Link Between HbA1c and Mortality in Diabetes Not Clear-cut

Miriam E Tucker

February 25, 2015

A drop in HbA1c was associated with lower mortality among people with type 2 diabetes who had initial HbA1c values over 8%, but with a higher death rate for those who started out at 8% or lower, a 6-year study finds.

Results from the population-based, prospective observational study were published online January 30 in BMJ Open Diabetes Research & Care by Mette V Skriver, PhD, from Aarhus University, Denmark, and colleagues.

Greater variability in HbA1c over the median 6-year follow-up period was also linked to higher mortality among those with HbA1c levels of 8% or lower, but HbA1c variability had no effect on mortality in those with index HbA1c values greater than 8%.

"Our hypothesis going in was that high variation in HbA1c would be associated with higher mortality….We were surprised by the fact that the variation did not seem to matter for people with HbA1c values above 8%," Dr Skriver told Medscape Medical News.

While cautioning that this was an observational study and the reasons for the changes in HbA1c are not known, Dr Skriver noted that, nonetheless, "the results of this study clearly indicate that even though a person has obtained an HbA1c level below the recommended level, clinicians should still keep an eye on changes in HbA1c."

Mortality Results Diverge

Reducing the HbA1c level below a given limit is a widely used criterion for optimizing diabetes care, but the evidence is scarce on how variability in HbA1c or absolute changes in the individual HbA1c level affect mortality, Dr Skriver and colleagues explain in their paper.

From Danish public records, they identified 11,205 adults who had been diagnosed with type 2 diabetes during 2001–2006 and had had HbA1c measurements taken at the time they were entered in the register (index value), at 22 to 26 months later, and at least once in between.

A total of 2830 individuals died during the median 6 years of follow-up. Variability in HbA1c of more than 0.5 percentage points was associated with increased mortality for those with index HbA1c 8% or lower, but not for HbA1c greater than 8%. For those with index HbA1c values of 6.6% to 7.4%, the hazard ratio for one--percentage-point variability in HbA1c was 1.3.

The reason for the lack of association between HbA1c variability and mortality for those with higher index HbA1c levels is unclear.

"Perhaps a persistent high glycemic load dwarfs the harm of high variability. We hope that future research will address this and clarify the pathway," Dr Skriver said.

For index HbA1c 8% or less, mortality increased when HbA1c declined but was stable when HbA1c rose. For index HbA1c greater than 8%, change in HbA1c was associated with mortality, with the lowest mortality for greatest decline (HR 0.9 for a two-percentage-point decrease).

Associations were similar between men and women, for those using different treatments, and for different diabetes durations.

"Thus, we have identified HbA1c variability and absolute changes in HbA1c to be associated with mortality independently of the index HbA1c level," the researchers observe.

However, as only two studies have previously addressed variability in HbA1c and mortality in type 2 diabetes, "and as our study is an observational study, the findings should be replicated," they observe.

"Hopefully, in the long term, our study in combination with future research can lead to a targeted prevention of complications by more individualized treatment, presumably by aiming at reducing HbA1c variability for people with HbA1c below 8%," Dr Skriver concluded.

The study was supported by an unrestricted grant from the Tryg Foundation and a PhD fellowship from Aarhus University. The authors have no other relevant financial relationships.

BMJ Open Diab Res Care. Published online January 30, 2015. Article

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