(49) Comparative Effectiveness and Safety of Sodium–Glucose Cotransporter 2 Inhibitors (SGLT2i) Versus Dipeptidyl Peptidase 4 Inhibitors (DPP-4i) in T2D Patients Across Different HbA1c Levels

Publication Number: 723

Background: Sodium–glucose cotransporter 2 inhibitors (SGLT2i) showed cardiovascular benefits in randomized controlled trials of patients with type 2 diabetes (T2D). However, little is known about the generalizability of those results as well as the safety profile of these medications in patients with different HbA1c levels at baseline.

Objectives: To evaluate the effectiveness and safety of SGLT2i vs dipeptidyl peptidase 4 inhibitors (DPP-4i) in patients with T2D across different baseline HbA1c levels.

Methods: Using a U.S. commercial claims database (April 2013 - June 2021), we selected T2D patients ≥ 18 years who initiated SGLT2i or DPP-4i and stratified them based on baseline HbA1c values ( < 7.5%, 7.5-9%, > 9%), identifying a 1:1 propensity score-matched cohort for each stratum. Primary effectiveness outcomes were a modified major adverse cardiovascular event (MACE) (i.e., myocardial infarction, stroke, or all-cause death) and hospitalization for heart failure (HHF). Safety outcomes were hypovolemia, non-vertebral fractures (i.e., humerus, wrist, hip, pelvis), falls, genital infections, diabetic ketoacidosis, and acute kidney injury (AKI). We estimated hazard ratios (HRs) and 95% confidence intervals (CI), controlling for 128 baseline covariates.

Results: We identified 24,052 matched pairs with HbA1c < 7.5%, 32,290 with HbA1c 7.5-9%, and 30,932 with HbA1c > 9%. Compared to those with HbA1c 7.5-9% and < 7.5%, patients with HbA1c > 9% were younger (57.7 vs 62 and 62.4 years), more likely to receive insulin (20% vs 14% and 7.4%) and had higher eGFR (83.2 vs 77.6 and 75). Across the three strata, SGLT2i vs DPP-4i initiators had similar modified MACE risk (HbA1c < 7.5%: HR 0.84 [95% CI 0.66, 1.07]; HbA1c 7.5-9%: HR 0.88 [0.72, 1.07]; HbA1c > 9%: HR 0.83 [0.68, 1.00]) and reduced HHF risk (HbA1c < 7.5%: HR 0.48 [0.33, 0.72]; HbA1c 7.5-9%: HR 0.44 [0.30, 0.64]; HbA1c > 9%: HR 0.47 [0.31, 0.71]), over a median follow-up of ∼5 months. Compared to DPP-4i, SGLT2i initiation showed an increased risk of genital infections (HbA1c < 7.5%: HR 2.41 [2.04, 2.85]; HbA1c 7.5-9%: HR 3.10 [2.68, 3.58]; HbA1c > 9%: HR 1.82 [1.60, 2.08]), a reduced AKI risk (HbA1c < 7.5%: HR 0.72 [0.59, 0.89]; HbA1c 7.5-9%: HR 0.70 [0.59, 0.84]; HbA1c > 9%: HR 0.79 [0.66, 0.94]), and a trend toward an increased risk of DKA, regardless of the pre-exposure HbA1c patient level. Consistently across the HbA1c strata, no differences in risk were noted for the other safety outcomes.

Conclusions: In a large study of adult patients with T2D who initiated SGLT2i vs DPP-4i, SGLT2i were associated with a reduced HHF risk, a trend toward a decreased MACE risk, an increased risk of genital infections, a lower risk of AKI, and a trend toward an increased DKA risk, regardless of their baseline HbA1c. Effectiveness and safety profile of SGLT2i does not seem to vary based upon pre-exposure HbA1c levels.