Clinical and Physiological Implications of Diabetes Induced by Benzothiadiazines.

Chlorothiazide, the first of the diuretic and antihypertensive benzothiadiazines, was introduced into medical practice in 1958. In 1959 it was followed by hydrochlorothiazide, and since then other similar derivatives, some more potent, some longer acting, have been introduced into therapy. While these compounds were originally used for the treatment of edema and congestive heart failure, physicians soon recognized their usefulness as antihypertensive agents, and they have, in current practice, become the baseline of antihypertensive therapy. In 1961 some 30,000,000 prescriptions were issued in this country for diuretic substances, and it is probable that the majority of these were for compounds of the benzothiadiazine (BZD) series. Finnerty was one of the first to notice the hyperglycemic effect of this group of compounds. Similar effects were noted by Goldner et al., Halprin, Sugar, Hollis, Wilkins, Freis, Mach, Saudan, and Curchod. Hyperglycemia after BZD was thought to occur in either mildly diabetic patients, or in those suffering from subclinical diabetes. Shapiro and his colleagues showed in short-term experiments that BZD could have a hyperglycemic effect in hypertensive patients, and that this was accentuated by obesity, a family history of diabetes, and previous notation of an abnormal blood glucose. In the clinical studies reported above, the deterioration in the metabolic status was relieved when the diuretic compounds were discontinued, though few adequate follow-up studies were included. In view of the known association of hypertension and diabetes (Karmer), it was considered that BZD-induced diabetes occurred mainly in predisposed individuals. The hyperglycemic activity of BZD in experimental animals had not been reported until recently. During the course of a controlled double blind study concerned with the evaluation of antihypertensive treatment, "Wolff et al. noted over a period up to four years an increasing incidence of hyperglycemia and clinical diabetes occurring in patients receiving BZD therapy, as compared with controls receiving placebos only. Clinical diabetes in these patients was of different degrees of severity and responded to oral hypoglycemic treatment. Eighteen months have now elapsed since five of the patients had developed diabetes on BZD, and antidiabetic treatment is still required to avoid symptoms of diabetes. No adequate baseline studies concerning carbohydrate metabolism were obtained in these studies, as the initial purpose was directed towards an over-all evaluation of the place of antihypertensive therapy in the treatment of essential hypertension, and the occurrence of abnormalities of carbohydrate metabolism was unexpected. Several of the patients developing clinical diabetes with BZD were thin and had no family history of the disease, but the limitations of relying upon the adequacy of a family history are apparent. Early in 1962 the antihypertensive and sodium retaining benzothiadiazine, diazoxide, became available for clinical trial. Studies in hypertensive patients by Wilson et al.," Okun et al.,' and Dollery et al. soon revealed the diabetogenic activity of this agent, particularly when combined with a saluretic BZD. The first published evaluation of diazoxide in animals had apparently not revealed hyperglycemic activity; Rubin et al. and Langdon et al. first reported systematic observations of diabetogenic activity in dogs of combined diazoxide and trichlormethiazide. Gulbenkian et al. and Tabachnick et al. have since reported their studies concerned with the hyperglycemic activity of diazoxide in dogs, rats, rabbits and mice; and they refer to the work of Eggert et al. (not yet published) concerning the hyperglycemic activity of combined diazoxide and trichlormethiazide. Tabachnick et al. also reported that a further blood glucose increase was observed when diazoxide (10 to 40 mg. per kilogram) was administered to depancreatized dogs. Studies by Wolff et al. have since revealed that the combined administration of the two benzothiadiazines produces a form of experimental diabetes of unusual interest. Marked hyperglycemic activity in dogs after a combination of diazoxide and trichlormethiazide was unassociated with changes in the beta cells, and the experimental animals remained sensitive to exogenous insulin. Though diazoxide by itself was hyperglycemic in the experimental dog and rat, its action was markedly increased by combination with any other saluretic BZD. Pancreatectomized dogs receiving combined diazoxide and BZD also remained sensitive to exogenous