A plethora of diabetes studies and established clinical guidelines show the strong salutary benefit of aerobic, resistance, and/or combination exercise for improved glycemic and cardiovascular outcomes. Promotion of physical fitness is a cornerstone approach to improved diabetes management especially since subjects with diabetes have reduced baseline aerobic exercise capacity (i.e., reduced cardiorespiratory fitness) with associated increased risk for premature all-cause and cardiovascular mortality. Since medications are often used in conjunction with fitness promotion this can result in complex interaction between management modalities. More recently, newer options such as glucose transporter-2 inhibitors and incretin agonists have shown to improve cardiovascular disease (CVD) outcomes in cardiovascular outcomes trials. Indeed, both classes of agents have experimentally the potential to synergize with exercise training but clinical data vis-à-vis cardiorespiratory fitness is still preliminary. Review of the interaction of exercise and metformin shows no improvement in cardiorespiratory fitness. The use of glucose transporter-2 inhibitors may improve fitness performance in those with diabetes and heart failure. Although incretin agonists have physiological effects on the vasculature and heart, they lack similar clinical supportive data.