Optimizing Metabolic Management on Integrase-based ART (OPTIMAR): study protocol for a 2x2 factorial, randomised, double-blind placebo-controlled trial to compare the addition of dapagliflozin versus placebo, and rosuvastatin plus ezetimibe versus pitavastatin, in people with HIV on integrase strand transfer inhibitor-based antiretroviral therapy with elevated metabolic risk

Background People with HIV have an increased cardiovascular disease (CVD) risk due to both HIV and adverse effects of treatments. The currently preferred class of anti-retroviral drugs, integrase strand transfer inhibitors (INSTIs), have variably been linked to higher CVD risk and weight gain. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce CVD events and heart failure hospitalisations in people with or without type 2 diabetes, while also reducing weight and blood pressure, but have not been studied in people with HIV. Pitavastatin lowers CVD events in those with HIV, although it is not widely available. Methods OPTIMAR is a 2x2 factorial, randomised, placebo-controlled, double-blind, phase III/IV trial and will examine the efficacy and safety of dapagliflozin 10mg versus placebo on metabolic parameters and of rosuvastatin 10mg + ezetimibe 10mg versus pitavastatin 4mg. A cardiac substudy will determine the effect of dapagliflozin versus placebo on epicardial adipose tissue (EAT) volume and coronary plaque characteristics. Adults aged 40–75 years with HIV with weight gain or obesity who have been virologically stable on INSTI-based ART for over 12 months will be included. Participants will be randomised 1:1 to blinded dapagliflozin or placebo, followed by 1:1 randomisation to open label rosuvastatin + ezetimibe or pitavastatin. The primary endpoints will be body weight and LDL reduction for the SGLT2i and statin randomisations respectively in the modified intention-to-treat population. Follow-up will continue to 48 weeks with primary analysis at week-24 and follow-up analysis at week-48. Discussion OPTIMAR is the first trial to investigate the use of SGLT2i as a cardiometabolic intervention in people with HIV. Demonstrating favourable cardiometabolic effects of SGLT2i will introduce an innovative approach to primary CVD prevention in this at-risk population and support conducting larger trials evaluating clinical endpoints including major adverse cardiovascular events. If the combination of rosuvastatin and ezetimibe is found to be similar or superior to pitavastatin, this will inform a more feasible lipid management approach for people with HIV internationally, especially in resource-limited settings. The cardiac sub-study will further clarify the cardioprotective role of SGLT2i and provide mechanistic insights. Trial registration: ClinicalTrials.gov, NCT06317051 (https://clinicaltrials.gov/study/NCT06317051?cond=HIV&intr=Dapagliflozin&aggFilters=status:not%20rec&rank=2). Registration date: 21 February 2024.