Using a large-scale regional database from Japan reflecting routine clinical practice, we found that, among adults with type 2 diabetes without prior major cardiac or renal disease who began monotherapy with either a biguanide or an SGLT2 inhibitor and avoided the alternate class during the first year (while allowing any other concomitant drugs), first‐line SGLT2 treatment did not lower risks of cardio‐cerebrovascular events, all‐cause mortality, or diabetic complications compared with metformin and incurred approximately 50% higher costs. The gene discussed is SLC5A2; the disease is type 2 diabetes mellitus.