoint
Change in IL-18 from baseline to follow-up at weeks 24 and 52.
Time frame: Baseline, Week 24 and Week 52
SAA Endpoint
Change in SAA from baseline to follow-up at weeks 24 and 52.
Time frame: Baseline, Week 24 and Week 52
Lp-PLA2 Endpoint
Change in Lp-PLA2 from baseline to follow-up at weeks 24 and 52.
Time frame: Baseline, Week 24 and Week 52
sCD163 Endpoint
Change in sCD163 from baseline to follow-up at weeks 24 and 52.
Time frame: Baseline, Week 24 and Week 52
IL-6 Endpoint
Change in IL-6 from baseline to follow-up at weeks 24 and 52.
Time frame: Baseline, Week 24 and Week 52
D-Dimer Endpoint
Change in D-Dimer from baseline to follow-up at weeks 24 and 52.
Time frame: Baseline, Week 24 and Week 52
Fibrinogen Endpoint
Change in fibrinogen from baseline to follow-up at weeks 24 and 52.
Time frame: Baseline, Week 24 and Week 52
T-cell Endpoint
Change in T-cell marker from baseline to follow up at weeks 24 and 52.
Time frame: Baseline, Week 24 and Week 52
B-cell Endpoint
Change in B-cell marker from baseline to follow up at weeks 24 and 52.
Time frame: Baseline, Week 24 and Week 52
Monocyte activation Endpoint
Change in monocyte activation marker from baseline to follow up at weeks 24 and 52.
Time frame: Baseline, Week 24 and Week 52
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