Implications for the United Kingdom

D iabetes is a metabolic disorder primarily characterized by elevated blood glucose levels and by microvascular and cardiovascular complications that substantially increase the morbidity and mortality associated with the disease and reduce the quality of life. Type 1 diabetes is characterized by total reliance on exogenous insulin for survival and comprises 10% of all cases of diabetes. The more prevalent form of diabetes, called type 2, comprising 90% of all people with diabetes, is characterized by insulin deficiency and/or insulin resistance. An association between the complications of diabetes and elevated blood glucose levels was postulated in the early part of this century. However, only in the last 3 decades has a substantial body of animal experimental studies and human observational studies and clinical trials directly linked hyperglycemia with the development of diabetic complications (1). Some of these studies have also demonstrated that treatment that lowers blood glucose reduces the risks of diabetic retinopathy, nephropathy, and neuropathy. Notable are the results of the Diabetes Control and Complications Trial (DCCT) (2) and the similarly designed but smaller Stockholm Diabetes Intervention Study (3). These studies showed unequivocally in type 1 diabetes that lowering blood glucose delayed the onset and slowed the progression of microvascular complications. Risk reductions for various outcomes ranged from 35 to 75%. Secondary analyses in these studies showed strong relationships between the risks of developing these complications and glycemic exposure over time. Moreover, there was no discernable glucose threshold, i.e., there was a continuous reduction in complications as glycemic levels approached the normal range. Improved glycemic control was also associated with reduced cardiovascular events in the DCCT, but the difference was not statistically significant. Perhaps this was because the population studied was young adults and therefore the event rate was very low. Many of the observational studies also support a correlation between glycemic control and diabetic complications in patients with type 2 diabetes, but until now, there have been only three randomized controlled trials attempting to test the benefit of lowering blood glucose on the incidence of complications. The first of these studies was the University Group Diabetes Program (UGDP), which showed no benefit of glycemic control in new-onset type 2 diabetic patients (4). However, in the UGDP, there were only 200 subjects in each treatment group, HbA1c was not available as a reliable method for measuring chronic glycemia, and the difference in glucose control between the most intensively treated group and the other treatment groups was only a fasting plasma glucose of 30 mg/dl (1.7 mmol/l). Of note, a major concern emanating from the UGDP was the observation that the sulfonylurea agent (tolbutamide) and a biguanide (phenformin) used to reduce hyperglycemia were associated with increased cardiovascular mortality. The suspicion that glucose lowering with oral agents in patients with type 2 diabetes may actually be harmful has persisted since publication of the UGDP data in 1970. The second controlled trial in type 2 diabetes was only recently reported (5). This small study conducted in 110 lean Japanese subjects showed that multiple insulin injections resulting in better glycemic control (HbA1c 7.1%) compared with conventional treatment (HbA1c 9.4%) significantly reduced the microvascular complications of diabetes. The extent of the risk reduction in this Japanese study was similar to that in the DCCT, thereby supporting the hypothesis that glycemic control is important in both types of diabetes. The third trial in type 2 diabetes was a pilot study that randomized 153 men to intensive or conventional therapy (6). Despite a 2% absolute HbA1c difference in glycemic control between the two groups, the trial reported no significant difference in cardiovascular events (when adjusted for baseline characteristics) in a follow-up period of only 27 months. With this background, we now have the results of the largest and longest study on type 2 diabetic patients that has ever been performed (7–10). The United Kingdom Prospective Diabetes Study (UKPDS) recruited 5,102 patients with newly diagnosed type 2 diabetes in 23 centers within the U.K. between 1977 and 1991. Patients were followed for an average of 10 years to determine 1) whether intensive use of pharmacological therapy to lower blood glucose levels would result in clinical benefits (i.e., reduced cardiovascular and microvascular complications) and 2) whether the use of various sulfonylurea drugs, the biguanide drug metformin, or insulin have specific therapeutic advantages or disadvantages. In addition, patients with type 2 diabetes who were also hypertensive were randomized to “tight” or “less tight” blood pressure control to ascertain the benefits of lowering blood pressure and to ascertain whether the use of an ACE inhibitor (captopril) or -blocker (atenolol) offered particular therapeutic advantages or disadvantages.