Combination therapies with insulin in type 2 diabetes.

The U.K. Prospective Diabetes Study (UKPDS) demonstrated that intensive glucose control with insulin or sulfonylureas markedly reduces the risk of microvascular complications (1). For myocardial infarction, the reduction in risk (16% for a 0.9% decrease in HbA1c) was of borderline significance but corresponded closely to epidemiological predictions (14% decrease for a 1% drop in HbA1c) (2). These data demonstrated that neither insulin nor sulfonylureas, despite causing hyperinsulinemia and weight gain, have adverse effects on cardiovascular outcome. Glycemic control deteriorated continuously, however, even in intensively treated patients in the UKPDS (1). In the UKPDS, the worsening of glycemic control has been attributed to the natural course of type 2 diabetes and lack of efficacy of current antihyperglycemic therapies (1). Insulin therapy consisted of a single injection of ultralente or isophane insulin. If the daily dose exceeded 14 U, regular insulin was added and homeglucose monitoring was encouraged (1). Combination therapy regimens with insulin and oral agents were not used. We now know that 14 U of long-acting insulin is insufficient to control fasting glycemia in most type 2 diabetic patients (3). Since 1977, when the UKPDS was started, several studies have tried to define the optimal insulin treatment regimen for type 2 diabetic patients. These studies are the focus of this review and include studies comparing insulin alone to combination therapy with insulin and sulfonylureas (subject to meta-analyses in 1991 and 1992) (4,5) and more recent trials using metformin, glitazones, or acarbose in insulin combination therapy regimens. They do not contain data on cardiovascular end points but only on surrogate markers of risk of microand macrovascular complications, mostly data on glycemia, body weight, insulin doses, lipids, and in a few studies, also accurate data on the frequency of hypoglycemias. According to a Medline search (1966– 2000), insulin alone has been compared with insulin combination therapy in a total of 34 prospective studies that lasted at least 2 months and reported data on HbA1 or HbA1c in type 2 diabetic patients. Studies comparing glycemic control, weight gain, hypoglycemias, and insulin requirements between the two modes of treatment in insulin-naı̈ve patients are listed in Table 1 and in previously insulin-treated patients are listed in Table 2. The studies have been ranked according to glycemic control at the end of the trial.