International Journal of General Medicine Dovepress

open access to scientific and medical research

Open Access Full Text Article

REVIEW

Correlation Between Glycemic Variability and

Diabetic Complications: A Narrative Review
Lining Huang 1 , Ying Pan 1 , Kaixin Zhou 2 , Hongying Liu 3
, Shao Zhong 1
1
International Journal of General Medicine downloaded from https://www.dovepress.com/

Department of Endocrinology, Gusu School, Nanjing Medical University, The First People’s Hospital of Kunshan, Kunshan, 215300, People’s Republic
of China; 2Guangzhou Laboratory, Guangzhou, 510005, People’s Republic of China; 3Hangzhou Kang Ming Information Technology Co., Ltd,
Hangzhou, 310000, People’s Republic of China

Correspondence: Shao Zhong, Department of Endocrinology, Gusu School, Nanjing Medical University, The First People’s Hospital of Kunshan,
Kunshan, 215300, People’s Republic of China, Tel +86 13328056828, Email [email protected]; Hongying Liu, Hangzhou Kang Ming Information
Technology Co., Ltd, Hangzhou, 310000, People’s Republic of China, Email [email protected]

Abstract: Diabetes mellitus is a metabolic disorder with a complex etiology in which glycemic dynamics are disturbed and the body
is unable to maintain the process of glucose homeostasis through the pancreas. Persistent symptoms of high blood glucose or low
For personal use only.

blood glucose may lead to diabetic complications, such as neuropathy, nephropathy, retinopathy, and cardiovascular diseases.
Glycemic variability which can represent the presence of excessive glycemic excursions is an indicator for evaluating glucose
homoeostasis. Limiting glycemic variability has gradually become an emerging therapeutic target in improve diabetes metabolism
and prevent associated complications. This article reviews the progress of research on the various quantifiable parameters of glycemic
variability and their relationships with vascular lesions and mechanisms.
Keywords: diabetes mellitus, glycemic variability, glycemic variability parameters, vascular lesions of diabetes mellitus

Introduction
Diabetes is a common lifelong chronic disease whose prevalence continues to increase worldwide. The chronic high
blood glucose levels caused by the disease have a negative impact on the blood vessels, leading to the development of
several diabetes-related vascular diseases, such as diabetic microvascular complications and diabetic macrovascular
complications.1 Research has shown that people with diabetes are 2–4 times more likely to develop cardiovascular and
cerebrovascular disease than those without diabetes. Pre-diabetes also increases the risk of developing macrovascular
disease.2 Patients with type 2 diabetes mellitus (T2DM) and heart failure have a significantly increased risk of death.3 In
addition, hyperglycemia can also damage the small blood vessels of the kidney, leading to the development of diabetic
nephropathy (DN).4 The onset and progression of these complications in people with diabetes continually reduces their
quality of life and even threatens their lives.
Chronic low-grade inflammation is common in patients with diabetes and is considered one of the major factors
contributing to diabetes-related complications. Recent studies have shown that a novel adipokine, neuregulin-4 (Nrg-4),
can regulate glucose and lipid metabolism, reduce chronic inflammation and predict the risk of microvascular complica­
tions in patients with early-stage T2DM.5 Serum levels of Nrg-4 are negatively correlated with glycated hemoglobin A1c
(HbA1c), fasting plasma glucose (FPG) and microalbuminuria. The inflammatory marker C-reactive protein (CRP) is
also considered an independent risk factor for DN.6 The monocyte/lymphocyte ratio (MLR), a novel inflammation index,
is significantly positively correlated with microalbuminuria7 and has some predictive power for diabetic retinopathy
(DR).8 In addition, glycemic fluctuations, also known as glycemic variability, are important factors in the development of
diabetes-related complications. Previous studies have shown that dynamic fluctuations in blood glucose between high and
low levels can activate oxidative stress pathways, exacerbate endothelial cell dysfunction and chronic inflammation,
promote platelet activation, alter gene expression, and consequently lead to vascular damage, increasing the risk of
diabetes-related complications.9–11 In recent years, the assessment of blood glycemic variability has been increasingly

International Journal of General Medicine 2023:16 3083–3094 3083

Received: 25 April 2023 © 2023 Huang et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.
Accepted: 11 July 2023 php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the
work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For
Published: 21 July 2023 permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
 Huang et al Dovepress

enriched. More and more research studies have shown that parameters of blood glycemic variability calculated from
values such as glycated HbA1c and FPG are associated with complications in patients with diabetes. In assessing the risk
of related complications in patients with diabetes, it has been found that the higher the index of blood glycemic
variability, the higher the risk of complications. At the same time, studies have also shown that controlling blood
glycemic variability within a certain range can reduce the occurrence and development of complications in patients with
diabetes.
With the widespread use of blood glucose monitoring systems and electronic health records, clinicians and patients
with diabetes have gained a better understanding of blood glycemic variability over the course of a day or over longer
periods of time. Blood glycemic variability indices can be calculated using different blood glucose monitoring methods.
Both long-term and short-term blood glycemic variability indices correlate with the onset and development of diabetes-
related complications. However, different blood glycemic variability indices have different clinical significance for
different diabetes-related complications. Domestic and foreign researchers are continuously exploring and identifying
more quantitative indices representing blood glycemic variability and their correlation with diabetes-related complica­
tions. They have confirmed that various quantitative indices evaluating long-term and short-term blood glycemic
variability are to some extent correlated with the risk of all-cause mortality, cardiovascular and cerebrovascular diseases,
and microvascular complications in patients with diabetes. To overview the current state of research, we searched
PubMed using the terms diabetes, glycemic variability, glucose fluctuation, hyperglycemia, and vascular complications.
This review summarizes various quantitative parameters of short-term and long-term blood glycemic variability and their
correlation with the occurrence and development of macrovascular and microvascular complications in patients with
diabetes. The aim is to improve the implementation of glycemic control in clinical practice and to predict, prevent, delay
and reduce the occurrence and development of related complications in patients with diabetes.

Glycemic Variability
Definition of Glycemic Variability
Glycemic variability (GV), also known as blood glucose fluctuations, refers to the dynamic changes in blood glucose
levels between low and high levels in the body, which can provide more information about blood glucose changes. It
includes short-term blood glycemic variability, such as within-day and between-day variability, as well as long-term
blood glycemic variability over weeks, months, or years.12 Most studies use FPG, glycated hemoglobin A1c (HbA1c),
and other parameters to represent glycemic variability.

Methods for Monitoring Glycemic Variability

Monitoring parameters mainly include amplitude, which reflects the degree of blood glycaemic variability, and
frequency, which reflects the variability of blood glucose over time.13 Those measurements can be done using sensors
of continuous glucose monitoring (CGM) and self-monitoring of blood glucose (SMBG). Studies have shown a good
correlation between SMBG and CGM blood glucose levels.14

Parameters of Glycemic Variability

Parameters of the Short-Term Glycemic Variability
Mean of Daily Differences (MDD): The best parameters for assessing intra-day glycemic variability, reflecting the
repeatability of daily glucose fluctuations.15 It is calculated by taking the absolute difference between corresponding
measurements over 2 consecutive days and calculating the average.13
Average Glucose Profile (AGP): Reflects whether there is daily synchrony in blood glucose patterns within a given
time period, usually expressed as the IQR of the AGP.13,16,17
Coefficient of variation (CV): (standard deviation/mean) × 100%, is a parameter independent of the mean13 and
reflects only the magnitude of glucose variation.
Standard deviation (SD): The arithmetic square root of the variance, which represents the distribution of blood
glucose readings around the mean or variability. SD is strongly influenced by average blood glucose.

3084 https://doi.org/10.2147/IJGM.S418520 International Journal of General Medicine 2023:16

DovePress

Powered by TCPDF (www.tcpdf.org)

 Dovepress Huang et al

Mean amplitude of glycemic excursions (MAGE): The average value obtained by taking the first valid direction of
fluctuation to calculate the magnitude of the blood glucose fluctuation after removing all fluctuations that do not exceed
a certain threshold (usually 1 SD).
Time in Range (TIR): The percentage of time spent in the target glucose range (70–180 mg/dL or 3.9–10.0 mmol/L)
within 24 hours.18
Time above range (TAR): The time that glucose is above the target range (181–250 mg/dL or 10.1–13.9 mmol/L).18
Time below range (TBR): The time that glucose is below the target range (<70 mg/dL or 3.8 mmol/L) and (<54 mg/
dL or 2.0 mmol/L).
Incremental glucose peak (IGP): Calculated by subtracting the FPG from the absolute glucose peak (AGP).19
Glycemic variability percentage (GVP): GVP = (L/L0-1) × 100%, where L and L0 are the lengths of the true
glycemic variability trajectory and the no glycemic variability trajectory, respectively, within a given time period.

Parameters of Long-Term Glycemic Variability

HbA1c, FPG and postprandial plasma glucose (PPG) are mostly used in long-term glucose fluctuation clinics with
multiple long-term follow-ups, and the variability is expressed as CV, SD, VIM, etc.
Visit-to-visit variability (VVV): During long-term follow-up, FPG and HbA1c are measured at certain intervals and
standardized to obtain the blood glycemic variability of multiple time periods, namely FPG-VVV and HbA1c-VVV.20
SD, CV, VIM, and ARV can all be used as indices of VVV.
Variation Independent of Mean (VIM): Logarithmic curve fit. VIM = SD/meanβ, where β is the regression coefficient
based on the ln of the SD over the ln of the mean.21
Average Real Variability (ARV): Refers to the average difference between consecutive values; ARV can roughly
estimate the variation of each episode, rather than simply calculating the dispersion of the data.13
HbA1c variability: Reflects long-term blood glucose fluctuations; expressed using CV, SD, VIM, and other para­
meters to measure its variability.
HbA1c variability score (HVS): Reflects long-term blood glucose fluctuations, and HVS refers to the percentage of
HbA1c measurements with a change of at least 0.5% from the previous measurement.13
FPG and PPG variability: Reflects long-term fasting and postmeal glucose fluctuations; expressed using CV, SD,
VIM, ARV, and other parameters to measure their variability.13 (Table 1)

Glycemic Variability in Diabetes Mellitus and Its Association with Some

Complications
Mechanisms Research
Oxidative Stress
Oxidative stress refers to the imbalance between cellular pro-oxidants and antioxidants.23 High glycemic variability can
exacerbate oxidative stress and accelerate cell apoptosis and damage.24 High blood glucose, glycemic variability, and
hypoglycemia are all associated with the production of reactive oxygen species (ROS). Hyperglycemia promotes the
production of advanced glycation end products (AGEs) by inducing excessive ROS and oxidative stress (OS), activating
protein kinase C (PKC), and promoting overactivity of the hexosamine and polyol pathways, leading to the development
of insulin resistance, impaired insulin secretion, and endothelial dysfunction. Research suggests that compared with
chronic hyperglycemia, GV is associated with increased production of ROS leading to vascular damage, possibly through
the same mechanisms as hyperglycemia, but may also have adverse effects associated with hypoglycemia.23,25
Hypoglycemia may also play an important role in promoting diabetic vascular complications through OS, inflammation,
thrombotic events, and endothelial dysfunction.23

Activation of Inflammatory Response

Diabetes mellitus is a chronic low-grade inflammatory disease. Activation of the inflammatory pathway is critical for the
onset and development of complications in patients with diabetes.25 On one hand, hyperglycemia can activate the immune
response within the islets, promoting the synthesis and release of inflammatory factors such as IL-1β, TNF-α, IL-6 and

International Journal of General Medicine 2023:16 https://doi.org/10.2147/IJGM.S418520

3085
DovePress

Powered by TCPDF (www.tcpdf.org)

 Huang et al Dovepress

Table 1 Evaluation Parameters for Short-Term and Long-Term Blood Glucose Fluctuations
Parameters of Glycemic Measurement Definition
Variability Methods

Parameters of the short-term

glycemic variability
MDD SMBG, CGM Calculate the absolute value of the difference obtained by subtracting the corresponding
measurements over 2 consecutive days and then calculate the mean value.22
AGP CGM The distribution of glucose data for a given time point is usually expressed in the form of
IQR of AGP.16,17,22
CV SMBG, CGM It was used to measure the stability of blood glucose.
SD SMBG, CGM The magnitude of the change in blood glucose compared to the mean blood glucose.
MAGE SMBG, CGM Mean difference between peak and minimum values
TIR SMBG, CGM The percentage of time within the target range of glucose levels, 70–180 mg/dL (3.9–10.0
mmol/L), within a 24-hour period.19
TAR SMBG, CGM 181–250 mg/dL (10.1–13.9mmol/l).19
TBR SMBG, CGM <70 mg/dL (3.8 mmol/l) and <54 mg/dL (2.0mmol/l)
IGP CGM IGP=AGP - FPG.20
GVP SMBG, CGM GVP= (L/L0-1) ×100%
Parameters of the long-term
glycemic variability
VVV SMBG, CGM The inter-following variability of FPG and HbA1c is assessed using FPG and HbA1c
obtained from measurements over multiple time periods.21 SD, CV, VIM and ARV can all
be used as indices of VVV.
VIM SMBG, CGM Calculations based on logarithmic curve fitting. VIM=SD/meanβ
ASV SMBG, CGM Average of the differences between consecutive values.
Variability of HbA1c SMBG, CGM Reflects long-term blood glucose fluctuations and expresses its variability in terms of CV,
SD, VIM, etc.
HVS SMBG, CGM The proportion of the number of HbA1c changes ≥0.5% from the previous time in the
total number of HbA1c measurements.22
Variability of FPG and PPG SMBG, CGM It was used to estimate the variability of fasting and postprandial glucose over a follow-up
period of months or years, the variability is expressed in terms of CV, SD, VIM, ARV,
etc.22
Abbreviations: AGP, Average glucose profile; ARV, Average real variability; ASV, Average successive variability; CGM, Continuous glucose monitoring; CV, Coefficient of
variation; GVP, Glycemic variability percentage; HbA1c, Hemoglobin A1c; HVS, HbA1c variability score; IGP, Incremental glucose peak; MAGE, Mean amplitude of glycemic
excursions; MDD, Mean of daily differences; PPG, Postprandial plasma glucose; SD, Standard deviation; SMBG, Self-monitoring of blood glucose; TAR, Time above range;
TBR, Time below range; TIR, Time in range; VIM, Variation independent of the mean; VVV, Visit-to-visit variability; IQR, interquartile range.

VCAM-1 into the blood, creating a local microenvironment with them. Within this microenvironment, immune cells are
activated, initiating an inflammatory response that worsens insulin resistance and further impairs islet function.24,26 On the
other hand, blood glucose fluctuations promote the production of inflammatory factors such as IL-6 and TNF-α, exacerbating
the occurrence and development of microangiopathy in patients with diabetes.27 At the same time, inflammatory factors
associated with blood glucose fluctuations become more active. They not only damage pancreatic β-cells, inducing apoptosis
and impairing β-cell function and insulin secretion, but also exacerbate blood glucose fluctuations, creating a vicious cycle.28

Endothelial Cell Damage

Endothelial cell damage is a key indicator of diabetic vascular complications. Fluctuations in blood glucose levels
stimulate the production of cytokines, adhesion molecules, and apoptotic genes, leading to endothelial damage in both
larger vessels and microvessels, ultimately compromising vasodilator function.29,30 Fluctuating hyperglycemia also
increases susceptibility to oxidative stress, which further exacerbates endothelial cell damage and results in impaired
vasoconstriction.24

3086 https://doi.org/10.2147/IJGM.S418520 International Journal of General Medicine 2023:16

DovePress

Powered by TCPDF (www.tcpdf.org)

 Dovepress Huang et al

Activation of Coagulation Mechanism

Hypercoagulation is one of the major pathophysiological mechanisms of diabetic vascular complications. Platelet
aggregation and activation are closely related to the magnitude of glycemic variability. Increased levels of coagulation
factors and thrombin promote thrombus formation and atherosclerosis, increasing the likelihood of acute cardiovascular
events.24 Wang et al found that the amplitude of blood glucose fluctuations in T2DM patients was related to the degree of
platelet aggregation and activation, and the level of MAGE was significantly positively correlated with the expression
levels of peripheral blood PAG and platelet membrane protein CD62p.31

Other Related Mechanisms

Studies have shown that glycemic fluctuations in patients with diabetes have a bidirectional effect on neovascular­
ization. Acute glycemic fluctuations promote vascular formation while inhibiting the production of vascular
endothelial growth factor (VEGF). In addition, excessive glycemic fluctuations have been shown to cause more
significant renal fibrosis in diabetic nephropathy. Excessive glycemic variability may also cause progressive
deterioration of pancreatic β-cell function, thereby exacerbating the onset and development of diabetes and its
complications.25 Both short-term and long-term glycemic fluctuations may promote the occurrence of diabetic
vascular complications through mechanisms such as oxidative stress, endothelial cell injury, activation of inflam­
matory responses, and activation of coagulation. Abnormal long-term glycemic fluctuations may increase the risk of
hypoglycemia, which stimulates the activation of inflammatory mediators and platelets. Therefore, there may be
some differences in the pathophysiological mechanisms between long-term and short-term glycemic fluctuations and
diabetic vascular complications. Thus, there may be some correlation between long-term and short-term glycemic
fluctuations.

Clinical Research
Impact of the Short-Term Glycemic Variability on the Risks of Macrovascular and
Microvascular Complications in Diabetes
Gerbaud et al proposed that during the initial hospitalization period, SD-assessed GV (critical value >2.70 mmol/
L) was an independent predictor of macrovascular complications such as acute myocardial infarction, acute heart
failure, and cardiogenic death in patients with diabetes and acute coronary syndrome.32 During hospitalization, GV
as assessed by MAGE is an independent predictor of poor prognosis in patients with cerebrovascular disease and
acute coronary syndrome.33 In addition, MAGE correlates with the severity of coronary artery disease (CAD) in
acute myocardial infarction patients with poor diabetes control. Early assessment of GV may help to identify high-
risk patients and may serve as a therapeutic target for primary and secondary prevention.34 Daily GV is associated
with coronary artery spasm in patients with glycemic disorders.35 During the oral glucose tolerance test (OGTT),
IGP is independently correlated with aortic stiffness and poor carotid artery remodeling, but not with carotid
intima-media thickness, stiffness, microvascular function, etc.19 Liang et al pointed out that controlling GV can
improve insulin resistance, reduce carotid intima-media thickness, and reduce the risk of CVD.36 In addition, TIR
during hospitalization was negatively related with increased risk of all-cause and cardiovascular death.37
A 7-point glucose curve study using the Diabetes Control and Complications Trial (DCCT) dataset confirmed a negative
association between TIR and the risk ratio for developing retinopathy or microalbuminuria. A 10% decrease in TIR was
associated with a 64% increase in the risk of progression to retinopathy and a 40% increase in the risk of microalbuminuria.38
Picconi et al found that short-term glycemic variability assessed by CV, SD, and MAGE was associated with early retinal
neurodegeneration in patients with type 1 diabetes.39 TIR was independently associated with DR at different stages, such as
mild-DR, moderate-DR, and vision loss-DR, while the severity of DR was negatively correlated with TIR quartile (r =
−0.147; P <0.001).40 In addition, TIR was significantly associated not only with microalbuminuria and DR, but also with
CAN. TIR was negatively correlated with all stages of CAN, and was lower in patients with more severe CAN.41 The
correlation between TIR and microalbuminuria, DR, and CAN persisted after calibration for parameters of glycemic

International Journal of General Medicine 2023:16 https://doi.org/10.2147/IJGM.S418520

3087
DovePress

Powered by TCPDF (www.tcpdf.org)

 Huang et al Dovepress

variability (eg, SD, MAGE, and CV) and baseline factors (eg age, sex, and duration of diabetes). This suggests that the
association between TIR and microvascular complications is not influenced by other GV parameters.40–42

Impact of the Long-Term Glycemic Variability on the Risks of Macrovascular and

Microvascular Complications in Diabetes
A randomized study in patients with T2DM showed that FPG parameters (FPG-CV, FPG-ARV) were significantly
associated with the incidence of cardiovascular disease (CVD). This association remained evident after adjustment for
mean fasting plasma glucose and multiple baseline risk factors. However, there was no significant association between
HbA1c variability index and CVD.43 Another randomized controlled trial showed that FPG-VVV was related to both
macrovascular and microvascular complications (P=0.005 and P<0.001, respectively).20,44 Compared with FPG-CV,
HbA1c-CV showed a weaker association and poorer consistency. Lee et al showed that long-term FPG-VIM had
a positive dose-response relationship with the risk of stroke, myocardial infarction, and all-cause mortality in patients
with diabetes and was independent of glucose-lowering medications, mean fasting glucose, and metabolic risk factors.45
FPG-SD, FPG-CV, and FPG-ARV have similar predictive validity. FPG-CV was identified as a risk factor for ischemic
stroke in a Taiwanese population of patients with diabetes.46 A study conducted in a German population showed that
HbA1c-CV was a risk factor for stroke, myocardial infarction, and severe hypoglycemia in patients who had just started
insulin hypoglycemic therapy.47 Similar results were found in Chinese patients with diabetes, with long-term FPG-CV
increasing the risk of CVD and all-cause mortality.48 In addition, studies have found that increases in HbA1c-CV and
FPG-CV are both associated with accelerated progression of coronary artery plaques in patients with T2DM.49
Cardiovascular autonomic neuropathy (CAN) is also common in people with diabetes but is one of the most overlooked
macrovascular complications. HbA1c-CV and HbA1c-SD independently influence the severity of CAN and are positively
correlated with patient scores on the composite autonomic scoring scale.50
HbA1c-CV and HbA1c-SD are both connected with the occurrence of heart failure with preserved ejection fraction
(HFpEF) in patients with T2DM.51 HbA1c variability may serve as a predictor of HFpEF progression.52 Other studies
have suggested that FPG-VVV is a novel risk factor for long-term adverse changes in left heart structure and systolic
function in patients with T2DM.53 Yang et al found that FPG variability is an independent predictor of poor left
ventricular remodeling after ST-segment elevation myocardial infarction in patients with T2DM.52 Li et al reported that
patients with HVS > 60% had a significantly increased risk of all-cause mortality and adverse cardiovascular events.54
Glycemic variability is a better parameter than average HbA1c for assessing the development or worsening of
complications such as diabetic nephropathy and peripheral neuropathy in patients with T2DM during long-term follow-
up.55 Several studies have shown that patients with T2DM have an increased risk of developing diabetic polyneuropathy
(DPN), painful diabetic peripheral neuropathy (PDPN) and peripheral artery disease (PAD), which are significantly
associated with FPG-CV.56 FPG-CV is also associated with a higher risk of painful diabetic peripheral neuropathy
(PDPN) in patients with T2DM.57 In addition, some studies have identified FPG-CV as an effective predictor of diabetic
polyneuropathy (DPN) in T2DM patients.58 Risk factors for progression of DN and DR differ, with HbA1c-SD
significantly correlating with DN progression and mean HbA1c significantly associated with DR progression.59 HbA1c
control can also reduce the risk of patients developing stage 3–4 chronic kidney disease.60 Ceriello et al found that high
variability in HbA1c-SD increases the risk of DN.61 Several studies have shown that FPG variability is associated with
an increased risk of moderate to severe DN.62 HbA1c-CV is also closely associated with DPN and is considered
a predictive parameter for patients with diabetes with DPN.63,64 Lai et al showed that high HbA1c variability is closely
associated with the severity of DPN.65 Lee et al demonstrated that high HbA1c-CV is an independent risk factor for renal
function decline66 and is also independently associated with the severity of cardiovascular autonomic neuropathy.50 Li
et al found that patients with an HbA1c-CV greater than 60% have a significantly increased risk of diabetic retinopathy,
peripheral neuropathy, diabetic foot ulcers, and chronic kidney disease.54 In addition, some studies have suggested that
HbA1c-CV is a better predictor of microvascular complications than HbA1c-SD and HVS.67 However, there is also
evidence that FPG-SD, FPG-CV, HbA1c-SD, and HbA1c-CV are risk predictors for all microvascular and macrovascular
complications at 24 months of follow-up, and their predictability is better than that of mean HbA1c.55 Conversely, mean

3088 https://doi.org/10.2147/IJGM.S418520 International Journal of General Medicine 2023:16

DovePress

Powered by TCPDF (www.tcpdf.org)

 Dovepress Huang et al

HbA1c was better at predicting the risk of DR and the progression of complications such as peripheral neuropathy in
patients with poor glycemic control. Overall, the 24-month glycemic variability parameter was a more favorable
predictor than the 12-month glycemic variability parameter.

Discussion
Both long-term and short-term parameters of glycemic variability are associated with a variety of different vascular
complications of diabetes, in addition to neurological disorders, cognitive function, even the risk of hypoglycemia,
prolonged hospital stay, and postoperative infection.25 However, the correlation between different parameters of long-
term or short-term glycemic variability parameters and diabetes-related complications varies. With regard to long-term
FPG, FPG-CV, FPG-VIM and other quantitative parameters have certain differences in the correlation with the same
long-term complication in patients with diabetes. The same GV quantitative parameters have different predictive effects
on the risk of different complications. The same is true for short-term glycemic variability parameters, as shown in
Table 2. Besides, both long-term and short-term glucose fluctuations may lead to related complications through oxidative
stress, endothelial cell damage, activation of the inflammatory response, activation of coagulation, and other mechanisms.
However, long-term glucose fluctuations may increase the risk of hypoglycemia, which stimulates the activation of

Table 2 Correlations Between Glycemic Variability Parameters and Diabetic Complications

Parameters of Glycemic Calculation Method Macrovascular Complications and Microvascular
Variability Mortality Complications and
Neuropathy

Parameters of the short-

term glycemic variability
SD Arithmetic square root of the squared Acute myocardial infarction, acute heart -
deviation from the mean failure and sudden cardiac death.
MAGE After removing all blood glucose Cerebrovascular diseases such as acute -
fluctuations that do not exceed coronary syndrome, coronary artery
a certain threshold (usually 1 SD), the disease, coronary artery spasm.
average is obtained by calculating the
amplitude of blood glucose fluctuations
according to the direction of the first
valid fluctuation
IGP IGP=AGP - FPG.20 Aortic stiffness and poor carotid -
remodelling.
TIR The percentage of time within the target DR, Microalbuminuria and
range of glucose levels, 70–180 mg/dL CAN
(3.9–10.0 mmol/L), within a 24-hour
period.19
Parameters of the long-
term glycemic variability
FPG-CV (SD/mean) ×100% CVD, ischaemic stroke, accelerated DPN, PDPN, PAD and
progression of coronary atherosclerosis, other microangiopathy
poor left heart structure and systolic
function, other large vessel lesions and
mortality
HbA1c-CV (SD/mean) ×100% Coronary atherosclerosis, HFpEF and DN, DPN, CAN and all
other large vessel lesions microangiopathy
FPG-ARV The average of the differences between CVD -
successive measurements over a given
time period.

(Continued)

International Journal of General Medicine 2023:16 https://doi.org/10.2147/IJGM.S418520

3089
DovePress

Powered by TCPDF (www.tcpdf.org)

 Huang et al Dovepress

Table 2 (Continued).

Parameters of Glycemic Calculation Method Macrovascular Complications and Microvascular

Variability Mortality Complications and
Neuropathy

HbA1c-VVV SD, CV, VIM and ARV can all be used as Macrovascular disease and mortality -
indices of VVV.
FPG-VVV SD, CV, VIM and ARV can all be used as Macrovascular disease and all-cause Microangiopathy
indices of VVV. mortality
FPG-VIM VIM= SD/meanβ Stroke, myocardial infarction, poor left
ventricular reconstruction after
infarction and all-cause mortality
FPG-SD Arithmetic square root of the squared Poor left ventricular reconstruction All microangiopathy
deviation from the mean after infarction and other large vessel
lesions
HbA1c-SD Arithmetic square root of the squared HFpEF and other large vessel lesions DPN, CAN and all
deviation from the mean microangiopathy
HVS>60% The proportion of the number of All-cause mortality and adverse Diabetic peripheral
HbA1c changes ≥0.5% from the cardiovascular lesions neuropathy, diabetic foot
previous time in the total number of ulcers and chronic kidney
HbA1c measurements.22 disease
Mean HbA1c Average value - DR in patients with poor
glycemic control and
peripheral neuropathy
Abbreviations: ARV, Average real variability; CAN, Cardiac autonomic neuropathy; CV, Coefficient of variation; CVD, Cardiovascular disease; DN, Diabetic nephropathy;
DR, Diabetic retinopathy; DPN, Diabetic polyneuropathy; DR, Diabetic retinopathy; FPG, Fasting plasma glucose; HFpEF, Heart failure with preserved ejection fraction; HVS,
HbA1c variability score; IGP, Incremental glucose peak; MAGE, Mean amplitude of glycemic excursions; PAD, Peripheral artery disease; PDPN, Painful diabetic peripheral
neuropathy; SD, Standard deviation; TIR, Time in range; VIM, Variation independent of the mean; VVV, Visit-to-visit variability.

inflammatory mediators and platelets. This suggests that the pathophysiological mechanisms of long-term and short-term
glucose fluctuations leading to diabetes-related complications may be different.22
There may also be some correlation between different quantitative parameters that quantify long-term glucose
variability or short-term glucose variability. Nevertheless, few studies have been conducted to explore whether there is
a certain correlation between long-term glycemic variability and short-term glycemic variability. Previous studies have
investigated the relationship between blood glucose concentration at different times and HbA1c levels. The results
showed that premeal glucose was more strongly correlated with HbA1c than postmeal glucose.68 However, Ehehalt et al
suggested that postprandial glucose had a higher correlation with HbA1c in patients with better glycemic control, while
the correlation between FPG and HbA1c gradually increased with the deterioration of diabetic glycemic control.69 In
other words, there may be some correlation between long-term glycemic variability parameters in patients with poor
glycemic control. Some studies have confirmed that TIR is negatively correlated with HbA1c and glycated albumin in
patients with impaired glucose tolerance, T1DM and T2DM.70 Researchers observed the correlation between HbA1c and
several glycemic variability parameters derived from CGMs in T2DM patients and found that HbA1c was correlated with
TIR (r= −0.75), mean blood glucose (r=0.8), TAR (r= 0.75), and TBR (r= −0.39).71 There was a negative correlation
between TIR and Glucose Management Indicator (GMI) (estimates of mean HbA1c).72 Similar results were observed in
elderly male patients with T2DM, and patients with lower TIR had greater long-term glycemic variability.73 In addition
to long-term glycemic variability parameters such as HVS, a retrospective study showed that calibrated HbA1c SD was
positively correlated with TBR (r=0.501, P=0.009), and mean glucose was positively correlated with TAR (r=0.525,
P=0.006) and MODD (r=0.570, P=0.002) in patients with T2DM.74 Some researchers have also found that TIR is
associated with mean HbA1c and Hba1C-VVV, while MODD is associated with Hba1C-VVV.75 Consistently, TIR was
significantly associated with GMI (r=−0.822, P<0.001) and HbA1c (r=−0.563, P<0.001) in T1DM patients, and TIR had
a highly inverse linear relationship with GMI (R2=0.676, P<0.001), while GMI was positively correlated with SD,

3090 https://doi.org/10.2147/IJGM.S418520 International Journal of General Medicine 2023:16

DovePress

Powered by TCPDF (www.tcpdf.org)

 Dovepress Huang et al

MAGE, and MODD, but not with CV.76 These results highlight a certain correlation between the quantitative parameters
of long-term and short-term glycemic variability in patients with diabetes. The correlation between SMBG glycemic
variability parameters and MAGE in CGM is another topic that has attracted much attention from scientists. Studies
found that the standard deviation of blood glucose level (SDBG) calculated from the seven-point SMBG data, the
postprandial glucose excursion (PPGE), the largest amplitude of glycemic excursions (LAGE), CV, MAGE and other
glycemic variability parameters were closely related to MAGE obtained by CGM, especially SDBG.77 Therefore, there is
also some correlation between short-term glycemic variability parameters. However, most studies have examined the
correlation between HbA1c glycemic variability and short-term glycemic variability parameters during long-term follow-
up, and few studies have investigated the correlation between FPG glycemic variability from long-term monitoring and
various short-term glycemic variability parameters.
Therefore, we can further explore the correlation between long-term and short-term glycemic variability parameters in
patients with diabetes in the future. For example, we can investigate whether there is a correlation between long-term and
short-term fasting glycemic variability. What statistical methods can we use to do this research? Can we use Pearson’s
correlation coefficient to study the correlation between long-term and short-term blood glucose fluctuations? Or are there
other research methods that can be used to study their correlation and the specific nature of their correlation? How
effective is this correlation in predicting the risk of complications in patients with diabetes? Is the predictive power of
this correlation for the risk of complications in patients with diabetes different if the risk of complications is predicted
independently from long-term or short-term glycemic variability? Does this correlation improve the predictive power of
glycemic variability on the risk of complications in patients with diabetes? Can we also use a subset of the glucose
variability data available to patients with diabetes to predict their risk of relevant complications? After exploring these
questions, specific statistical methods may be used to calculate certain glycemic variability indicators in clinical practice
to predict and prevent some complications in patients with diabetes. This will help patients with diabetes who do not
have access to both long-term and short-term blood glucose monitoring data, and avoid the time-consuming calculation
of additional glycemic variability indicators with similar predictive power, and reduce the number of blood samples taken
from patients. This will not only improve the efficiency of the management of complication risk, but will also improve
patient compliance, thereby benefiting the patients.

Conclusion and Future Prospects

In conclusion, both long-term and short-term glycemic variability parameters may contribute to the development and
progression of complications in patients with T2DM by influencing oxidative stress, endothelial cell damage, activation
of inflammatory responses, and coagulation activation. In addition, there is some correlation between long-term and
short-term glycemic variability parameters, although the pathophysiological mechanisms by which they influence the
development of the disease may be different. In future research, it is essential to further investigate the correlation
between long-term and short-term glycemic variability parameters, in order to lay a solid foundation for the development
of improved strategies for blood glucose monitoring and management.

Funding
This work was supported by Suzhou Science and Technology Project (No: SLT2021006).

Disclosure
The authors declare no conflicts of interest related to this work/review article.

References
1. Papatheodorou K, Papanas N, Banach M, et al. Complications of Diabetes 2016. J Diabetes Res. 2016;2016:6989453. doi:10.1155/2016/6989453
2. Chinese Cardiovascular Disease Prevention Guidelines (2017) Writing group, Editorial Board of Chinese Journal of Cardiovascular Diseases.
Chinese Guidelines for Prevention of cardiovascular diseases (2017). Chin J Cardiovasc Dis. 2018;46(1):10–25.
3. Cavender MA, Steg PG, Smith SC, et al. Impact of diabetes mellitus on hospitalization for heart failure, cardiovascular events, and death.
Circulation. 2015;132(10):923–931. doi:10.1161/CIRCULATIONAHA.114.014796
4. Caramori ML, Mauer M. Diabetes and nephropathy. Curr Opin Nephrol Hypertens. 2003;12(3):273–282. doi:10.1097/00041552-200305000-00008

International Journal of General Medicine 2023:16 https://doi.org/10.2147/IJGM.S418520

3091
DovePress

Powered by TCPDF (www.tcpdf.org)

 Huang et al Dovepress

5. Kocak MZ, Aktas G, Atak BM, et al. Is Neuregulin-4 a predictive marker of microvascular complications in type 2 diabetes mellitus? Eur J Clin
Invest. 2020;50(3):e13206. doi:10.1111/eci.13206
6. Bilgin S, Kurtkulagi O, Tel BMA, et al. Does C-reactive protein to serum Albumin Ratio correlate with diabetic nephropathy in patients with type 2
Diabetes MELLITUS? The Care Time study. Prim Care Diabetes. 2021;15(6):1071–1074. doi:10.1016/j.pcd.2021.08.015
7. Kocak MZ, Aktas G, Duman TT, et al. Monocyte lymphocyte ratio as a predictor of diabetic kidney injury in type 2 diabetes mellitus; the
MADKID study. J Diabetes and Metab Disord. 2020;19(2):997–1002. doi:10.1007/s40200-020-00595-0
8. Yue S, Zhang J, Wu J, et al. Use of the monocyte-to-lymphocyte ratio to predict diabetic retinopathy. Int J Environ Res Public Health. 2015;12
(8):10009–10019. doi:10.3390/ijerph120810009
9. Škrah J, Šoupal J, Škrah J, et al. Glucose variability, HbA1c and microvascular complications. Rev Endocr Metab Disord. 2016;17(1):103–110.
doi:10.1007/s11154-016-9347-2
10. Yapanis M, James S, Craig ME, et al. Complications of diabetes and metrics of glycemic management derived from continuous glucose monitoring.
J Clin Endocrinol Metab. 2022;107(6):e2221–e2236. doi:10.1210/clinem/dgac034
11. Ceriello A, Novials A, Ortega E, et al. Vitamin C further improves the protective effect of GLP-1 on the ischemia-reperfusion-like effect induced by
hyperglycemia post-hypoglycemia in type 1 diabetes. Cardiovasc Diabetol. 2013;12(1):97. doi:10.1186/1475-2840-12-97
12. Wang ZF, Zhu MX, Wang ZP. Research progress on the relationship between blood glucose fluctuation and vascular complications in type 2
diabetes mellitus. Adv Cardiol. 2018;39(6):1064–1068.
13. Ni JY, Ma XJ, Zhou J. Research progress of abnormal blood glucose fluctuation and diabetes complications. China Diabetes. 2022;14(4):388–392.
14. Liu ZG, Yao B, Lin BS, et al. Study on the correlation between blood glucose fluctuation index and average blood glucose fluctuation amplitude in
self-blood glucose monitoring. Chin J Diabetes. 2021;13(5):476–481.
15. Molnar GD, Taylor WF, Ho MM. Day-to-day variation of continuously monitored glycaemia: a further measure of diabetic instability.
Diabetologia. 1972;8(5):342–348. doi:10.1007/BF01218495
16. Bailey T, Bode BW, Christiansen MP, et al. The performance and usability of a factory-calibrated flash glucose monitoring system. Diabetes
Technol Ther. 2015;17(11):787–794. doi:10.1089/dia.2014.0378
17. Hoss U, Budiman ES. Factory-calibrated continuous glucose sensors: the science behind the technology. Diabetes Technol Ther. 2017;19(S2):S44–
S50. doi:10.1089/dia.2017.0025
18. Sun B, Luo Z, Zhou J. Comprehensive elaboration of glycemic variability in diabetic macrovascular and microvascular complications. Cardiovasc
Diabetol. 2021;20(1):9. doi:10.1186/s12933-020-01200-7
19. Foreman YD, Brouwers MCGJ, Berendschot TTJM, et al. The oral glucose tolerance test-derived incremental glucose peak is associated with greater
arterial stiffness and maladaptive arterial remodeling: the Maastricht Study. Cardiovasc Diabetol. 2019;18(1):152. doi:10.1186/s12933-019-0950-x
20. Hirakawa Y, Arima H, Zoungas S, et al. Impact of visit-to-visit glycemic variability on the risks of macrovascular and microvascular events and
all-cause mortality in type 2 diabetes: the ADVANCE trial. Diabetes Care. 2014;37(8):2359–2365. doi:10.2337/dc14-0199
21. Kim JA, Lee JS, Chung HS. Impact of visit-to-visit fasting plasma glucose variability on the development of type 2 diabetes: a nationwide
population-based cohort study. Diabetes Care. 2018;41(12):2610–2616. doi:10.2337/dc18-0802
22. J-Y N, X-J M, Zhou J. Research progress of abnormal blood glucose fluctuation and diabetic complications. Chin J Diabetes. 2022;14(4):388–392.
23. Papachristoforou E, Lambadiari V, Maratou E, et al. Association of glycemic indices (Hyperglycemia, Glucose Variability, and Hypoglycemia) with
oxidative stress and diabetic complications. J Diabetes Res. 2020;2020:7489795. doi:10.1155/2020/7489795
24. Sheng MY. Study on the Correlation Between Blood Glucose Fluctuation and the Degree of Vascular Lesions in Type 2 Diabetes Patients with
Normal HbAlc. Soochow University; 2020.
25. Klimontov VV, Saik OV, Korbut AI. Glucose variability: how does it work? Int J Mol Sci. 2021;22(15):7783. doi:10.3390/ijms22157783
26. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet.
2014;383(9922):1068–1083. doi:10.1016/S0140-6736(13)62154-6
27. Su HW, Kang S, Long YW, et al. Relationship between diabetic nephropathy and blood glucose fluctuation and inflammatory factors. Chi
J Geriatric Heart Brain Vessel Dis. 2015;17(3):273–276.
28. Quan W, Jo E-K, Lee M-S. Role of pancreatic β-cell death and inflammation in diabetes. Diabetes Obes Metab. 2013;15(s3):141–151. doi:10.1111/
dom.12153
29. Palazzo P, Maggio P, Altavilla R, et al. Cerebral hemodynamics and systemic endothelial function are already impaired in well-controlled type 2
diabetic patients, with short-term disease. PLoS One. 2013;8(12):e83287. doi:10.1371/journal.pone.0083287
30. Ceriello A, Quagliaro L, Piconi L, et al. Effect of postprandial hypertriglyceridemia and hyperglycemia on circulating adhesion molecules and
oxidative stress generation and the possible role of simvastatin treatment. Diabetes. 2004;53(3):701–710. doi:10.2337/diabetes.53.3.701
31. Wang JS, Huang Y, Chen KJ, et al. Relationship between blood glucose fluctuation and vascular endothelial injury, platelet activation and PKCβ1
expression in patients with type 2 diabetes mellitus. Chin J Integr Med. 2016;36(10):1184–1190.
32. Gerbaud E, Darier R, Montaudon M, et al. Glycemic variability is a powerful independent predictive factor of midterm major adverse cardiac
events in patients with diabetes with acute coronary syndrome. Diabetes Care. 2019;42(4):674–681. doi:10.2337/dc18-2047
33. Takahashi H, Iwahashi N, Kirigaya J, et al. Glycemic variability determined with a continuous glucose monitoring system can predict prognosis
after acute coronary syndrome. Cardiovasc Diabetol. 2018;17(1):116. doi:10.1186/s12933-018-0761-5
34. Benalia M, Zeller M, Mouhat B, et al. Glycaemic variability is associated with severity of coronary artery disease in patients with poorly controlled
type 2 diabetes and acute myocardial infarction. Diabetes Metab. 2019;45(5):446–452. doi:10.1016/j.diabet.2019.01.012
35. Ito T, Ichihashi T, Fujita H, et al. The impact of intraday glucose variability on coronary artery spasm in patients with dysglycemia. Heart Vessels.
2019;34(8):1250–1257. doi:10.1007/s00380-019-01353-w
36. Liang S, Yin H, Wei C, et al. Glucose variability for cardiovascular risk factors in type 2 diabetes: a meta-analysis. J Diabetes Metab Disord.
2017;16(1):45. doi:10.1186/s40200-017-0323-5
37. Lu J, Wang C, Shen Y, et al. Time in range in relation to all-cause and cardiovascular mortality in patients with type 2 diabetes: a prospective cohort
study. Diabetes Care. 2021;44(2):549–555. doi:10.2337/dc20-1862
38. Beck RW, Bergenstal RM, Riddlesworth TD, et al. Validation of time in range as an outcome measure for diabetes clinical trials. Diabetes Care.
2019;42(3):400–405. doi:10.2337/dc18-1444

3092 https://doi.org/10.2147/IJGM.S418520 International Journal of General Medicine 2023:16

DovePress

Powered by TCPDF (www.tcpdf.org)

 Dovepress Huang et al

39. Picconi F, Parravano M, Ylli D, et al. Retinal neurodegeneration in patients with type 1 diabetes mellitus: the role of glycemic variability. Acta
Diabetol. 2017;54(5):489–497. doi:10.1007/s00592-017-0971-4
40. Lu J, Ma X, Zhou J, et al. Association of time in range, as assessed by continuous glucose monitoring, with diabetic retinopathy in type 2 diabetes.
Diabetes Care. 2018;41(11):2370–2376. doi:10.2337/dc18-1131
41. Guo Q, Zang P, Xu S, et al. Time in range, as a novel metric of glycemic control, is reversely associated with presence of diabetic cardiovascular
autonomic neuropathy independent of HbA1c in Chinese type 2 diabetes. J Diabetes Res. 2020;2020:5817074. doi:10.1155/2020/5817074
42. Yoo JH, Chol MS, Ahn J, et al. Association between continuous glucose monitoring-derived time in range, other core metrics, and albuminuria in
type 2 diabetes. Diabetes Technol Ther. 2020;22(10):768–776. doi:10.1089/dia.2019.0499
43. Zhou JJ, Schwenke DC, Bahn G, et al. Glycemic variation and cardiovascular risk in the veterans affairs diabetes trial. Diabetes Care. 2018;41
(10):2187–2194. doi:10.2337/dc18-0548
44. Slieker RC, van der Heijden AAWH, Nijpels G, et al. Visit-to-visit variability of glycemia and vascular complications: the Hoorn Diabetes Care
System cohort. Cardiovasc Diabetol. 2019;18(1):170. doi:10.1186/s12933-019-0975-1
45. Lee DY, Han K, Park S, et al. Glucose variability and the risks of stroke, myocardial infarction, and all-cause mortality in individuals with diabetes:
retrospective cohort study. Cardiovasc Diabetol. 2020;19(1):144. doi:10.1186/s12933-020-01134-0
46. Lin CC, Yang CP, Li CI, et al. Visit-to-visit variability of fasting plasma glucose as predictor of ischemic stroke: competing risk analysis in
a national cohort of Taiwan Diabetes Study. BMC Med. 2014;12(1):165. doi:10.1186/s12916-014-0165-7
47. Bonke FC, Donnachie E, Schneider A, et al. Association of the average rate of change in HbA1c with severe adverse events: a longitudinal
evaluation of audit data from the Bavarian Disease Management Program for patients with type 2 diabetes mellitus. Diabetologia. 2016;59
(2):286–293. doi:10.1007/s00125-015-3797-z
48. Wang A, Liu X, Xu J, et al. Visit-to-visit variability of fasting plasma glucose and the risk of cardiovascular disease and all-cause mortality in the
general population. J Am Heart Assoc. 2017;6(12):e006757. doi:10.1161/JAHA.117.006757
49. Li S, Tang X, Luo Y, et al. Impact of long-term glucose variability on coronary atherosclerosis progression in patients with type 2 diabetes:
a 2.3 year follow-up study. Cardiovasc Diabetol. 2020;19(1):146. doi:10.1186/s12933-020-01126-0
50. Lai Y-R, Huang -C-C, Chiu W-C, et al. HbA1C variability is strongly associated with the severity of cardiovascular autonomic neuropathy in
patients with type 2 diabetes after longer diabetes duration. Front Neurosci. 2019;13:458. doi:10.3389/fnins.2019.00458
51. Gu J, Fan YQ, Zhang JF, Wang C-Q. Association of hemoglobin A1c variability and the incidence of heart failure with preserved ejection fraction
in patients with type 2 diabetes mellitus and arterial hypertension. Hellenic J Cardiol. 2018;59(2):91–97. doi:10.1016/j.hjc.2017.08.001
52. Yang CD, Shen Y, Ding FH, et al. Visit-to-visit fasting plasma glucose variability is associated with left ventricular adverse remodeling in diabetic
patients with STEMI. Cardiovasc Diabetol. 2020;19(1):131. doi:10.1186/s12933-020-01112-6
53. Tang X, Zhong J, Zhang H, et al. Visit-to-visit fasting plasma glucose variability is an important risk factor for long-term changes in left cardiac
structure and function in patients with type 2 diabetes. Cardiovasc Diabetol. 2019;18(1):50. doi:10.1186/s12933-019-0854-9
54. Li S, Nemeth I, Donnelly L, et al. Visit-to-visit HbA1c variability is associated with cardiovascular disease and microvascular complications in
patients with newly diagnosed type 2 diabetes. Diabetes Care. 2019;43(2):426–432. doi:10.2337/dc19-0823
55. Cardoso CRL, Leite NC, Moram CBM, et al. Long-term visit-to-visit glycemic variability as predictor of micro- and macrovascular complications in
patients with type 2 diabetes: the Rio de Janeiro type 2 diabetes cohort study. Cardiovasc Diabetol. 2018;17(1):33. doi:10.1186/s12933-018-0677-0
56. Yang CP, Lin CC, Li CI, et al. Fasting plasma glucose variability and HbA1c are associated with peripheral artery disease risk in type 2 diabetes.
Cardiovasc Diabetol. 2020;19(1):4. doi:10.1186/s12933-019-0978-y
57. Pai YW, Lin CH, Lee IT, et al. Variability of fasting plasma glucose and the risk of painful diabetic peripheral neuropathy in patients with type 2
diabetes. Diabetes Metab. 2018;44(2):129–134. doi:10.1016/j.diabet.2018.01.015
58. Yang CP, Li CI, Liu CS, et al. Variability of fasting plasma glucose increased risks of diabetic polyneuropathy in T2DM. Neurology. 2017;88
(10):944–951. doi:10.1212/WNL.0000000000003682
59. Song KH, Jeong JS, Kim MK, et al. Discordance in risk factors for the progression of diabetic retinopathy and diabetic nephropathy in patients with
type 2 diabetes mellitus. J Diabetes Investig. 2019;10(3):745–752. doi:10.1111/jdi.12953
60. Lee MY, Huang JC, Chen SC, et al. Association of HbA1C variability and renal progression in patients with type 2 diabetes with chronic kidney
disease stages 3–4. Int J Mol Sci. 2018;19(12):4116. doi:10.3390/ijms19124116
61. De Cosmo S, Viazzi F, Piscitelli P, et al. Blood pressure status and the incidence of diabetic kidney disease in patients with hypertension and type 2
diabetes. J Hypertens. 2016;34(10):2090–2098. doi:10.1097/HJH.0000000000001045
62. Zhou JJ, Coleman R, Holman RR, et al. Long-term glucose variability and risk of nephropathy complication in UKPDS, ACCORD and VADT
trials. Diabetologia. 2020;63(11):2482–2485. doi:10.1007/s00125-020-05273-7
63. da Rosa LCGF, Zajdenverg L, Souto DL, et al. HbA1c variability and long-term glycemic control are linked to diabetic retinopathy and glomerular
filtration rate in patients with type 1 diabetes and multiethnic background. J Diabetes Complications. 2019;33(9):610–615. doi:10.1016/j.
jdiacomp.2019.05.022
64. Su J, Zhao L, Zhang X, et al. HbA1c variability and diabetic peripheral neuropathy in type 2 diabetic patients. Cardiovasc Diabetol. 2018;17(1):47.
doi:10.1186/s12933-018-0693-0
65. Lai Y-R, Chiu W-C, Huang -C-C. HbA1C variability is strongly associated with the severity of peripheral neuropathy in patients with type 2
diabetes. Front Neurosci. 2019;13:90. doi:10.3389/fnins.2019.00090
66. Lee CL, Chen CH, Wu MJ, et al. The variability of glycated hemoglobin is associated with renal function decline in patients with type 2 diabetes.
Ther Adv Chronic Dis. 2020;11:2040622319898370. doi:10.1177/2040622319898370
67. Yang CY, Su PF, Hung JY, et al. Comparative predictive ability of visit-to-visit HbA1c variability measures for microvascular disease risk in type 2
diabetes. Cardiovasc Diabetol. 2020;19(1):105. doi:10.1186/s12933-020-01082-9
68. Borg R, Kuenen JC, Carstensen B, et al. Associations between features of glucose exposure and A1C: the A1C-Derived Average Glucose (ADAG)
study. Diabetes. 2010;59(7):1585–1590. doi:10.2337/db09-1774
69. Ehehalt S, Wiegand S, Korner A, et al. Low association between fasting and OGTT stimulated glucose levels with HbA1c in overweight children
and adolescents. Pediatr Diabetes. 2017;18(8):734–741. doi:10.1111/pedi.12461
70. Ohigashi M, Osugi K, Kusunoki Y, et al. Association of time in range with hemoglobin A1c, glycated albumin and 1,5-anhydro-d-glucitol.
J Diabetes Investig. 2021;12(6):940–949. doi:10.1111/jdi.13437

International Journal of General Medicine 2023:16 https://doi.org/10.2147/IJGM.S418520

3093
DovePress

Powered by TCPDF (www.tcpdf.org)

 Huang et al Dovepress

71. Hirsch IB, Welsh JB, Calhoun P, et al. Associations between HbA 1c and continuous glucose monitoring-derived glycaemic variables. Diabet Med.
2019;36(12):1637–1642. doi:10.1111/dme.14065
72. Lu J, Ma X, Zhang L, et al. Glycemic variability modifies the relationship between time in range and hemoglobin A1c estimated from continuous
glucose monitoring: a preliminary study. Diabetes Res Clin Pract. 2020;161:108032. doi:10.1016/j.diabres.2020.108032
73. Fang FS, Liu XY, Yan ST, et al. Relationship between time in range and long-term glucose variability in elderly male patients with type 2 diabetes.
Chin Gen Pract. 2023;26(16):1979–1983.
74. Tokutsu A, Okada Y, Torimoto K, et al. Relationship between glycemic intraday variations evaluated in continuous glucose monitoring and HbA1c
variability in type 2 diabetes: pilot study. Diabetol Metab Syndr. 2021;13(1):45. doi:10.1186/s13098-021-00663-2
75. Tsuchiya T, Saisho Y, Murakami R, et al. Relationship between daily and visit-to-visit glycemic variability in patients with type 2 diabetes. Endocr
J. 2020;67(8):877–881. doi:10.1507/endocrj.EJ20-0012
76. Peng HM, Deng HR, Zhou YW, et al. Effect of glucose variability on the relationship between time in range and blood glucose management in
patients with type 1 diabetes mellitus. Chin Med J. 2022;102(16):1190–1195.
77. Liu ZG, Yao B, Lin BS, et al. Study on the correlation between blood glucose excursion index and mean amplitude of glucose excursion in
self-monitoring of blood glucose. Chin J Diabetes. 2021;13(5):476–481.

International Journal of General Medicine Dovepress

Publish your work in this journal
The International Journal of General Medicine is an international, peer-reviewed open-access journal that focuses on general and internal
medicine, pathogenesis, epidemiology, diagnosis, monitoring and treatment protocols. The journal is characterized by the rapid reporting of
reviews, original research and clinical studies across all disease areas. The manuscript management system is completely online and includes a
very quick and fair peer-review system, which is all easy to use. Visit http://www.dovepress.com/testimonials.php to read real quotes from
published authors.
Submit your manuscript here: https://www.dovepress.com/international-journal-of-general-medicine-journal

3094 DovePress International Journal of General Medicine 2023:16

Powered by TCPDF (www.tcpdf.org)