Impact of Visit-to-Visit Glycemic Variability on the Risks of Macrovascular and Microvascular Events and All-Cause Mortality in Type 2 Diabetes: The ADVANCE Trial

Abstract

OBJECTIVEThere is no consensus on the importance of visit-to-visit glycemic variability in diabetes. Therefore, we assessed the effects of visit-to-visit variability (VVV) in HbA 1c and fasting glucose on major outcomes in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) trial. RESEARCH DESIGN AND METHODSADVANCE was a factorial randomized controlled trial of intensive glucose control and blood pressure lowering in patients with type 2 diabetes. VVV in the intensive glucose treatment group was defined using the SD of five measurements of HbA 1c and glucose taken 3-24 months after randomization. Outcomes were combined macro-and microvascular events and all-cause mortality occurring post 24 months. Sensitivity analyses were performed using other indices of variability and in the standard glucose treatment group. RESULTSAmong 4,399 patients in the intensive group, an increase in VVV of HbA 1c was associated with an increased risk of vascular events (P = 0.01) and with mortality (P < 0.001): highest versus lowest tenth hazard ratio (95% CI) 1.64 (1.05-2.55) and 3.31 (1.57-6.98), respectively, after multivariable adjustment. A clear association was also observed between VVV of fasting glucose and increased risk of vascular events (P < 0.001; 2.70 [1.65-4.42]). HbA 1c variability was positively associated with the risk of macrovascular events (P = 0.02 for trend), whereas glucose variability was associated with both macro-and microvascular events (P = 0.005 and P < 0.001 for trend, respectively). Sensitivity analyses using other indices, and patients in the standard glucose treatment group, were broadly consistent with these results. CONCLUSIONSConsistency of glycemic control is important to reduce the risks of vascular events and death in type 2 diabetes.

A 3-year follow-up of the Silent Diabetes Study

“…The 3-year follow-up of the Silent Diabetes Study extends the knowledge on risk factors for mortality in patients without [2,3]. The non-significant difference in 2 h post-load plasma glucose (8.6 vs 8.0 mmol/l; p=0.068) may also support the view.…”

Long-term Glycemic Variability and Risk of Adverse Outcomes: A Systematic Review and Meta-analysis

“…Twenty studies in 87,641 participants met the inclusion criteria. Ten studies included participants from Europe (10,11,14,(16)(17)(18)(19)26,29,35,36), eight from Asia (12,13,15,18,20,24,27,28), four from North America (6,18,23, 25), and one from Australasia (18). The number of participants in each study ranged from 234 to 35,891.…”

“…Thirteen studies included 43,620 participants with type 2 diabetes (12,13,(15)(16)(17)(18)(19)(20)23,24,(26)(27)(28)36). These comprised six retrospective cohort studies (13,15,20,23,28,36), five prospective cohort studies (12,16,17,19,26,27), and two post hoc analyses of randomized controlled trials (18,24).…”

“…A recent meta-analysis concluded that HbA 1c variability, assessed by the SD, is associated with renal disease in type 1 and type 2 diabetes (9). However, no systematic reviews or meta-analyses have evaluated the relationship between long-term glycemic variability and other complications in diabetes, despite contradictory literature providing evidence in support (6,(10)(11)(12)(13)(14)(15) and against (16)(17)(18)(19)(20) such a relationship.…”

Glucose Control and Vascular Outcomes in Type 2 Diabetes: Is the Picture Clear?

“…As our perspective on glucose control should be long-term, consistency of HbA 1c and glucose targets over time becomes important, since variability of these measures is associated with higher risk of vascular events and mortality, as shown in ADVANCE (43). More recently, long-term results from ACCORD, ADVANCE, and VADT, describing results over the years after a previous period of intensive glucose lowering, have become available (24,44,45).…”