Type 2 diabetes

Glycaemic fluctuations predict chronic vascular complications

Dr Emma Scott

Glycaemic variability (GV) predicts the development of chronic micro- and macrovascular conditions and death in people with type 2 diabetes despite good glycaemic control, new Australian research shows.

Investigators say the study shows the harmful impact of long-term blood glucose fluctuations and highlights the potential clinical impact of treating GV.

The findings are based on a post hoc analysis of the FIELD study, which looked at the effect of the lipid lowering drug fenofibrate on the development of vascular complications over five years in more than 9700 participants with type 2 diabetes.

In the current analysis, researchers from the NHMRC Clinical Trials Centre at the University of Sydney looked at whether GV over the first two years of the study could predict subsequent diabetes complications.

Speaking to the limbic, endocrinologist and lead author Dr Emma Scott, of the Royal North Shore Hospital, Sydney, said the study used a landmark statistical approach to investigate the association between GV and vascular complications.

“We used a rigorous statistical adjustment and what we particularly wanted to adjust for was baseline and two-year HbA1c or fasting glucose levels, to account for the trajectory of glucose change. That’s important because we know that people who have a higher HbA1c tend to have more variability so we wanted to make sure that what we were looking for here was the glycaemic variability effect, not just the effect of people developing more complications from having higher HbA1c.”

GV was also calculated on a number of measures – a coefficient of variation (CV) and standard deviation (SD) of HbA1c and of fasting plasma glucose.

Dr Scott said at five years follow up all measures of GV were associated with an increased risk of chronic complications.

While glucose GV was associated with retinopathy, and coronary events, HbA1c GV was linked with stroke, cardiovascular mortality and coronary mortality.

“That’s an interesting finding and you might infer that the complications associated with glucose variability reflect the impact of short-term fluctuations day-to-day, whereas the coronary complications associated with HbA1c variability reflect the effects of longer-term fluctuations.”

Meanwhile baseline factors associated with on-study GV included greater use of hypoglycaemic agents and insulin, longer diabetes duration, younger age and male gender.

Similarly, higher GV individuals had a more adverse metabolic profile at baseline, with elevated BMI, waist-to-hip ratio, triglycerides and were more likely to be current smokers.

The association between high GV and male gender in particular has not been consistently observed, said Dr Scott who said the finding may relate to the greater size and power of the FIELD study.

Meanwhile ‘number needed to treat’ analyses of HbA1c CV ranged from 21 to 100 persons to prevent an additional vascular complication or death, highlighting the potential clinical impact of long-term GV improvement.

The findings could change the way clinicians screen for diabetes complications, Dr Scott said.

“It’s about being aware about the impact of glycaemic variability as a contributor to complication risk over time. Whether that’s variability over the short term or the long term it’s an awareness that those fluctuations might be harmful, and potentially that we should be looking at how HbA1c is fluctuating over months to years,” she said.

“Potentially, for someone in whom there has been a number of rapid changes in HbA1c or fasting plasma glucose levels we might be aware that these people could be at greater risk for complications. This should encourage us to explore the reasons why with the person with diabetes. It may for example relate to missed medications or changes in diet, physical activity or weight.”

“With time that would alter our screening approach – we may want to screen for compilations at greater frequency in people with higher glucose variability. This is just a hypothesis as yet but it’s something for clinicians to be a little more aware of.”

The study also raises the question about the value and potential impact of establishing clinical targets for GV, according to Dr Scott.

While clinical targets for short term GV and time in target range, usually assessed by glucose levels assessed by interstitial fluid glucose monitoring, have already been endorsed for individuals with diabetes as yet there are no guidelines for long-term HbA1c related GV, she says.

“We have targets for HbA1c but potentially we should be looking at how the HbA1c or fasting plasma glucose is fluctuating over months to years and targeting that to minimise fluctuations to reduce the risk of complications. So perhaps it’s another measure we should be looking at in our diabetes consultations.”

The findings are published in the Journal of Clinical Endocrinology and Metabolism.

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