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Both long- and short-term glycemic variability have been associated with incident diabetes complications. We evaluated their relative and potential additive effects on incident renal complications in the Action to Control Cardiovascular Risk in Diabetes trial. A marker of short-term glycemic variability, 1,5-anhydroglucitol (1,5-AG), was measured in 4,000 random 12-month postrandomization plasma samples (when hemoglobin A1c [HbA1c] was stable). Visit-to-visit fasting plasma glucose coefficient of variation (CV-FPG) was determined from 4 months postrandomization until the end point of microalbuminuria or macroalbuminuria. Using Cox proportional hazards models, high CV-FPG and low 1,5-AG were independently associated with microalbuminuria after adjusting for clinical risk factors. However, only the CV-FPG association remained after additional adjustment for average HbA1c. Only CV-FPG was a significant risk factor for macroalbuminuria. This post hoc analysis indicates that long-term rather than short-term glycemic variability better predicts the risk of renal disease in type 2 diabetes. Article HighlightsThe relative and potential additive effects of long- and short-term glycemic variability on the development of diabetic complications are unknown. We aimed to assess the individual and combined relationships of long-term visit-to-visit glycemic variability, measured as the coefficient of variation of fasting plasma glucose, and short-term glucose fluctuation, estimated by the biomarker 1,5-anhydroglucitol, with the development of proteinuria. Both estimates of glycemic variability were independently associated with microalbuminuria, but only long-term glycemic variability remained significant after adjusting for average hemoglobin A1c. Our findings suggest that longer-term visit-to-visit glucose variability improves renal disease prediction in type 2 diabetes. 

Abstract Aims The association of glycemic variability with microvascular disease complications in type 2 diabetes (T2D) has been under-studied and remains unclear. We investigated this relationship using both Action to Control Cardiovascular Risk in Diabetes (ACCORD) and the Veteran Affairs Diabetes Trial (VADT). Methods In ACCORD, fasting plasma glucose (FPG) was measured 1 to 3 times/year for up to 84 months in 10 251 individuals. In the VADT, FPG was measured every 3 months for up to 87 months in 1791 individuals. Variability measures included coefficient of variation (CV) and average real variability (ARV) for fasting glucose. The primary composite outcome was time to either severe nephropathy or retinopathy event and secondary outcomes included each outcome individually. To assess the association, we considered variability measures as time-dependent covariates in Cox proportional hazard models. We conducted a meta-analysis across the 2 trials to estimate the risk of fasting glucose variability as well as to assess the heterogenous effects of FPG variability across treatment arms. Results In both ACCORD and the VADT, the CV and ARV of FPG were associated with development of future microvascular outcomes even after adjusting for other risk factors, including measures of average glycemic control (ie, cumulative average of HbA1c). Meta-analyses of these 2 trials confirmed these findings and indicated FPG variation may be more harmful in those with less intensive glucose control. Conclusions This post hoc analysis indicates that variability of FPG plays a role in, and/or is an independent and readily available marker of, development of microvascular complications in T2D.