2194-P: Is Polycythemia Part of the Causal Pathway between SGLT2i and Peripheral Artery Disease and Amputation Events?

Introduction and Objective: Association of SGLT2i and amputation/revascularization is inconsistent. We tested the hypothesis that the causal pathway between SGLT2i and peripheral artery disease (PAD) was mediated through polycythemia. DPP4i users are the comparator. Methods: A retrospective cohort combined Veterans Administration, Medicare, and National Death Index databases. Exposure Outcome pathway: New users with hemoglobin <16 mg/dL were followed from first prescription fill until PAD or censored (stop/change drugs, death, study end). PAD was defined as the earliest amputation, stent, or revascularization. The mediator, polycythemia, was defined as the earliest outpatient hemoglobin>16.5 mg/dL. Exposure Outcome (PAD) and Exposure Mediator (polycythemia) associations were estimated in inverse probability of treatment weighted cohort and confirmed via covariate adjusted proportional hazards. Exposure-Mediator-Outcome pathway then evaluated polycythemia to PAD association and percentage of effect mediated via time-varying covariate adjusted proportional hazards models. Results: The unweighted cohort included 103,822 SGLT2i vs 191,907 DPP4i episodes with 1,218(1.2%) vs 2,239(1.2%) PAD and 6,294(6.1%) vs 4,010 (2.0%) polycythemia events respectively. The SGLT2i to PAD association was HR 1.12 (1.03, 1.22). The SGLT2i to polycythemia association was HR 3.89 (3.69, 4.10). There were 67 SGLT2i vs 45 DPP4i users with polycythemia followed by PAD events. The polycythemia to PAD association was 0.98 (0.81, 1.19). The percentage of the SGLT2i to PAD association mediated through polycythemia was 0% (-9%, 8%). Conclusion: While the use of SGLT2i vs DPP4i was associated with polycythemia, the association for polycythemia and PAD was null in this analysis. Only 3% of PAD events were preceded by an observed polycythemia. None of the SGLT2i to PAD association was mediated through polycythemia. This analysis relied on elevated outpatient hemoglobin to capture polycythemia. Future research should explore hemoglobin over broader values Disclosure A. Gosmanov: Research Support; Current; Eli Lilly and Company. C. Beck: None. A.J. Hackstadt: Research Support; Current; Bristol-Myers Squibb Company. D. Gemoets: None. A.M. Hung: None. C. Roumie: None. Funding This project was funded by the VA Office of Research and Development investigator-initiated grant CX000570-13 (Roumie) and the VETWISE-LHS Center of Innovation Tennessee Valley Healthcare System (CIN 24-128, Roumie) - Veterans Health Administration.