Observational analyses from ADVANCE and ADVANCE‐ON

Abstract

Aims To explain, and document, the epidemiological work associated with the action in diabetes and vascular disease: preterax and diamicron‐modified release controlled evaluation (ADVANCE) clinical trial. Materials and methods ADVANCE was designed as a randomized controlled multicentre factorial trial in high‐risk patients with diabetes. The two interventions were blood pressure lowering medications versus placebo, and intensive glucose control versus standard glucose control. Following termination of the trial, an observational study of surviving participants, able to join, was mounted: the ADVANCE ‐ observational study (ADVANCE‐ON). Other epidemiological analyses that were undertaken treated the trial as a cohort study, including using biomarkers from the blood samples taken from ADVANCE subjects as risk exposures. Results More than 50 publications have reported epidemiological results from ADVANCE. The main results from ADVANCE‐ON suggested attenuated benefits of ADVANCE's blood pressure lowering treatment on all‐cause and cardiovascular death, but no such long‐term benefits for intensive glucose control, although this did give persistent benefit for end‐stage renal disease. The other epidemiological studies found, amongst other things, strong effects of NT‐terminal pro‐B‐type natriuretic peptide and high‐sensitivity cardiac troponin T on macrovascular events, microvascular events and all‐cause death. Conclusions Embedding post‐randomization and epidemiological analyses into clinical trials is worthwhile and can be highly productive in advancing scientific knowledge.

Advance

“…To this end, the ADVANCE-ON extension was also worthwhile, for it established how the glycaemic lowering benefit persisted after the termination of the trial. 5 In conclusion, the ADVANCE trial has significantly improved our understanding of the treatment of diabetes. It established that the lessons of the UKPDS relating to BP control and glycaemic control in the newly diagnosed were also applicable to those in a wider geographical context and with established diabetes.…”

“…The ADVANCE trial began to recruit nearly 20 years ago 1 and it is apposite to review the trial results in the light of the history and progress made in therapeutics in the treatment of type 2 diabetes since the main results were published in 2008. 2 In this series of articles in this supplement, Zoungas, Knudsen & Cooper, Chalmers & Woodward, and Marre outline the history and the findings on the ADVANCE trial in some detail, covering explicitly the lessons learned about glycaemic control, 3 renal disease, 4 observational studies, 5 and blood pressure (BP) control. 6 Long-term outcome trials are expensive and labour-intensive.…”

“…In this series of articles in this supplement, Zoungas, Knudsen & Cooper, Chalmers & Woodward, and Marre outline the history and the findings on the ADVANCE trial in some detail, covering explicitly the lessons learned about glycaemic control, renal disease, observational studies, and blood pressure (BP) control …”

“…Luckily, there are those who believe that signals found in many measurements can point to real effects, and so extending data and extending trial measurements are often helpful. To this end, the ADVANCE‐ON extension was also worthwhile, for it established how the glycaemic lowering benefit persisted after the termination of the trial …”