A Summary of the ADVANCE Trial

The publication of the U.K. Prospective Diabetes Study (UKPDS) in 1998 helped to shape the management of type 2 diabetes in recent years (1). The study demonstrated several points. First, sulfonylureas are as safe as insulin in controlling blood glucose. Second, metformin reduced cardiovascular disease in an overweight subgroup. Third, the same benefit of glycemic control in reducing microvascular disease (previously noted in type 1 diabetes) is applied equally to patients with type 2 diabetes. A separation in A1C of ∼1% in the UKPDS reduced the risk of microvascular disease (largely diabetic retinopathy) by ∼25%. This reflected the data from the Diabetes Control and Complications Trial, where a separation in A1C of 2% in intensive and standard groups led to a reduction in microvascular disease of ∼50% (2).

A fourth demonstration was that there was no significant reduction in macrovascular disease but a trend toward fewer myocardial infarctions with more intensive glucose control. Fifth, using the current treatment of the time (first-generation sulfonylureas, human ultratard insulin, or metformin), it proved impossible to maintain glucose control, which tended to deteriorate throughout the study. It is now generally believed that the progressive fall in endogenous insulin production as β-cell numbers decline makes it difficult, if not impossible, to maintain tight control using standard treatment. Sixth, the UKPDS also showed that in those patients with hypertension, lowering blood pressure (BP) to moderate levels with either captopril or atenolol could reduce microvascular disease (3).

In a subsequent study, the UKPDS investigators presented the rates of both micro- and macrovascular disease according to the achieved levels of A1C during the study (4). They showed a linear relationship between A1C and both groups of complications. The implication of the article was that if glycemic control could be tightened below the levels achieved in the UKPDS, then it might be possible to reduce rates, not only of microvascular complications, but also cardiovascular disease as well.

The aim of the glucose arm of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial (5) was to build on the information gained by the UKPDS and to answer the question as to whether intensifying glucose control to achieve an A1C of <6.5% would provide additional benefit in reducing the risk of both micro- and macrovascular disease.

ADVANCE also asked questions about BP lowering in patients with type 2 diabetes. The aims of the BP arm were to establish whether routine provision of BP-lowering therapy produced additional benefits in terms of macro- and microvascular disease, irrespective of baseline BP, and added to the benefits produced by other cardiovascular preventive therapies, including ACE inhibitors.