Incretin Microdosing for Cardiometabolic Health in People With HIV: The REINFORCE Trial - PROJECT SUMMARY Cardiometabolic diseases are leading causes of non-AIDS-related morbidity and mortality among people living with HIV (PWH). Obesity, a global epidemic, further increases cardiometabolic disease risk. Long-acting glucagon-like peptide-1 receptor agonists (GLP-1RA) promote clinically significant weight loss and reduction of cardiometabolic risk in adults with and without HIV. Problematically: there are no established strategies to maintain therapeutic benefits of GLP-1RA except for continued, full-dose therapy; lifelong, high-dose GLP-1RA therapy is impractical, costly and may have yet unknown risks; and drug cessation is associated with rapid weight regain and loss of cardiometabolic benefit. As such, strategies to maintain benefit after initial induction therapy are urgently needed. To fill this critical knowledge gap, and in response to PAS-23-086 Small R01s for Clinical Trials Targeting Diseases within the Mission of NIDDK, we propose to determine: 1) a preliminary effect size of semaglutide microdosing (0.5 mg subcutaneously weekly) in maintaining weight and cardiometabolic benefits in PWH following induction therapy and 2) the tolerability and acceptability of semaglutide induction (2.4 mg subcutaneously weekly) and microdosing in PWH. We will accomplish this novel work in two aims: Aim 1: To determine the rate of weight regain in PWH receiving semaglutide microdosing following induction therapy. Thirty adult PWH will be given semaglutide titrated to 2.4 mg subcutaneously weekly for 12 weeks (induction), followed by 2:1 randomization to maintenance with semaglutide 0.5 mg sc weekly (n=20) or no additional drug (n=10) for an additional 48 weeks. Using participants as their own controls, we will determine if microdosing provides at least partial efficacy in preventing weight regain in PWH. These critical preliminary data will inform sample size calculations for a larger RCT of incretin microdosing. Aim 2: To determine preliminary effect sizes of semaglutide microdosing on additional endpoints. To ascertain the preliminary efficacy of semaglutide microdosing in maintaining cardiometabolic benefit, we will measure fat and lean mass quantity and distribution by dual energy x-ray absorptiometry, muscle function by physical function testing, circulating cardiometabolic and inflammatory biomarker profiles, health self-perceptions during the induction and maintenance phases and tolerability and acceptability of microdosing among PWH. These data will inform secondary and exploratory endpoint effect size determination for a larger, future RCT. Development of microdosing as a strategy to maintain weight and cardiometabolic health in PWH following induction therapy is novel, important and will also inform intervention strategies in populations without HIV, providing significant value added.
