OBJECTIVES: To evaluate the incidence and risk of major adverse cardiovascular events (MACE) and all-cause mortality in type-2 diabetic patients with metformin failure in second-line treatment with hypoglycemic drugs, using real-world data in Italy.

METHODS: A retrospective study was conducted using administrative databases from a sample of Italian Local Health Units. During 01/2015-12/2017, all adult type-2 diabetic patients who failed metformin therapy and in second-line with hypoglycemic drugs: sulfonylurea (SULF), dipeptidyl peptidase inhibitors (i-DPP-4), glucagon-like-peptide-1 (GLP-1), or inhibitors of the sodium/glucose-2 co-transporter (SGLT-2i), alone or combined with metformin, were included. Index-date corresponded to 1^stprescription date; patients were followed-up from index-date to end of 2019. The Propensity Score Matching (PSM) methodology was applied to abate covariates variability among cohorts.

RESULTS: Among the 18,818 patients included (mean age 65.6 years, 57.5% male), 40.3% had SULF as second-line, 36.1% i-DPP-4, 15.3% SGLT-2i, 8.3% GLP-1. After PSM, the incidence rate per 100 person-years of MACE was 3.7 for SULF patients, 3.1 for i-DPP-4 patients, 2.7 for SGTL-2i patients, and 2.6 for GLP-1a patients. All-cause death incidence rate per 100 person-years was higher in SULF cohort (1.4) than DPP-4 (1.3), SGLT2-i (0.7) and GLP-1 (0.9) (p= 0.001). Compared to SULF patients, SGLT-2i and GLP-1 had a 26% (p-value=0.013) and 30%(p-value=0.003) lower risk of MACE events, respectively. SGLT-2i and GLP-1 patients were also associated to a lower risk (SGLT-2i:52%, p-value=0.001; GLP-1:40%, p-value=0.012) of all-cause death rather than SULF cohort.

CONCLUSIONS: This study provides an evaluation from real-world data of the clinical profile of patients in second-line with hypoglycemic agents after metformin failure. Our findings showed that in matched cohorts, lower incidences and risks of MACE and all-cause death were observed among GLP-1 and SGLT2-i patients than in SULF ones. These data suggest that the evaluation of clinical outcomes with therapeutic interventions might support health-decision making, to also improve prescriptive appropriateness.