Canagliflozin May Increase Thromboembolic Events in Males With Erythrocytosis but Not in Females

• Canagliflozin significantly raised hematocrit levels compared to placebo, even in patients with erythrocytosis.

• Baseline hematocrit levels modified the effect of canagliflozin on thromboembolism, indicating harm in males with erythrocytosis.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are increasingly recognized as a common cause of drug-induced erythrocytosis. SGLT2 inhibitor-induced erythropoiesis may increase blood viscosity and precipitate thromboembolism, particularly in patients with pre-existing erythrocytosis. We conducted a post hoc, pooled analysis of patient-level data from the randomized, double-blind, placebo-controlled CANVAS Program and CREDENCE trials, which assessed the safety and efficacy of canagliflozin in patients with type 2 diabetes. The primary outcome, a composite of myocardial infarction (MI), stroke, and any thromboembolism, was evaluated using sex-specific Cox models, with baseline hematocrit as an effect modifier. Among participants with available baseline hematocrit values (98.5% [14,321/14,543]), 35% were female. Canagliflozin significantly increased hematocrit levels compared to placebo even in patients with erythrocytosis (males >49%, females >48%) and raised the proportion of individuals with erythrocytosis at 1 year (males: 16.9% vs. 5.5%; females: 5.2% vs. 1.0%). Overall, canagliflozin did not alter the risk of the primary outcome in either males (hazard ratio [HR] 0.97; 95% CI, 0.86-1.10) or females (HR 0.95; 95% CI, 0.78-1.15). However, in males, baseline hematocrit levels modified the treatment effect on the primary outcome, whether assessed categorically (anemia, normal, erythrocytosis) or continuously with fractional polynomial (FP) analysis (P interaction <0.05). FP analysis showed treatment benefits in anemic males but harm in those with erythrocytosis, primarily driven by an increased risk of MI. Meanwhile, no heterogeneity was seen in females for these outcomes. In conclusion, canagliflozin may pose a safety concern for thromboembolism in males with erythrocytosis at baseline, warranting further investigations. NCT01032629, NCT01989754, and NCT02065791