Given the complete lack, or rather, the limited availability of systematic analyses (however often contradictory or inconclusive) surveying the lower limb safety outcomes of SGLT2-is, in this review our aims are to establish whether this drug class plays a protective, neutral, or noxious role towards a so far unexplored event, i.e., osteomyelitis, and re-assess its effects on some of the other major diabetic complications affecting this body district. The gene discussed is SLC5A2; the disease is osteomyelitis.