Diabetes mellitus (DM) is a metabolic disorder presenting with high blood glucose concentrations which exert detrimental damage to structures and functions of multiple organs and tissues due to chemical as well as physical changes in the milieu of long time exposure to hyperglycemia. The frequent co-existence of hypertension, dyslipidemia, and chronic kidney disease as significant cardiovascular disease risk factors may further cause and exaggerate severities of pathophysiological changes in both micro- and macro-vascular systems. To minimize the detrimental impact on health caused by this continuum of cardio-metabolic disorder, it is imperative to bring the above-mentioned disorders back to normal status as early and as much as possible, with hyperglycemia the most fundamental element encountered by health-care givers involved in management of DM. Nevertheless, mostly the stringent goals of glycemia intensely pursued can only be achieved by the use of intensified anti-diabetic pharmacological therapies. And, while doing so patients may frequently be frustrated by facing the opposite side of glycemic spectrum, which is hypoglycemia, an even worse and unwanted impact that may result in deteriorating function in cardiovascular, neurological, and cognitive functions, or even death in vulnerable patient groups. Patients at risk including the elderly, the frail, and those with poor renal function and/or cardiovascular diseases must be identified, anti-diabetic regimen individually tailored, structured diabetes education programs and, when applicable, appropriate modern technologies regarding glycemic monitoring provided, to minimize risk of hypoglycemia while optimal glycemic control is managed in a comprehensive manner. (J Intern Med Taiwan 2022; 33: 16-33)