Pharmacological intervention: the antidiabetic approach.

Impaired glucose tolerance (IGT) progresses to non-insulin-dependent diabetes mellitus (NIDDM) in many but not all IGT subjects. It remains unsettled whether long-term antidiabetic (i.e. antihyperglycaemic) pharmacotherapy delays the development of NIDDM, and whether such treatment influences macrovascular morbidity and mortality. This report summarizes the results from long-term (> 4 years) antihyperglycaemic interventions addressing these issues. In an American study, tolbutamide (0.5 g 2-3 times daily) promoted a 4-year improvement of glucose tolerance in young, non-obese, mildly diabetic asymptomatic subjects who apparently comprised a mixture of IGT and NIDDM. In a Swedish 5-year study on 178 survivors of myocardial infarction, of whom 79 had intravenous IGT, tolbutamide treatment was associated with improved glucose tolerance, reduced triglyceride levels, and improved 18-month survival. A British 5-year study on a subgroup of about 200 middle-aged men from the Whitehall cohort indicated that phenformin (50 mg once daily) did not influence the deterioration of glucose levels. In a 10-year British study, 241 middle-aged men and women were 4-square randomized to control, weight reduction, placebo and tolbutamide (0.5 g twice daily). A non-lasting reduction of arterial disease was recorded in those on tolbutamide. No reduction of NIDDM development was seen. In a Swedish 10-year study on middle-aged men with IGT, follow-up comprised 59 controls, 98 on diet advice with or without placebo, and 23 on tolbutamide (0.5 g three times daily) added to diet advice. A total of 29% developed NIDDM among controls and 13% in the diet group. In contrast, no subject maintaining tolbutamide treatment developed NIDDM. Moreover, the tolbutamide-treated subjects had reduced blood pressure, triglyceride and cholesterol levels, as well as fewer macrovascular complications. Recently, a lower mortality rate at 22 years after the start of tolbutamide treatment has been recorded. To summarize, treatment with insulin-releasing drugs might help to reduce the development of NIDDM and macrovascular disease in IGT subjects. However, further studies are needed to verify or refute this notion.