Polycythemia, SGLT2 inhibitors, and associated outcomes across the cardio-kidney-metabolic spectrum: a pooled analysis of randomized trials

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BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) use increase hemoglobin, and some patients may develop or aggravate polycythemia. Whether the presence or development of polycythemia impact the cardiorenal benefits of SGLT2i across different cardio-kidney-metabolic (CKM) populations is unknown. AIMS: Assess the proportion of patients with polycythemia both at baseline and during follow-up, study the risk factors for its occurrence, and whether the SGLT2i effect may vary by polycythemia status. METHODS: Pooled analysis of placebo-controlled trials: EMPEROR-Preserved, EMPEROR-Reduced, EMPA-REG OUTCOME, CANVAS-R, and CREDENCE. Polycythemia was defined as a hemoglobin>16.5g/dL in men or >16.0g/dL in women. Multivariable-adjusted Cox models were applied, stratified by trial, to study the association of polycythemia at baseline and week 52 on clinical outcomes, including treatment-by-polycythemia interaction. Primary outcome was the composite of non-fatal stroke or myocardial infarction or cardiovascular mortality. RESULTS: 26,064 patients were included with 723 (2.8%) and 1,324 (6.3%) presenting polycythemia at baseline and 52 weeks, respectively. Smoking and obstructive lung disease associated with polycythemia at baseline, and randomization to SGLT2i (vs placebo) associated with a 6-fold increased risk of polycythemia at week-52 (OR 6.44 95%CI 5.42-7.65). Polycythemia (vs no polycythemia) at baseline and week-52 was associated with an increased risk of the primary outcome (HR 1.35 95%CI 1.09-1.66 and HR 1.42 95%CI 1.15-1.74, respectively), but not with heart failure (HF) hospitalizations. No statistical evidence of treatment effect modification (SGLT2i vs placebo) was observed in patients with pre-existing of incident polycythemia across cardiovascular outcomes (interactionP>0.1 for all cardiovascular outcomes). CONCLUSION: Polycythemia was associated with higher risk of atherosclerotic events. While careful evaluation is warranted, the benefits of SGLT2i were not modified in a significant manner among those with pre-existing or who develop polycythemia after treatment initiation.

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