Diabetes management is advancing in many areas. One such area is the glucose control concept. Evidence suggests that HbA1C will no longer be the sole glucose control marker utilized in the management of this disease – an expanded approach with novel drugs and more frequent glucose monitoring is set to substantially improve diabetes mortality and morbidity risk.
The Hemoglobin A1C (HbA1C) blood test reflects and integrates an average of the mean blood glucose level from the past two to three months, thus providing a measure of “long-term glucose level”. This is the most used and recommended marker for glucose control. It has strong diagnostic and prognostic value for the development of diabetes complications (showing continuous, non-linear correlation with vascular and non-vascular mortality in diabetes)16,17 and is therefore extremely important for managing diabetes.
However, while HbA1C control has clear benefits for microvascular complications, there is a lack of definitive or consistent support for its value in reducing macrovascular complications.9,18
In fact, intensive glucose control has been associated with an increase in cardiovascular mortality.1 This is thought to be due to its most common side effect, hypoglycemia – defined as an abnormally low level of blood glucose caused unintentionally by medications given to lower the glucose levels of (hyperglycemic) diabetes patients. Hypoglycemia has multiple impacts. The best-known presentation is neuroglycopenia (including cognitive alteration, seizure and coma), but there are also less well known, but significant, vascular and cardiac complications driven by proinflammatory and electrophysiological effects, which can lead to progressive vascular changes and potentially to serious arrhythmias and sudden death.6,11,*
With the above caveats, HbA1C remains an important marker for diabetes management, but the current approach to optimal glucose control is now set to be significantly improved upon in a way that should substantially improve patient mortality and morbidity.
Glucose level (intra- and inter-day) fluctuations, the degree and speed of fluctuation and time spent within a desired glucose level range are now also being recognized as useful markers for diabetes management.
Individuals with the same HbA1C level can have widely varying intra- and inter-day glucose level fluctuations (figure 1).3
In recent novel drug trials, the novel glucose-lowering medications, the GIP1 analogs and SGLT2 inhibitors, demonstrated robust mortality reductions, though the overall benefit was not necessarily proportional in extent to improvements from HbA1C control.
These medications have since been observed to provide greater glucose level stability than previous glucose-lowering medications, suggesting that glucose level stability could be in part responsible for the mortality reduction.
There’s now growing evidence that it’s not just hyperglycaemia and hypoglycaemia, but also abnormal glucose variability and sudden shifts in glucose levels (with or without hypoglycaemia), that are detrimental to diabetes patients (see following section for more details).
Glucose level (intra- and inter-day) fluctuations, the degree and speed of fluctuation and time spent within a desired glucose level range are as a result now also being recognized as useful markers for diabetes management.
Abnormal glucose variability has now been found to be correlated with an increased risk of microvascular, cardiovascular complications and all-cause mortality.4,5,15 Glucose level stability is therefore a newly recognized factor for diabetes management – this requires that the glucose level stays within a target range (usually 3.9 to 10 mmol/L, apart from in special circumstances such as pregnancy), without sudden shifts within that range**, and for as long as possible.3 Abnormal glucose variability results if the criteria for glucose level stability are not met (and to various degrees).
Why no sudden shifts? It has been demonstrated4,11 that in addition to being caused by hypoglycemia, life threatening cardiac arrhythmias can also be caused by an upward or downward (with or without hypoglycemia, i.e., not necessarily reaching the levels that define hypoglycemia) sudden glucose level shift. A sudden oscillation in glucose level is a component of severe hypoglycemia because its treatment with oral or intravenous sugar is followed by a dramatic upward glucose level shift (iatrogenic).5,6
Time in range (TIR) is the proportion of time (for example, percentage hours per day) that a diabetic’s glucose level stays within the desired target range (see example in figure 1). The more time spent in TIR, the better.3
Figure 1: Three diabetes patients with identical HbA1C values (a long-term, 2-3 month average glucose control marker) display varying short-term (inter-day) fluctuations in glucose levels. The more time spent in the desired target range, here 3.9-10 mmol/L, known as “Time in Range (TIR)”, the lower the patient’s mortality and morbidity risk. Source: Ceriello (2022).3
Glucose levels can be monitored on a short or longer-term (in which case HbA1C testing is ideal) basis. Short-term monitoring refers to intra-day levels (measured ‘at any time’, including via fasting glucose level and 1- and 2-hour postprandial glucose levels tests) or inter-day glucose levels (how these intra-day measures move day by day).
Advanced technology enabling frequent or continuous glucose monitoring therefore has great benefit here, capturing the full, short-term wave form of glucose levels.20 Availability/accessibility remains limited, but as this widens, patient outcomes will improve.
The new findings indicate that it’s not just long-term glucose levels (monitoring via HbA1C) that matter for diabetes management, but also, in order to reduce the risk of adverse cardiovascular events and all-cause mortality, how the glucose level moves over a much shorter time-frame – including how often it moves out of the target range and whether sudden shifts take place.
Therefore, to improve diabetes mortality and morbidity, the aim of glucose control is now to move beyond reaching and maintaining optimal HbA1C values, to also achieving more stable desired long- and short-term glucose levels via novel glucose-lowering drugs and the more frequent monitoring of glucose levels i.e. via new tech.
Please contact us if you would like to find out more about this development for diabetes management and/or to discuss the mortality and morbidity impacts or new product initiatives. We would be happy to set up a meeting with you.
Dr. Emoke Posan, Chief Medical Officer, North America
*: Progressive retinopathy is also a well-known complication of recurrent hypoglycemia (Dandona). Hypoglycemia is proarrhythmic: can cause sudden epinephrine release with sudden electrophysiological changes, heterogeneity in repolarization, QT prolongation leading to various arrhythmias, atrial fibrillation, ventricular arrhythmias and sudden cardiac arrest.
**: A sudden downward shift within or below the target range is not necessarily indicative of hypoglycemia (defined as abnormally low levels of blood glucose).