Protective effect of intensive glucose lowering therapy on all-cause mortality, adjusted for treatment switching using G-estimation method, the ACCORD trial

Previous analysis of the action to control cardiovascular risk in diabetes showed an increased risk of mortality among patients receiving intensive glucose lowering therapy using conventional regression method with intention to treat approach. This method is biased when time-varying confounder is affected by the previous treatment. We used 15 follow-up visits of ACCORD trial to compare the effect of time-varying intensive vs. standard treatment of glucose lowering drugs on cardiovascular and mortality outcomes in diabetic patients. The treatment effect was estimated using G-estimation and compared with accelerated failure time model using two modeling strategies. The first model adjusted for baseline confounders and the second adjusted for both baseline and time-varying confounders. While the hazard ratio of all-cause mortality for intensive compared to standard therapy in AFT model adjusted for baseline confounders was 1.17 (95% CI 1.01–1.36), the result of time-dependent AFT model was compatible with both protective and risk effects. However, the hazard ratio estimated by G-estimation was 0.64 (95% CI 0.39–0.92). The results of this study revealed a protective effect of intensive therapy on all-cause mortality compared with standard therapy in ACCORD trial.