Triple Therapy with Dpp4 Inhibitor, Insulin, or Thiazolidinediones and Risks of Cardiovascular Diseases and All-Cause Mortality in Patients with Failed Metformin-SU Therapy

Abstract

Objective: To examine risks of all-cause mortality, cardiovascular (CV) diseases and severe hypoglycaemia (SH) in patients with diabetes who were intensified with dipeptidylpeptidase-4 (DPP4) inhibitors, insulin, or Thiazolidinediones (TZDs) following metformin-sulfonylurea dual therapy failure. Design and method: We assembled a retrospective cohort data of 17,494 patients who were free of CV diseases, failed to metformin-sulfonylurea dual therapy, and were intensified with DPP4 inhibitors (n = 8,281), insulin (n = 6,559), or TZD (n = 2,654) from January 1, 2006 to January 31, 2018. Propensity-score (PS) weighting was used to balance out baseline covariates across the three groups. Hazard ratios (HRs) for all-cause mortality, CV diseases and SH were assessed using Cox proportional hazard models. Results: Over a mean follow-up period of 34 months with 50,188 person-years, cumulative incidences of all-cause mortality, CVD and SH were 0.061, 0.074, and 0.120, respectively. Patients intensified with insulin and TZD had the most incidences of all-cause mortality [(Incidence rate (IR) = 2.993/100 person-years) and CVD (IR = 3.579/100 person-years), respectively. Insulin users were associated with the higher risks in all cause-mortality (HR = 2.24, P < 0.01; 2.07, P < 0.01) and SH (HR = 1.17, P < 0.01; HR = 1.53, P < 0.01) than TZD and DPP4 inhibitor users. When compared to DPP4 inhibitors, TZDs were associated with higher risk of SH (HR = 1.31, P < 0.01) and CV diseases (HR = 1.28, P < 0.01). Conclusions: This study sheds new light on the understanding of insulin, DPP4 inhibitor and TZD in terms of their associated risks of all-cause mortality, SH and CV disease events. These findings are one of many factors that should be taken into account when making clinical decisions in deciding the choices of third-line glucose-lowering medications. DPP4 as the third-line medication has the lowest risk of SH and CV adverse effects, and posed no increased risks for mortality.