PROJECT SUMMARY
Despite the advent of safer antiretroviral therapy agents with low potential for mitochondrial toxicity,
accumulation of central and ectopic fat remains a common and significant challenge facing HIV providers and
threatens the well-being of individuals living with HIV. Limited progress has been made in understanding and
managing lipohypertrophy. Initially linked to the use of protease inhibitors, we have recently reported similar
gains in peripheral and central fat after initiation of successful HIV treatment with both protease inhibitors and
integrase inhibitors. These observations have challenged current beliefs and raised the concerns that fat
accumulation may indeed be due to HIV itself, directly and/or indirectly, through the heightened inflammatory
state that accompanies HIV. The role of alteration in gut hormone secretion and gut epithelial barrier
dysfunction in HIV-associated metabolic disorders is largely unknown, but it is plausible since chronic
inflammation (such as that seen in HIV) has been shown to affect the secretion of gut hormones.
Studies of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in diabetics have shown them to be
safe, well-tolerated, with very low to no concerns about drug-drug interactions, and, importantly, have caused
weight loss that appear to occur, at least in some studies, preferentially via losses in visceral fat. Some GLP-
1RAs have even shown to decrease clinical CVD events in diabetics. Thus, this promising class of drugs may
offer a powerful tool to fight the triple threat facing the success of long-term HIV treatment: namely, 1) excess
fat accumulation and ectopic fat deposition, 2) insulin resistance and a high prevalence of diabetes, and 3)
endothelial dysfunction and cardiovascular disease (CVD) risk. GLP-1RAs act by partially-delineated
mechanisms, several of which will be studied in this proposal.
We will conduct a randomized, double-blinded, placebo-controlled clinical trial to assess whether a
potent and safe GLP-1RA may positively affect visceral fat and ectopic fat accumulation, insulin resistance,
inflammation markers, and the downstream effect on CVD in people living with HIV. A similarly-designed trial
will enroll an HIV-uninfected, obese group, matched to the group with HIV by key factors and will run in
parallel. Including a parallel study of people without HIV will be helpful in making significant observations about
the specificity of the findings to the HIV population.
Major strengths of this study include the extensive experience of the primary site’s principle investigator
in leading clinical trials involving cardiometabolic complications in HIV, as well as the expertise and successful
collaborative record of the investigative team on HIV-related metabolic complications, CVD risk, and immune
activation, as well as GLP-1 physiology, pathophysiology and treatment of obesity and diabetes, and statistical
expertise.
