(252) Comparative effectiveness of sodium-glucose co-transporter 2 inhibitors vs dipeptidyl peptidase 4 inhibitors on liver outcomes in patients with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been linked to improving liver enzymes among patients with type 2 diabetes (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD). However, no observational study has been conducted to evaluate the effectiveness of SGLT2 inhibitors in reducing the risk of major liver outcomes (MLOs) including cirrhosis and hepatocellular carcinoma (HCC) in patients with T2DM and MASLD.

Objectives: To evaluate the effectiveness of SGLT2 inhibitors on liver outcomes among patients with T2DM and MASLD.

Methods: Adult patients with T2DM and MASLD using metformin were identified from the IBM MarketScan claims database. Those with a history of substance use disorder, concomitant liver disease, prior liver transplant, or bariatric surgery were excluded. To evaluate the effectiveness of SGLT2 inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors were selected as an active comparator, given their lack of association with improved liver outcomes in prior studies. Individuals who were initiated on SGLT2 or DPP-4 inhibitors between January 1, 2014, and December 31, 2020, and had a 12-month continuous enrollment prior to treatment were included. The primary outcome, identified by ICD codes, was the time to the first MLO. Patients were followed until the occurrence of the outcome or the administrative end of the study. Overlap weighting was used to balance covariates and integrated with a Cox proportional hazards model for survival analysis. The inverse probability of the treatment adherence weighting method was used to estimate the per-protocol effect sizes.

Results: Among 44,651 patients, 22,100 initiated SGLT2 inhibitors, and 22,551 began DPP-4 inhibitors. After weighting, the incidence rate of MLO in SGLT2 inhibitor group was 3.8 per 1,000 patient-years, and 3.9 per 1,000 patients-years in DPP4 inhibitor group, resulting in an adjusted hazard ratio (HR) of 0.82 (95% CI, 0.60-1.10). SGLT2 inhibitors initiation was not associated with cirrhosis (aHR: 0.77; 95% CI, 0.55-1.06) or HCC (aHR: 0.99; 95% CI, 0.47-1.83) separately. Subgroup and sensitivity analyses did not yield significant results. Per-protocol analysis showed that the initiation of SGLT2 inhibitors was not associated with lower MLOs compared to DPP-4 inhibitors (aHR: 0.94; 95% CI, 0.79-1.12).

Conclusions: In patients with T2DM and MASLD, SGLT2 inhibitors did not demonstrate a lower risk of major liver outcomes compared to DPP-4 inhibitors. Clinicians should consider the overall patient conditions and the additional benefits of SGLT2 inhibitors to support the decision to switch from DPP-4 inhibitors.