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Crossing the Bridge from HbA1c to time in range

22nd February 2023

Continuous glucose monitoring allows a person with diabetes to monitor time in range (TIR), which gives a more complete picture of glycaemic control than HbA1c measurements. So should TIR therefore replace HbA1c in diabetes management or do they complement one another? Speaking at the recent International Diabetes Federation conference, Chantal Mathieu, Professor of Medicine at KU, Leuven, Belgium, gave an expert comparison of TIR and HbA1c. Dr Susan Aldridge reports.

The widespread use of HbA1c measurement in diabetes care started with the Diabetes Control and Complications Trial (DCCT), which revealed the link between higher HbA1c and complications. “It was clear that HbA1c is a good biomarker for glycaemic control and for complications, such as retinopathy, nephropathy, neuropathy and microalbuminuria,” said Professor Mathieu, “and today we use HbA1c to see how the person with diabetes is, when they are sitting in front of us in the clinic. We use HbA1c as an outcome in all our trials evaluating drugs for glucose control and in all our guidelines.”

In other words, HbA1c has now gained status as the gold standard in diabetes measurement, even though its use is relatively recent. However, as all clinicians know, there are many factors that can alter HbA1c, such as short turnover of erythrocytes, physiological states and the use of various medications.

Continuous glucose management (CGM) then came along and it became obvious that HbA1c and self-reported blood glucose values are only a snapshot and do not show the full story. “It’s like driving your car to the airport and opening an eye every now and then,” said Professor Mathieu. “This brought about the idea that we need new biomarkers to add to our measures of glycaemic control.”

HbA1c and TIR compared

A person with diabetes can have the same HbA1c, but different glucose variability and there is now plenty of evidence of the dangers of higher glucose variability. For instance, one of these studies shows an association – although not necessarily causation – between glucose variability and hypoglycaemia, major adverse cardiovascular outcomes and all-cause mortality.

HbA1c and TIR are actually complementary, as follows. HbA1c is a single measurement, usually done every three months. CGM, on the other hand, gives continuous measurements, can be done at any time and measures glucose variability, excursions and time spent in the safe glucose range (neither too high nor too low). HbA1c cannot record the immediate effects of a change in therapy, but CGM does. So, for instance, if you start someone on an SGLT-2 inhibitor, its impact on glycaemia can be seen straightaway. And, as mentioned above, HbA1c is prone to interference, affecting its accuracy, while CGM is not.

Finally, there have been many long-term studies of HbA1c, showing it has a good correlation to clinical endpoints, while there have been far fewer such studies on CGM.

TIR guidelines

The big diabetes societies are now accepting TIR. The abundance of data offered by CGM offers the opportunity to analyse patient data with more granularity than was previously possible, providing additional information to help in reaching glycaemic targets. Accordingly, the American Diabetes Association, for instance, has updated its Standards of Medical Care to include consensus on TIR.

“So is it time to move from HbA1c to TIR?” Professor Mathieu asked. “One thing I learned from COVID-19 was that with all the technology that was around, it was possible to follow people’s glucose control by sharing in the Cloud.”

For people with type 1 diabetes on CGM, TIR is now becoming the gold standard for self-monitoring, especially now that the technology is being integrated more and more with smart insulin pens, which give the time of injections. Then there is also hybrid closed-loop, which integrates CGM with pumps that can shut down and prevent an incoming hypo.

All this has led to new metrics in diabetes management, focused upon times spent in different glucose ranges. TIR itself is usually 70 to 180mg/dl, time below range is 70 to 54 mg/dl, with a hypo being defined as less than 54 mg/dl, while time above range is 180 to 250 mg/dl, with a hyper being defined as glucose above 250 mg/dl.

“These numbers are there for a reason,” said Professor Mathieu. “For instance, the American Diabetes Association says that 70 mg/dl is a ‘warning moment’ where you should consider taking action. A lot of work has gone into these cut-off values, especially the 180 mg/dl cut off.”

The relationship between TIR and HbA1c can be quite complicated. “As more data has been gathered, it has become clear that the same HbA1c can be achieved with very different types of glycaemic control,” said Professor Mathieu. “For example, 70% TIR can be correlated with HbA1c as low as 5.6% and or as high as 8.3%, so TIR gives you the stability of your glucose control. This is very important and tells you why we like this idea of TIR more and more. So we will be aiming for TIR of 70%, as we do for an HbA1c of 7%.”

An international consensus on the use of CGM has come up with a spectrum of different TIR targets, covering people with type 1 and type 2 diabetes, older people and high-risk pregnancies involving type 1 diabetes or gestational diabetes. 

TIR and complications

What about the correlation of TIR with complications? While there are, as yet, no studies like the DCCT for TIR, evidence is growing. For instance, Professor Mathieu highlighted a study from Belgium showing that TIR can be correlated with a range of microvascular and macrovascular complications, as well as hospitalisation for diabetic ketoacidosis and hypoglycaemia.

TIR is also being used as an outcome in medication studies. For example, a trial of insulin degludec versus insulin glargine showed no change in TIR, while a study on insulin Icodec, the weekly insulin, showed an increase in TIR for those previously on a daily insulin.

Then there is the ALERTT1 trial, which is a comparison of intermittently scanned versus real-time CGM with alarms. The findings of this trial show that the latter is associated with an increase in TIR, while the former is not. “So now, gradually, TIR is creeping into our evidence base,” said Professor Mathieu. Very recently, an international consensus paper on metrics and CGM has been published, which will provide guidance on when CGM can be a valuable endpoint in a clinical trial. 

Who should cross the bridge?

The value of TIR in type 1 diabetes is well established and there is now some evidence that it is also valuable in type 2 diabetes. For instance, one trial showed that those with advanced diabetic retinopathy had less TIR and more glucose variability, while another showed that less TIR is also associated with more distal peripheral neuropathy.

There has also been research on macrovascular complications that linked carotid intima media thickness, which can predict cardiovascular disease and major cardiovascular outcomes with TIR. “These studies further validate TIR in my mind as a surrogate marker for the risk of complications,” said Professor Mathieu.

So how important is TIR to people with diabetes? When diaTribe carried out an online survey of people with type 1 and type 2 diabetes, both on or not on insulin, asking them what was really important to them, TIR came out on top and Professor Mathieu knows why. “It gives a real-time view for people with diabetes on how they are doing. I’m sure you all remember when someone with type 1 came into clinic and said, ‘I hope my HbA1c is good’ and now they can say, ‘my TIR is 82%’. It’s very different and it’s really motivating for people, so that is very important for people with diabetes. My gut feeling would have predicted this for people on insulin, not for people not on insulin – but they like TIR as well.”

In conclusion, TIR is a valuable outcome parameter, both in clinical care and diabetes research. The relationship between TIR and complications is becoming clear, but whether the exact relationship is dependent on HbA1c or not is not yet clear. So, Professor Mathieu concluded, “I don’t think that TIR will replace HbA1c in the coming years but it adds to what we learn from it.”

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.