OBJECTIVES: In patients with type 2 diabetes mellitus (T2DM), three-drug combination would be considered when A1C target is not achieved after 3 months of dual therapy, which mainly contains metformin plus another type of oral antihyperglycemic agent (OHA). However, little evidence is available to guide the regimen choice of triple therapy. This study aimed to compare the clinical outcomes of a basal insulin and OHA as the third add-on drug.

METHODS: We conducted a retrospective cohort study using claims data of the year 2008-2015 from the National Health Insurance program in Taiwan. We included T2DM patients previously treated with metformin and sulfonylurea as the first two anti-diabetic agents and as the subsequent dual combination. Subjects initiating an add-on agent following the dual therapy were then identified and classified into 3^rd-line basal insulin users and OHA users. Propensity score matching was used to balance patient characteristics. The risk of major adverse cardiovascular event (MACE) and hypoglycemia was compared by Cox proportional hazards models.

RESULTS: A total of 233,896 T2DM patients with triple therapy after receiving metformin and sulfonylurea were identified. After propensity score matching, we included 6,115 patients with basal insulin and 24,460 with a third OHA as the add-on drug. In the as-treated analysis, patients receiving basal insulin were more likely to have a MACE (HR 1.37, 95% CI 1.14-1.64) and hypoglycemic event (HR 1.82, 95% CI 1.54-2.15) compared to those with a third OHA. The risk estimates were consistent when using an alternative intention-to-treat approach.

CONCLUSIONS: Initiating a different OHA, compared to basal insulin, as the add-on drug to OHA dual therapy may lead to better effectiveness and safety outcomes in T2DM patients. Further analyses are needed to identify high-risk patients with basal insulin-based combination and examine the effect of different types of OHAs as the 3^rd-line add-on drug.