Variability of A1c Predicts All-Cause Mortality in Type 2 Diabetes

According to a recent published study, HbA1c variability is a better predictor of mortality in patients with type 2 diabetes compared with HbA1c averages.

This study was done to evaluate various measures of hemoglobin HbA1c variability, compared with average HbA1c, as independent predictors of mortality and looked at the average HbA1c and HbA1c variability in 15,733 patients with type 2 diabetes enrolled between 2006 and 2008 using three to five measures obtained from nine centers two years before the study enrollment.

They enrolled 15,733 patients with type 2 diabetes from 19 diabetes clinics during 2006-2008. A total of three to five HbA1c measures, obtained during the 2-year period before enrolment, were available from nine centers (8,290 patients) and were used to calculate average HbA1c (HbA1c-MEAN) and HbA1c variability, measured as intra-individual standard deviation (HbA1c-SD), SD adjusted for the number of HbA1c assessments (HbA1c-AdjSD) and coefficient of variation (HbA1c-CV), that is the HbA1c-SD to HbA1c-MEAN ratio. Vital status on October 31, 2015 was retrieved for 8,252 patients (99.5%).

Prior research has suggested that variations in glycemic control may be related to the occurrence of adverse outcomes in patients with T2D. HbA1c variability, defined as changes in HbA1c values per visit, is one measure of assessment that requires more investigation. For this study, investigators collected patient data from the Renal Insufficiency and Cardiovascular Events study (ClinicalTrials.gov identifier: NCT00715481), an observational, prospective, cohort study, originally designed to determine the effect of estimated glomerular filtration rate on morbidity and mortality in patients with T2D.

Of the sites, nine participating centers had collected at least three HbA1c measures on their patients (n=8290) during the 2-year period before enrollment. Average HbA1c and HbA1c variability, defined as intra-individual standard deviation (HbA1c-SD), were calculated from this subset of patients. Then in October 2015, vital statuses were obtained for 99.5% of the participants (n=8252) using the Italian Health Card database for assessment of mortality.

The results showed that HbA1c-MEAN and measures of HbA1c variability were associated with all-cause mortality; however, the strength of association of HbA1c-MEAN was lower than that of HbA1c-SD, HbA1c-CV or HbA1c-AdjSD, and disappeared after adjusting for confounders and any of the measures of HbA1c variability. Mortality increased with quartiles of HbA1c-MEAN, HbA1c-SD, HbA1c-CV and HbA1c-AdjSD, but only the association with HbA1c variability measures remained after adjustment for confounders and/or each other measure. In the fully adjusted model, mortality risk was lower for HbA1c-SD below the median and higher for HbA1c-SD above the median, regardless of whether HbA1c-MEAN was below or above the median.

From the results it was concluded that the HbA1c variability is a strong, independent predictor of all-cause mortality in type 2 diabetes and appears to be even more powerful than average HbA1c in predicting mortality.

Two milestone intervention trials have provided compelling evidence that intensive glycemic control is effective in preventing microvascular and macrovascular complications in both type 1 and type 2 diabetes. Post hoc analyses of these trials showed that long-term glycemic exposure, expressed as the updated mean of hemoglobin HbA1c levels over time, is the main risk factor for development of complications, and that the average HbA1c level explained virtually all of the difference in risk of complications between the intensive and conventional treatment groups. However, it has been suggested that adverse outcomes in individuals with diabetes may be related also to the variability in glycemic control, which includes glucose variability and HbA1c variability.

Glucose variability relates to within-day fluctuations in glycemia, with alternations in peaks, especially post-prandial, and in troughs, which may fall into the hypoglycemic range. Both hyperglycemic and hypoglycemic episodes may trigger a pro-inflammatory, pro-oxidant and pro-coagulant response, thus favoring the development and progression of complications. However, despite its biological plausibility, the detrimental effect of glucose variability is still a matter of debate because of the conflicting results of existing studies. Conversely, HbA1c variability relates to changes in HbA1c from one visit to the next.

Although the underlying mechanisms are less clear, the experimental evidence supporting a role for HbA1c variability in the development of complications is more robust than that for glucose variability, as shown by two recent meta analyses. In detail, studies in patients with type 1 diabetes consistently showed that HbA1c variability is an independent risk factor for microvascular complications, and one such study also found a relation with cardiovascular disease (CVD), even after adjusting for average HbA1c. Studies in subjects with type 2 diabetes were concordant in reporting an independent association of HbA1c variability with diabetic kidney disease (DKD), especially albumin uric DKD, whereas conflicting results were obtained for diabetic retinopathy (DR ) and CVD.

Finally, a few studies reported an association of HbA1c variability with mortality, independent of average HbA1c. They used the large cohort of the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicenter study (NCT00715481;www.ClinicalTrials.gov) to evaluate various measures of HbA1c variability, compared with average HbA1c, as independent predictors of mortality in patients with type 2 diabetes.

After adjustment for confounders, data analysis revealed associations between all-cause mortality and HbA1c-SD only. An association between all-cause mortality and average HbA1c was not shown. Additionally, mortality risk was decreased in HbA1c-SD values below the median and higher for values above the median.

From the results the authors concluded that, “HbA1c variability is a strong, independent predictor of all-cause death in type 2 diabetes and appears to be even more powerful than average HbA1c in predicting mortality. Further studies are required to understand whether HbA1c variability acts as a mediator or innocent bystander in this relationship.”

Practice Pearls:

• The takeaway from this study is that the average HbA1c and the variability of the HbA1c are both important when looking at predictors of mortality.
• In order to detect HbA1c variability you need to test for the A1c more frequently, than every 90 or 180 days.
• HbA1c variability is a strong and independent predictor of total mortality in patients with type 2 diabetes and the fact that It also shows that HbA1c variability is apparently more powerful than average HbA1c in predicting all-cause mortality.

Orsi E, Solini A, Bonora E et al; Renal Insufficiency And Cardiovascular Events (RIACE) Study Group. Hemoglobin A1c variability is a strong, independent predictor of all-cause mortality in patients with type 2 diabetes [published online March 26, 2018]. Diabetes Obes Metab. doi:10.1111/dom.13306