Observational analyses from ADVANCE and ADVANCE-ON

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.