SGLT2i as fourth-line therapy and risk of mortality, end-stage renal diseases and cardiovascular diseases in patients with type 2 diabetes mellitus.

AIM: Current guideline recommends insulin as fourth-line glucose-lowering medications. However, treatment effects of sodium glucose co-transporter-2 inhibitors (SGLT2i) on the risk of complications are uncertain. This study examines risks of all-cause mortality, cardiovascular diseases (CVD) and end-stage renal diseases (ESRD) in type 2 diabetes mellitus (T2DM) patients on triple oral glucose-lowering medications initiating SGLT2i, insulin or other oral medications. METHODS: A population-based retrospective cohort of patients with T2DM between 2006-2017 was extracted from Hong Kong Hospital Authority database. Patients who were initiated a fourth-line therapy with SGLT2i, insulin or other oral medications were included. Hazard ratios (HRs) for all-cause mortality, CVD and ESRD were assessed using Cox proportional hazard models. RESULTS: Over a median follow-up period of 18.5 months with 63,122 person-years, SGLT2i and insulin group had the lowest and highest incidence rate of all-cause mortality, CVD and ESRD (1.06, 0.65 and 0.61 vs 4.25, 5.58 and 4.39/100 person-years), respectively. Initiating SGLT2i as fourth-line medication had more benefits on CVD, in particular coronary heart disease and stroke. Insulin users had higher risks of CVD (HR=8.04, 95%CI=3.06-21.12) than SGLT2i users. SGLT2i was associated with insignificant reduction in ESRD (HR=4.62, 95%CI=0.73-29.09) and all-cause mortality (HR=3.06, 95%CI=0.75-12.45), and HF (HR=2.99, 95%CI=0.37-24.42) among patients without established HF. CONCLUSION: Among T2DM patients initiating fourth-line therapy, SGLT2i users had significant benefits in lowering risk of CVD, and potential benefits in lowering risks of ESRD and all-cause mortality. SGLT2i was the preferred fourth-line glucose-lowering medication least likely to be associated with complication risks.