The relative effectiveness of combined oral therapy with tolbutamide and phenformin was studied in a group of 80 clinic patients with ketoacidosis-resistant diabetes mellitus who had been imperfectly or inadequately regulated by a single oral drug. The tolbutamide-phenformin regimen was observed to bring about significant improvement in 70 per cent of patients previously imperfectly controlled by tolbutamide alone and in 60 per cent of patients imperfectly controlled by phenformin alone. Many of the gratifying responses to combination therapy occurred in extremely difficult patients in whom prior therapy with chlorpropamide, metahexamide, and insulin had been unsatisfactory. The results indicate that tolbutamide-phenformin combination therapy is the most potent of the oral antihyperglycemic regimens tested and makes adequate control with oral drugs a practical possibility for most ketoacidosis-resistant diabetics in whom single oral agents have been unsuccessful.
Unger RH, Madison LL, Carter NW. Tolbutamide-Phenformin in Ketoacidosis-Resistant Patients. JAMA. 1960;174(17):2132-2136. doi:10.1001/jama.1960.03030170022005