In the large trial populations studied to date, the absolute excess risks of amputation and ketoacidosis with SGLT-2 inhibitors are approximately an order of magnitude lower than the absolute benefits on cardiac and renal outcomes in people with type 2 DM at high ASCVD risk, or with CKD, and approaching two orders of magnitude smaller for people with recently hospitalization with HF. This evidence concerns the gene SLC5A2 and chronic kidney disease.