Real-world outcomes and safety of low- vs. standard-dose SGLT2 inhibitors in heart failure

Abstract Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a cornerstone in heart failure (HF) treatment. Unlike other guideline-directed medical therapies (GDMT), which require dose titration, SGLT2i were studied and approved at a fixed dose (e.g., 10 mg/day dapagliflozin or empagliflozin). However, lower doses are sometimes prescribed in real-world practice due to safety concerns, despite lacking clinical trial validation. These alternative dosing strategies have not been systematically studied, raising uncertainty about their clinical effectiveness and safety. Purpose To evaluate real-world outcomes of low-dose versus standard-dose SGLT2i in HF patients. Methods A retrospective cohort study using ICES administrative health databases was conducted. We identified HF patients aged ≥65 years in Ontario, Canada, who were newly prescribed either a low dose (5 mg daily) or standard dose (10 mg daily) of empagliflozin or dapagliflozin between June 1, 2016, and December 31, 2022. The primary outcome was all-cause mortality or cardiovascular (CV) hospitalization. Secondary outcomes included CV and HF hospitalizations, mortality, and adverse drug reactions. Propensity score matching (1:1) was used to adjust for confounders. Multivariable Fine-Gray proportional hazards models examined differences in outcomes between groups. Exclusion criteria included type 1 diabetes, long-term care residents, contraindications to SGLT2i, canagliflozin use and non-Ontario residency. Follow-up continued until treatment discontinuation, dose adjustment, a predefined outcome event, death or end of follow-up (December 31, 2023). Results Among 202,881 HF patients prescribed SGLT2i, 25,595 received a low dose and 177,286 a standard dose. Patients in the low-dose group tended to be older, had lower eGFR, and higher comorbidity burdens but fewer prior CV events and revascularizations. After matching, 46,218 patients remained (23,209 in each group) and baseline characteristics were well-balanced (absolute standardized differences < 0.1). The primary outcome incidence was 6.0 per 100 person-years in both groups. After multivariable adjustment, Low-dose SGLT2i was associated with a lower risk of the composite outcome (HR 0.93, 95% CI 0.88–0.99, p=0.02) and CV hospitalization (HR 0.84, 95% CI 0.78–0.91, p<0.0001), with no significant differences in HF hospitalization (HR 0.93, p=0.33) or mortality (HR 1.04, p=0.47). The incidence of genital mycotic infections and other adverse events was similar in both groups. Conclusion Low-dose SGLT2i was associated with a lower risk of the composite outcome (all-cause mortality or CV hospitalization) and a reduced risk of CV hospitalization compared to standard doses. There was no evidence of increased risk for HF, mortality, or adverse drug reactions. These findings support the consideration of low-dose SGLT2i in selected HF patients. Further studies are needed to clarify the long-term implications of this dosing approach.

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