Post-transplant diabetes mellitus (PTDM) is a metabolic alteration in organ transplant patients, with an incidence ranging from 2% to 65%. PTDM leads to an increased risk of organ rejection, infections, cardiovascular (CV) events, and reduced survival. The incidence of PTDM depends on various factors occurring in the post-transplant period, from changes in lifestyle and eating habits, with subsequent increase of visceral weight and fat, to the direct action of immunosuppressive drugs. In recent years, cardiovascular outcome studies have shown that two drug classes, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose-cotransporter-2 inhibitors (SGLT-2i) have cardiovascular and renal protection effects on patients with type 2 diabetes, substantially modifying the guidelines on the therapeutic management of these patients. Given the effects on glycometabolic control and the several glucose-independent effects, GLP-1RAs and SGLT-2i potentially play a predominant role in the management of PTDM. The evidence gathered so far in the literature is still limited. Though no drug interactions are present, GLP-1RAs may still interfere with the absorption of immunosuppressants due to the effect of slowing gastric emptying. On the other hand, SGLT-2i already increases the risk of genitourinary infections, which could be more frequent and severe in immunosuppressed patients. Nevertheless, both drug classes appear to be safe and effective in transplanted patients, and though further controlled prospective studies are necessary, their mechanism of action, glucose-independent effects, and cardiovascular and renal protection effects seem to fully respond to the metabolic changes caused by PTDM.