Heart transplant (HT) recipients experience high rates of cardiometabolic disease. Novel therapies targeting hyperlipidemia, diabetes, and obesity, including proprotein convertase subtilisin/kexin inhibitors, sodium-glucose cotransporter-2 inhibitors, and glucagon-like peptide-1 agonists, are increasingly used for cardiometabolic risk mitigation in the general population. However, limited data exist to support the use of these agents in patients who have undergone heart transplantation. Herein, we describe the mechanisms of action and emerging evidence supporting the use of novel pharmacologic agents in the post-HT setting for cardiometabolic risk mitigation and review evidence supporting their ability to modulate immune pathways associated with atherogenesis, epicardial adipose tissue, and coronary allograft vasculopathy.