Abstract 17003: Associations of SGLT2 Inhibitor-Related Plasma Proteins With Incident Heart Failure: The Atherosclerosis Risk in Communities Study

Introduction: The mechanisms by which SGLT2 inhibitors reduce heart failure (HF) hospitalization is unclear. Data from EMPEROR-Reduced and two pilot clinical trials identified 288 plasma proteins modifiable by SGLT2 inhibitors.

Methods: Among participants in the community-based ARIC study who were free of HF and had aptamer-based proteomic measurements (SomaLogic, Boulder, CO) at Visit 2 (mid-life, n=10,983; 1991-1993) and Visit 5 (late-life, n=4,321; 2011-2013), we studied the association of these 288 SGLT2 inhibitor-related proteins with incident HF after Visit 2 (1149 incident HF events) and Visit 5 (453 events) using multivariable Cox proportional hazards regression models, cardiometabolic traits using multivariable linear regression and Mendelian randomization to assess for potential causal effects.

Results: The mean age was at 57±6 at Visit 2 and 76±5 at Visit 5 and 55% were women. Of 288 plasma proteins reported to be modulated by SGLT2 inhibition, 39 associated with incident HF after both Visit 2 and Visit 5: 24 with HFpEF [LVEF>50%], 2 with HFrEF, and 8 with both ( Figure ). These proteins also associated with plasma glucose levels, hematocrit and urine albumin-to-creatinine ratio and were enriched with immune signaling pathways and the fatty acid binding pathway. Two sample Mendelian randomization suggested causal effects of higher IGFBP1, lower CHRDL1 and higher B2M on higher incident HF risk (P<0.05).

Conclusions: Proteins impacted by SGLT2 inhibition and associated with risk of HF suggest glucose metabolism, erythropoiesis and kidney damage as potential contributors to the effect of SGLT2 inhibitors on HF outcomes.