Pioglitazone, SGLT2 inhibitors and their combination for primary prevention of cardiovascular disease and heart failure in type 2 diabetes: Real-world evidence from a nationwide cohort database

Objective: To evaluate the effect of SGLT2is, pioglitazone, and their combination on the risk of major adverse cardiovascular events (MACE) and heart failure in type 2 diabetes mellitus (T2DM) patients without a history of cardiovascular disease.Research design and methods: Using Taiwan National Health Insurance Research Database, we identified four groups based on medication use, including 1) both SGLT2is and pioglitazone, 2) SGLT2i, 3) pioglitazone and 4) non-study drugs (reference group). The four groups were matched by propensity score. The primary outcome was 3-point MACE, which included myocardial infarction, stroke, cardiovascular death, and the secondary outcome was incidence of heart failure.Results: After propensity-matching, each group included 15,601 patients. Compared with the reference group, the pioglitazone/SGLT2i combination group had a significantly lower risk for MACE (aHR 0.76, 95 % CI 0.66-0.88) and heart failure (aHR 0.67, 95 % CI 0.55-0.82). Pioglitazone was associated with a lower risk of MACE (aHR 0.82, 95 % CI 0.71-0.94) and there was no difference in risk of heart failure compared with the reference group. The incidence of heart failure was significantly decreased in the SGLT2i group (aHR 0.7, 95 % CI 0.58-0.86).Conclusion: Combination therapy with pioglitazone and SGLT2is is an effective treatment in the primary prevention of MACE and heart failure in patients with type 2 diabetes.