Glucocentric risk factors for macrovascular complications in diabetes: Glucose 'legacy' and 'variability'-what we see, know and try to comprehend.

Recognizing the role of dysglycaemia, 'ambient' hyperglycaemia, 'metabolic memory' and glycaemic variability as risk factors for macrovascular diseases is mandatory for effective diabetes management. Chronic hyperglycaemia, also referred to as 'ambient hyperglycaemia', was only fully acknowledged as a risk factor for adverse cardiovascular events when the beneficial effects of intensive glucose-lowering strategies were consolidated in the extended follow-up (> 10 years) of patients included in the United Kingdom Prospective Diabetes Study (UKPDS) and Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study. These studies led to the concept of the glucose-lowering 'legacy effect' (metabolic memory), which depends on the duration and magnitude of glucose-lowering, and is not a 'forever' phenomenon, as demonstrated in the 15-year follow-up of the Veterans Affairs Diabetes Trial (VADT). The relatively weak evidence for linking long- and short-term glycaemic variability to vascular complications in patients with diabetes is mainly due to a reliance on observational and retrospective studies, and the lack of randomized interventional trials. However, hypoglycaemia may play an intermediary role in accentuating the link between glycaemic variability and vascular events.