Critique of the therapeutic usefulness of the oral agents in diabetes

Abstract

When used in connection with a carefully restricted diet and in the absence of ketoacidosis, the sulfonylurea compounds provide “good” or “fair” control of hyperglycemia and glycosuria in 50 to 70 per cent of patients with onset of stable diabetes above the age of forty years and with a daily insulin requirement of 20 units or less. The mechanism of action appears to be that of stimulation of release of insulin from the pancreatic beta cells and the effect of such insulin first in the liver with decrease in the hepatic glucose output. Action in the periphery of insulin not bound in the liver is not precluded. The frequency of significant untoward effects from tolbutamide is small, and the drug is well tolerated by almost all persons. Chlorpropamide is likewise relatively free from side effects if used in dosage no larger than 500 mg. daily. Doses of 1 gm. per day or greater may lead to prolonged hypoglycemia due to the slow excretion of the drug and excessive accumulation in the body. Jaundice of reversible, cholestatic type may occur, apparently on the basis of hypersensitivity, but very few cases have been reported during the past three years when smaller doses have been the rule. Secondary failures (failure despite success initially for at least one month) in the Joslin Clinic series of 1,965 patients treated with tolbutamide for periods up to five years amounted to 22 per cent. However, poor adherence to diet, poor initial selection of patients and inadequate dosage of the drug seemed responsible for the bulk of the failures. The biguanides such as phenformin seem to be effective in the same group of middle-aged and elderly patients who are responsive to the sulfonylureas. As a supplement to insulin, they may reduce the insulin requirement and assist in the management of young patients and others with unstable diabetes. The modes and site of action are not clear although results of in vitro studies suggest inhibition of oxidative metabolism and increase in anaerobic glycolysis. Amounts of phenformin greater than 200 mg. daily often cause anorexia, nausea, vomiting and diarrheas. However, no instance of true tissue or organ toxicity has been reported. Great care should be taken in the selection of patients for treatment with oral hypoglycemic agents. Furthermore, patients must be kept under close supervision and the degree of control evaluated by frequent tests of the urine and blood for sugar. It is imperative that there be strict adherence to a diet which is nutritionally adequate but restricted in carbohydrate. The aim must be to maintain “good” control defined arbitrarily as that state in which, with the patient on an adequate diet, the majority of blood glucose values, both fasting and non-fasting, at three or more hours after the ingestion of food are 110 mg. per 100 ml. or lower.