Fasting Glucose Variation Predicts Microvascular Risk in ACCORD and VADT

Jin J. Zhou; Juraj Koska; Gideon Bahn; Peter Reaven


J Clin Endocrinol Metab. 2021;106(4):1150-1162. 

In This Article

Abstract and Introduction


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.


Microvascular complications (retinopathy, nephropathy, and neuropathy) are common pathologic consequences of type 2 diabetes (T2D). It is well recognized that chronic hyperglycemia is an important risk factor for the development of microvascular disease in patients with T2D.[1] As a result of this strong link between hyperglycemia and diabetes complications, the role of glycemic control (eg, intensive vs standard control of glucose or glycated hemoglobin A1c [HbA1c] levels) has been extensively studied.[2–4] Several clinical trials (eg, the UK Prospective Diabetes Study [UKPDS], Action to Control Cardiovascular Risk in Diabetes [ACCORD]) and meta-analyses of clinical trials show that more intensive glucose lowering in T2D improves microvascular outcomes (especially kidney and eye events) compared with standard glycemic control group.[5] However, the effects are often relatively modest, and are largely driven by improvements in proteinuria or background retinopathy, rather than in more clinically relevant outcomes such as end-stage renal disease or photocoagulation.

Glycemic control evaluated in previous trials examined only average glycemic exposure. It has been estimated that total glycemic exposure (derived from average HbA1c and duration of diabetes) predicted only 11% of the risk of developing retinopathy in the type 1 diabetic cohort of the Diabetes Control and Complications Trial (DCCT) cohort.[6,7] On the other hand, increasing evidence implicates glycemic variability as an important contributor to the development of microvascular diabetes complications. Using a newly diagnosed diabetes cohort extracted from the Tayside and Fife in the Scottish Care Information–Diabetes Collaboration (SCI-DC),[8] Li et al recently showed that patients with a higher HbA1c variability score had an increased risk of developing microvascular complications. Although their risk factors and outcomes were extracted from medical records based on ICD9/ICD10 codes or changes of lab results, ie, estimated glomerular filtration rate (eGFR), this work suggested that renal, eye, and nerve complications may be linked to visit-to-visit variation in HbA1c in new-onset T2D. This appears to be supported by findings in diabetes patients with a longer duration of diabetes, including those from the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) trial[9] and several observational studies. For example, HbA1c variability was an independent risk factor (after adjustment for average HbA1c) for albuminuria but was not associated with diabetic retinopathy in the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicenter study.[10] The Rio de Janeiro Study reported that glucose variability was associated with severe renal outcomes (eg, renal failure), but not retinopathy, after accounting for overall glucose control.[11] However, none of the studies have examined the relationship of glucose variability with microvascular complications during intensive vs standard glucose lowering—a clinical setting in which variability may be most relevant.

Therefore, the goal of the present study was to use 2 large comprehensive trials of glucose lowering (ACCORD and the Veteran Affairs Diabetes Trial [VADT]) to study the effects of fasting plasma glucose (FPG) variability on microvascular outcomes (including both nephropathy and retinopathy). As both ACCORD and VADT were designed to compare glucose-lowering strategies, we were able to assess the differential effects of FPG variability between intensive and standard treatment arms. By using consistent microvascular outcomes across the 2 studies, we were able to perform a meta-analysis to pool the information from the 2 trials to provide a more precise estimate of the risk of FPG variability. Our results show that FPG variability increased risk of microvascular events well beyond that accounted for by average glycemic levels in both trials. Interestingly, the effect of long-term visit-to-visit FPG variability was found to be stronger in the standard treatment group than in the intensive treatment group in both the ACCORD and VADT trials.