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Dr Angela Murphy expands on time in range and why it may become the most important of all glucose measurements in the future.

It’s estimated that about a half a billion people are living with diabetes worldwide. Most of them will have Type 2 diabetes, with about 10% living with Type 1 diabetes.

Large scale studies have proven that good glucose control reduces the complications associated with diabetes: cardiovascular disease, such as heart attack and stroke, kidney disease, vision loss and amputations.

At the heart of this statement are the words ‘good glucose control’. Until now, two main parameters have been used to determine diabetes control:

  1. Home glucose levels
  2. HbA1c

Blood glucose measurement

Initial testing of blood glucose levels in the 20th century was done using urine test kits. These were difficult to interpret and had no real correlation with complications of diabetes. The introduction of the Ames dextrostix, in the 1960s, paved the way for home glucose testing as we know it today.

We now have a choice of efficient, accurate glucometers. It’s possible to get a glucose reading from capillary blood in mere seconds, allowing the person living with diabetes (PWD) to act timeously.

In 1999, the first continuous glucose monitoring (CGM) device was approved. For the first time, blood glucose levels were measured continuously over a 24-hour period. A sensor is worn by the PWD which transmits readings to a reader, insulin pump or a smartphone. The real time sensors will alarm if the glucose level becomes too high or drops too low. This can assist the PWD to take more accurate and frequent actions to improve glucose control.

Figure 1:  CGM device showing current blood glucose level, arrow with direction of blood glucose rise and graph of previous 8 hour readings. (https://www.freestylelibre.com.au/getting-started-with-freestyle-libre-2)

HbA1c (glycated haemoglobin)

Researchers, Samuel Rahbar and Helen Rannay, found that haemoglobin (Hb) from blood samples of PWD had a specific pattern and this was named HbA1c.

HbA1c is formed when excess glucose in the blood attaches to the haemoglobin molecule, a process called glycation. Red blood cells are renewed on average every three months, so HbA1c is regarded as an average of blood glucose control over a three-month period.

Every PWD should be aware of their most recent HbA1c reading. Two landmark trials have proven that HbA1c correlates with complications.

  1. The Diabetes Control and Complications Trial (DCCT), which involved people living with Type 1 diabetes released its results in 1990. It conclusively showed that improved glucose control, defined as a HbA1c < 6.5%, reduced the risk of microvascular (small blood vessel) complications of the eyes, kidneys, and nerves.
  2. The United Kingdom Prospective Diabetes Study (UKPDS) confirmed these reductions in microvascular complications with good diabetes control in people living with Type 2 diabetes. Longer follow-up studies eventually showed the benefit in cardiovascular disease too.

Without HbA1c, this would have been nearly impossible to demonstrate.

Figure 2: Demonstrates the concept of a lower HbA1c: <7.0% being good, so it is green, whereas a higher HbA1c is dangerous and thus, is in red. HbA1c can be affected by several conditions that may make it less reliable, such as kidney failure, pregnancy, smoking and ethnicity (Quora.com).

Time to understand measuring glucose readings

Testing blood glucose regularly is an onerous task. It’s important therefore, to test with purpose.

Guidelines suggest that PWD treated with oral medications can measure blood glucose levels two to three times weekly. The timing of the test can vary from a fasting blood glucose to two-hour post-meal.

PWD using insulin will have to check their glucose readings more frequently. As a rule, the minimum tests should equal the number of injections per day. For PWD on four to five injections daily, this is taxing. However, we know that more frequent glucose testing does improve diabetes control.

How to understand continuous glucose monitoring

CGM devices are the machines of many a PWD’s dreams: a way of always seeing the blood glucose without having to open a conventional glucometer and prick a finger.

As the CGM devices became more advanced, they not only showed the current glucose reading, and of course the tracing of where the glucose had been but could predict where the glucose would go. In this way, PWD can be forewarned of hypoglycaemia or hyperglycaemia and take appropriate action to avoid these.

When this type of CGM technology works in tandem with insulin pumps, we see the makings of an artificial pancreas.

A CGM tracing can look like a rollercoaster. So where do we start to assess what the overall picture means?

Figure 3: CGM download showing blood glucose readings over a 24-hour period (Supplied by author).

Time in range

What data from CGM shows is that we cannot always rely on average blood glucose levels, even HbA1c, to fully assess overall diabetic control.  Averages do not show the extent of the high and low glucose readings.

Let me explain: if there are three blood glucose values of 6.0mmol/L, then obviously the average blood glucose is 6.0mmol/L. However, three readings of 12mmol/L, 2mmol/L and 5mmol/L will also give an average of 6.0mmol/L and yet only one reading is in the target range. This variation in glucose levels is called glucose variability.

CGM demonstrates patterns of glucose over a 24-hour period in detail so the swings in blood glucose levels are easily seen. The more frequently the blood glucose levels swing from highs to lows, the higher the glucose variability. There is concern that this variability can damage blood vessels and thus, may be implicated in diabetic complications.

Glucose targets

Based on data from all the large diabetes trials over the years, you can set targets for good diabetes control. This is not a one-size-fits-all range. Age, duration of diabetes, presence of complications, risk of hypoglycaemia and pregnancy all affect the target blood glucose levels.

In older PWD who have diabetic complications, particularly of the heart and kidneys, glucose levels are slightly higher than a young, newly diagnosed PWD.

Table 1: Glucose Targets set out by SEMDSA 2017 (Society of Endocrinology, Metabolism and Diabetes of South Africa).

In 2019, the International Consensus in Time in Range (TIR) defined the desired targets for CGM readings.  If blood glucose levels remain between the values of 4.0mmol/L and 10mmol/L 70% of the time (Time in Range – TIR), the corresponding HbA1c is around 6.5%. That equates to excellent diabetes control. Time below range (TBR) refers to readings < 4mmol/L and time above range (TAR) gives the percentage of time glucose readings are above 10mmol/L.

Figure 4: International Consensus of Time in Range (Battelino T et al., Diabetes Care 2019; https://doi.org/10.2337/dci19-0028)

Figure 4 illustrates the ideal range for patients with Type 1 and Type 2 diabetes and in pregnancy. Several medical aids will now consider reimbursement (with various levels of co-payment) for people living Type 1 diabetes who wish to use CGM devices.

Summary

To achieve good diabetes control, you try to get as close to physiological glucose levels as is safe. This has been proven to decrease both microvascular and macrovascular complications. Good control is not only a good average glucose, but also stability of glucose levels over time.  Time in range gives us insight into glucose stability and may become the most important of all glucose measurements in the future.

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