A group of 200 patients with diabetes mellitus were observed for periods of many months as to their response to continued administration of tolbutamide. The average maintenance dose when patients were responding satisfactorily was 1 Gm. per day. The dosage was raised to 3 Gm. per day before the drug was considered to be ineffective. Thirty-two cases were classified as primary failures because the patient did not respond from the beginning. Cases in which the patient gradually became unresponsive were classified as secondary failures. These failures occurred at a rate of about 3 % per month. When return to insulin therapy became necessary, the amount needed was on the average the same as before, but marked individual differences occurred. The loss of responsiveness was usually permanent. No clues were obtained whereby it might be possible to predict how soon tolbutamide would become ineffective in a given patient. A few of the patients with secondary failure later responded to chlorpropamide. Half of those with failures responded to phenethylbiguanide.
DeLawter DE, Moss JM, Tyroler S, Canary JJ. SECONDARY FAILURE OF RESPONSE TO TOLBUTAMIDE TREATMENT. JAMA. 1959;171(13):1786–1792. doi:10.1001/jama.1959.03010310018005
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