Preparing for Semaglutide Microdosing to Maintain Cardiovascular Health in People with HIV: The (pre-)SMASH CVD Trial
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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 PAR-25-032 NHLBI Clinical Trial Pilot Studies, we propose Preparing for Semaglutide Microdosing to Maintain Cardiovascular Health in People with HIV: The (pre-)SMASH CVD Trial to 1) determine preliminary effects of semaglutide microdosing in maintaining weight and cardiometabolic health in PWH following weight loss induction therapy; 2) assess the tolerability and acceptability of microdose semaglutide in PWH; 3) complete preparatory work critical to successful development of a larger, scientifically rigorous, Future randomized controlled trial (RCT). We will accomplish this in 3 aims: 1) To determine the rate of weight regain in PWH receiving semaglutide microdosing following induction therapy. Thirty adult PWH on suppressive antiretroviral therapy and with BMI 30 kg/m2 or 27 kg/m2 + 1 weight-related comorbidity will receive weight loss induction therapy with semaglutide 2.4 mg sc weekly for 12 weeks. Persons losing 5 lbs. (responders) will then be randomized 2:1 to maintenance with semaglutide 0.5 mg sc weekly (n=20) or no additional drug (n=10, the standard of care for “off-ramping”) for an additional 48 weeks. The primary outcome will be the difference in within-person weight regain between weeks 12 and 60. 2) To determine preliminary effects of semaglutide microdosing on additional endpoints. Some benefits of GLP-1RA, such as reduced CVD risk, are independent of weight and glucose lowering. We will characterize fat and lean mass quantity and distribution by DXA scan, muscle function by physical function testing, circulating cardiometabolic (glucose/lipid) and inflammatory biomarkers, blood pressure, ASCVD risk scores, semaglutide tolerability and acceptability and health self-perceptions. 3) To complete critical pre-trial work, including but not limited to development of the investigative teams, centralized imaging center, protocol and informed consents, supplemental and training materials, site training plans and database. These data are necessary for and will be sufficient to inform design of an efficient and high-impact Future RCT with cardiovascular endpoints. Development of a GLP-1RA microdosing strategy to sustain weight and cardiometabolic health in PWH following induction therapy is novel, significant and will undoubtedly provide valuable insights for intervention strategies in populations without HIV, adding substantial value to the field.
