GLP-1 Receptor Agonists to Decrease Ethanol and CVD Risk in HIV (GL1DER HIV RCT)

Vanderbilt University Medical Center, Nashville TN

Investigators

Abstract

Unhealthy alcohol consumption and cigarette smoking are leading causes of cardiovascular disease (CVD) and death, often co-occur, and are common among people with HIV (PWH) who bear a two-fold excess risk of CVD compared to people without HIV. Further, PWH experience higher mortality at lower levels of alcohol consumption than people without HIV. Alcohol use, smoking, and HIV each independently elevate systemic inflammation and undermine cardiometabolic health via myriad pathways including dyslipidemia and increased visceral adiposity. While modestly effective therapies exist for smoking, few exist for alcohol use, and more effective therapies for alcohol consumption and smoking are urgently needed to reduce CVD risk and mortality among PWH. Glucagon-like peptide receptor agonists (GLP-1 RA) reduce insulin resistance and inflammation, promote weight loss, and prevent CVD in patients with and without diabetes, setting a new standard of care to improve cardiometabolic health in people at high risk of CVD. GLP-1 is produced in the gut and brainstem and GLP-1 receptors throughout brain regions underlie reward and motivation (e.g., ventral tegmental area, nucleus accumbens, medial habenula). In preclinical studies, GLP-1 RA attenuate rewarding effects of alcohol and nicotine and reduce consumption of these substances. Early clinical trials report that GLP-1 RA lower alcohol craving and consumption, promote smoking abstinence, and blunt weight gain after abstinence. There is a strong scientific premise to study GLP-1 RA for alcohol use, smoking, and CVD risk, but no trials have tested these outcomes in PWH. To address this critical gap, we propose the GLP-1 Receptor Agonists to Decrease Ethanol and CVD Risk in HIV (GL1DER HIV) RCT, a double-masked placebo-controlled RCT to assess efficacy of the potent oral GLP-1 RA semaglutide for 12 weeks among 200 PWH who drink alcohol, most of whom also smoke. We will conduct GL1DER within the Tennessee Center For AIDS Research and recruit from the Vanderbilt University Medical Center Comprehensive Care Clinic, the largest HIV clinic in the Southeastern U.S. Our team has conducted RCTs using pharmacotherapy to treat alcohol use and smoking among PWH, as well as RCTs of GLP-1 RA in patients without HIV. Our Specific Aims will test the efficacy of oral semaglutide compared to placebo for (Aim 1): alcohol consumption (primary study outcome), craving, and abstinence; (Aim 2) cigarette smoking, craving, and abstinence; and (Aim 3): CVD risk outcomes including biomarkers of inflammation and gut permeability, body mass index (BMI), Reynolds (CVD) Risk Score, and the VACS (mortality) risk index. We hypothesize that participants allocated to semaglutide will have significantly: (Aim 1) lower alcohol consumption and craving and higher abstinence; (Aim 2) lower smoking rate, craving, and higher abstinence; and (Aim 3) lower CVD risk (e.g., biomarkers of inflammation, BMI, CVD risk score). IMPACT: GLP-1 RA could be paradigm-shifting for PWH through a “1 drug, 3 conditions” approach that simultaneously addresses alcohol consumption, smoking, and CVD risk.