Intensification with Dipeptidylpeptidase-4 Inhibitor, Insulin, or Thiazolidinediones and risks of all-cause mortality, cardiovascular diseases and severe hypoglycemia in patients on metformin-sulfonylurea dual therapy: A retrospective study

Background: Although patients with type 2 diabetes mellitus (T2DM) may fail to achieve adequate hemoglobin A1c (HbA1c) control despite metformin-sulfonylurea (Met-SU) dual therapy, a third-line glucose-lowering medication—including dipeptidyl peptidase-4 inhibitor (DPP4i), insulin, or thiazolidinedione (TZD)—can be added to achieve this. However, treatment effects of intensification with the medications on the risk of severe hypoglycemia (SH), cardiovascular disease (CVD), and all-cause mortality are uncertain. Study aim was to compare the risks of all-cause mortality, CVD, and SH among patients with T2DM on Met-SU dual therapy intensified with DPP4i, insulin, or TZD. Methods and findings: We analyzed a retrospective cohort data of 17,293 patients with T2DM who were free from CVD and on Met-SU dual therapy and who were intensified with DPP4i (n = 8,248), insulin (n = 6,395), or TZD (n = 2,650) from 2006 to 2017. Propensity-score weighting was used to balance out baseline covariates across groups. Hazard ratios (HRs) for all-cause mortality, CVD, and SH were assessed using Cox proportional hazard models. Mean age of all patients was 58.56 ± 11.41 years. All baseline covariates achieved a balance across the 3 groups. Over a mean follow-up period of 34 months with 49,299 person-years, cumulative incidences of all-cause mortality, SH, and CVD were 0.061, 0.119, and 0.074, respectively. Patients intensified with insulin had higher risk of all-cause mortality (HR = 2.648, 95% confidence interval [CI] 2.367–2.963, p < 0.001; 2.352, 95% CI 2.123–2.605, p < 0.001) than those intensified with TZD and DPP4i, respectively. Insulin users had the greatest risk of SH (HR = 1.198, 95% CI 1.071–1.340, p = 0.002; 1.496, 95% CI 1.342–1.668, p < 0.001) compared with TZD and DPP4i users, respectively. Comparing between TZDs and DPP4i, TZDs were associated with a higher risk of SH (HR = 1.249, 95% CI 1.099–1.419, p < 0.001) but not all-cause mortality (HR = 0.888, 95% CI 0.776–1.016, p = 0.084) or CVD (HR = 1.005, 95% CI 0.915–1.104, p = 0.925). Limitations of this study included the lack of data regarding lifestyle, drug adherence, time-varying factors, patients’ motivation, and cost considerations. A limited duration of patients intensifying with TZD might also weaken the strength of study results. Conclusions: Our results indicated that, for patients with T2DM who are on Met-SU dual therapy, the addition of DPP4i was a preferred third-line medication among 3 options, with the lowest risks of mortality and SH and posing no increased risk for CVD events when compared to insulin and TZD. Intensification with insulin had the greatest risk of mortality and SH events

DPP4i, thiazolidinediones, or insulin and risks of cancer in patients with type 2 diabetes mellitus on metformin–sulfonylurea dual therapy with inadequate control

INTRODUCTION: This study aims to compare the risks of cancer among patients with type 2 diabetes mellitus (T2DM) on metformin–sulfonylurea dual therapy intensified with dipeptidyl peptidase 4 inhibitors (DPP4i), thiazolidinediones, or insulin. RESEARCH DESIGN AND METHODS: We assembled a retrospective cohort data of 20 577 patients who were free of cancer and on metformin–sulfonylurea dual therapy, and whose drug treatments were intensified with DPP4i (n=9957), insulin (n=7760), or thiazolidinediones (n=2860) from January 2006 to December 2017. Propensity-score weighting was used to balance out baseline covariates across the three groups. HRs for any types of cancer, cancer mortality, and all-cause mortality were assessed using Cox proportional-hazards models. RESULTS: Over a mean follow-up period of 34 months with 58 539 person-years, cumulative incidences of cancer, cancer mortality, and all-cause mortality were 0.028, 0.009, and 0.072, respectively. Patients intensified with insulin had the highest incidence of all-cause mortality (incidence rate=3.22/100 person-years) and the insulin itself posed the greatest risk (HR 2.46, 95% CI 2.25 to 2.70, p<0.001; 2.44, 95% CI 2.23 to 2.67) compared with thiazolidinediones and DPP4i, respectively. Comparing between thiazolidinediones and DPP4i, thiazolidinediones was associated with higher risk of cancer (HR 1.43, 95% CI 1.25 to 1.63) but not cancer mortality (HR 1.21, 95% CI 0.92 to 1.58) and all-cause mortality (HR 0.99, 95% CI 0.88 to 1.11). Insulin was associated with the greatest risk of cancer mortality (HR 1.36, 95% CI 1.09 to 1.71; 1.65, 95% CI 1.31 to 2.07) compared with thiazolidinediones and DPP4i, respectively. CONCLUSIONS: For patients with T2DM on metformin–sulfonylurea dual therapy, the addition of DPP4i was the third-line medication least likely to be associated with cancer mortality and cancer effect among three options, and posed no increased risk for all-cause mortality when compared with thiazolidinediones