In other words, medications that potentiate insulin via insulin signaling (i.e. sulfonylureas, incretin-based therapies, TZDs) tend to increase the risk of heart failure, whereas medications that mitigate hyperinsulinemia and do not act through insulin signaling (i.e., metformin and SGLT-2 inhibitors) tend to improve on heart failure outcomes [69]. This evidence concerns the gene INS and hyperinsulinism.