Deciphering mortality risk of diabetes medications in heart failure patients with diabetes mellitus under triple guideline-directed medical therapy

Background Scientific evidence regarding the impact of different combinations of diabetes medications in heart failure patients with diabetes mellitus (HFwDM) remains limited. Aim We aimed to investigate the effect of monotherapy and combination therapy for DM on all-cause mortality in HFwDM under triple guideline-directed medical therapy (GDMT). Method This nationwide retrospective cohort study included adult HFwDM under triple GDMT between January 1, 2016 and December 31, 2022.We collected the data from the National Electronic Database of the Turkish Ministry of Health.We created various combination including different diabetes medications based on the current guidelines for DM.The primary endpoint was all-cause mortality. Results A total of 321,525 HFwDM under triple GDMT (female:49%, median age:68[61–75] years) were included. The highest rate of prescribed combination therapy was metformin and sulfonylureas (n = 55,266). In Cox regression analysis, insülin monotherapy had the highest risk for all-cause mortality (HR:2.25, 95CI%:2.06–2.45), whereas combination therapy including metformin, SGLT2i, and sulfonylureas provided the most beneficial effect on survival (HR:0.29, 95CI%:0.22–0.39) when compared to patients not receiving diabetes medication. Among patients taking diabetes medications, the inclusion of SGLT2i demonstrated a survival benefit (p < 0.05), despite concurrent use of volume-retaining medications such as insulin and thiazolidinediones. Conversely, combinations of diabetes medications without SGLT2i did not demonstrate any survival benefit compared to patients not taking diabetes medication (p > 0.05). Conclusion This study underscored the use of SGLT2i as monotherapy or as a part of combination diabetes medications to improve survival among HFwDM, while also highlighting that combinations lacking SGLT2i did not confer any survival benefit.