Introduction
Glucose control is key to preventing diabetes complications in people with type 1 diabetes [
1‐
4]. Analyses of glucose levels related to lower risk of diabetes complications have generally been based on the biomarker HbA
1c [
2]. HbA
1c does not measure glucose level per se, but instead is based on glycation of haemoglobin and may be influenced by factors such as erythrocyte turnover and glycation rate [
5,
6]. HbA
1c remains a key biomarker of complications in people with type 1 diabetes for several reasons. Landmark studies relating glucose control to complications have used HbA
1c as the metric of glucose control [
1‐
4]. Large population-based studies following the prognosis of patients over long time periods have also relied on HbA
1c [
3]. Furthermore, it is easy to measure and is a relatively cost-effective biomarker that is measured in most healthcare systems.
While HbA
1c generally remains the primary outcome for new indications of glucose-lowering treatments, many clinical judgements and research study endpoints are nowadays based on metrics obtained through continuous glucose monitoring (CGM) [
7,
8]. This situation may be challenging for both individuals with diabetes and healthcare providers, as individuals may reach targets for certain metrics such as mean glucose (MG), time in range (TIR; % of time with glucose levels 3.9–10 mmol/l) or HbA
1c but not all of them. The TIR target of 70% has been set due to its relationship with an HbA
1c level of <53 mmol/mol (<7.0%) rather than data from long-term diabetes complication trials [
7]. Therefore, it is important for clinicians to understand to what extent HbA
1c may differ in relation to both MG and TIR.
The treatment target for most adults with diabetes is an HbA
1c value or an MG-derived estimated HbA
1c glucose management indicator (GMI) [
9] of <53 mmol/mol (<7.0%) [
10], which corresponds to an MG of approximately 8.6 mmol/l (155 mg/dl). In clinical practice, questions may be raised when significant differences are observed between MG, TIR and HbA
1c if underlying explanatory factors such as anaemia could exist. Often such factors cannot be identified, complicating diabetes management for both individuals with diabetes and healthcare providers.
Genetic factors influencing the glycation rate of haemoglobin are probably important but are poorly understood and are not used in clinical practice. Deviations in glucose metrics are sometimes suspected to be due to insufficient CGM data being used to characterise overall glucose control. It is also speculative whether two individuals with the same MG but with different glucose patterns, such as long versus short periods with hypo- or hyperglycaemia, or high glycaemic variability versus stable glucose levels, will show different glycation rates and thereby different HbA
1c, as suggested by others [
11,
12]. Although earlier studies found a discordance between MG, TIR and HbA
1c [
13‐
17], the associations are poorly understood.
The primary aim of the present study was to determine the associations between MG and HbA1c using 2.5 years of data from the GOLD and SILVER trials, including whether different glucose patterns influence the relationship between MG and HbA1c. As a secondary aim, we also evaluated the associations between HbA1c and TIR. The results are intended to create a basis for guiding patients, clinicians and researchers in the management of type 1 diabetes.
Discussion
Clinical implications
There is a critical need for clinicians to be aware of the association between MG and HbA
1c. Values for these glucose indices are typically presented to individuals with type 1 diabetes during clinical visits, but they can also get information about their calculated GMI through CGM system-generated ambulatory glucose profile reports [
33]. We propose that clinicians should assess both HbA
1c and GMI, and not only acknowledge if a difference exists, but also record its magnitude and direction accurately. Repeated deviations between HbA
1c and GMI in the same direction will suggest whether an individual is a high or low glycator [
32]. A high glycator is indicated when HbA
1c is consistently higher than GMI, and vice versa for a low glycator. Large discordances between MG and HbA
1c may influence diabetes management [
32]. From a global perspective, CGM is not available to most people with type 1 diabetes. When possible, temporary use of CGM will be valuable to confirm the true MG and whether major discordances with HbA
1c exist.
Although insulin dosing per se is based on CGM or capillary glucose levels, it has been proposed that individuals with a low MG but high HbA
1c may be at increased risk of hypoglycaemia [
34]. Individuals with diabetes are generally aware of HbA
1c targets, as this information is repeatedly given to them by clinicians at clinical visits. Hence, there is a risk that some individuals may strive for intensified treatment if HbA
1c is high when GMI is on target, especially if healthcare providers do not inform the individual of discordances between the two [
34]. Moreover, individuals may experience increased anxiety regarding the risk of complications correlating with a higher HbA
1c [
35]. In contrast, on-target HbA
1c but high MG may lead to insufficient intensification of treatment [
34]. However, HbA
1c is still of primary focus in clinical practice and is also used for quality assessment between clinics and countries [
36,
37].
TIR has increasingly come into greater focus in clinical practice and research over time [
7,
8]. As HbA
1c differs in relation to MG, it is possible that it will also differ in relation to TIR, as TIR is closely related to MG at a certain TBR. As the target TIR of 70% was established based on its overall relationship with an HbA
1c of <53 mmol/mol (7.0%), clinicians need to be aware, as discussed earlier in the context of the MG–HbA
1c relationship, that discordances between HbA
1c and TIR for individuals must be recognised and considered in diabetes management. Moreover, for the same individual, a specific TIR for an individual with greater TBR will intuitively relate to lower HbA
1c due to lower MG, as confirmed in the current study. Hence, HbA
1c and GMI may shift over time while maintaining a stable TIR if, for example, adjustments in diabetes care are made that alter the magnitude of TBR or TAR.
At present, it is not known which glucose index (HbA
1c, TIR or MG/GMI) is the most effective indicator for diabetes complications. While it may seem reasonable that MG per se would be the most predictive, HbA
1c is considered a marker for the glycation rate and glycation end-products, which are related to complications beyond its relationship with MG [
38,
39]. Additionally, some studies have shown associations between TIR and complications [
40,
41]. Long-term studies, preferably following participants from the time of diagnosis (as profound legacy effects exist from previous hyperglycaemic episodes [
4]), are necessary but take time to perform. An international standardisation for CGM systems of their calibration to blood is also crucial, as CGM systems have been shown to systematically deviate from blood glucose values, which can influence CGM metrics [
42].
It is likely that HbA1c, TIR and MG/GMI will remain as essential complementary metrics. Thus, it is crucial that clinicians assess and communicate these metrics effectively to individuals with diabetes in an appropriate way to reduce complication risk and decrease diabetes-related distress.
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