SGLT2i As Novel Gout Care (SAVE-Care): A Randomized Controlled Trial - Gout is the most common inflammatory arthritis, affecting >12 million US adults (5.1%); its global disease burden continues to increase. As a metabolic-inflammatory condition, gout is strongly associated with multiple cardiometabolic and kidney comorbidities. The ‘modern gout epidemic’ and suboptimal gout care contribute to high rates of recurrent gout flares, the recent rise in opioid use in gout patients, and increasing emergency department visits and hospitalizations directly due to gout over the past several decades. Furthermore, gout patients experience premature all-cause and cardiovascular (CV) mortality, adjusting for serum urate (SU) levels and the ASCVD risk factors, implicating an underlying role of flare inflammation. Indeed, gout flare episodes are followed by a higher risk of major CV events. Thus, strategies that can simultaneously address gout flare and cardiometabolic risk are greatly needed in gout care. Importantly, landmark randomized controlled trials (RCTs) found no CV-kidney benefits with prototypic urate-lowering therapies (e.g., allopurinol). In contrast, since their initial approval for the treatment of hyperglycemia in type 2 diabetes, sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated multiple CV and kidney hard-endpoint benefits. Furthermore, post-hoc/secondary analyses of RCTs in diabetes or heart failure have found SGLT2i also lower SU levels; our retrospective observational study found gout patients with hyperuricemia, initiating SGLT2i had a SU reduction of 1.8 mg/dL over ≤3 months. Studies have also found SGLT2i are associated with a lower risk of incident gout than other second-line agents; our recent population-based study found SGLT2i were associated with a 34% lower rate of recurrent flares among gout patients, with a 30% lower flare rate during the first year of initiation, suggesting immediate anti-inflammatory benefits, without paradoxical flares. Urate-lowering effects are thought to be via glycosuria competing with urate for reabsorption in the proximal tubules; SGLT2i may inhibit NLRP3 inflammasome, IL-1β, IL-6, and TNF-α, mediators for flares, explaining the observed lack of paradoxical flares. While promising, existing RCT data were not from established gout patients meeting standardized criteria; such RCT data on SU efficacy, particularly among those needing treatment (SU ≥6mg/dL), are required for impactful gout care guideline changes. Based on the strong premise from our observational study findings of such gout patients, we propose to conduct the first RCT of SGLT2i among gout patients (SAVE- Care [SGLT2i As Novel Gout Care] trial), a double-blind RCT of 60 patients with gout and hyperuricemia over 12 weeks to determine the SU-lowering effects of empagliflozin (vs placebo in a 2:1 ratio) (Aim 1) as well as changes in hs-CRP and IL-6, and to estimate gout flare risk and medication adherence in preparation for a future RCT for clinical endpoints (Aim 2). This trial will provide immediately actionable evidence on the central outcome of SU levels, and also provide data for future trials, to overhaul modern gout care.
