Abstract
Introduction:
Time in range (TIR), a metric of continuous glucose monitoring (CGM) provides better information regarding the individual’s glycemic variability than a static measure like glycated hemoglobin (HbA1c). TIR is emerging as an independent risk factor for diabetic complications, both microvascular and macrovascular complications independent of HbA1c. Hence, this study evaluates the association between TIR and cardiac autonomic neuropathy (CAN) in type 2 diabetic patients.
Materials and Methods:
A total of 42 patients with type 2 diabetes mellitus were enrolled in this study and underwent a 3-day CGM using the “FreeStyle Libre Pro Flash Glucose Monitoring System Sensor” along with tests for CAN within the 3 days of attaching the CGM.
Results:
Out of 42 patients, 36 patients (85.7%) were diagnosed with CAN (early CAN 57.1% and definite CAN 28.6%) and the mean TIR was 64.4% ±23.5%. Out of those with TIR <70%, 42.9% were affected with definite CAN compared to only 14.3% among those with TIR >70%. Patients with more severe CAN were found to have a lower TIR (P = 0.115).
Conclusion:
The study found a high prevalence of cardiac autonomic neuropathy (CAN) of around 85.7% in type 2 diabetes patients. Lower TIR values were associated with a higher incidence of definite CAN (42.9% vs. 14.3% in TIR <70% vs. >70% groups). The findings suggest TIR is inversely associated with the presence and severity of cardiac autonomic neuropathy in type 2 diabetic patients and also a potential link between TIR and CAN severity.
Keywords: Cardiac autonomic neuropathy, continuous glucose monitoring, time above range, time below range, time in range, type 2 diabetes mellitus
Résumé
Introduction:
Le temps dans l’intervalle (TIR), une mesure de la surveillance continue du glucose (SGC), fournit de meilleures informations sur l’état de santé de l’individu. variabilité glycémique qu’une mesure statique comme l’hémoglobine glyquée (HbA1c). Le TIR est en train de devenir un facteur de risque indépendant pour les diabétiques complications microvasculaires et macrovasculaires indépendantes de l’HbA1c. Par conséquent, cette étude évalue l’association entre le TIR et la neuropathie autonome cardiaque (CAN) chez les patients diabétiques de type 2.
Matériel et méthodes:
Un total de 42 patients atteints de diabète sucré de type 2 ont été inclus dans cette étude et ont subi une SGC de 3 jours à l’aide du « FreeStyle Libre Pro Flash Glucose Monitoring System Sensor » ainsi que des tests de CAN dans les 3 jours suivant la fixation de la CGM.
Résultats:
Sur 42 patients, 36 patients (85,7 %) ont reçu un diagnostic de CAN (CAN précoce 57.1 % et CAN définitif 28.6 %) et le TIR moyen était de 64.4 % ±23.5 %). Parmi ceux qui ont un TIR, 70 %. Les patients atteints d’une CAN plus sévère présentaient un TIR plus faible (p = 0,115).
Conclusion:
L’étude a révélé une prévalence élevée de neuropathie autonome cardiaque (CAN) d’environ 85.7 % dans le diabète de type 2 patient. Des valeurs de TIR plus faibles étaient associées à une incidence plus élevée de CAN défini (42.9 % contre 14.3 % dans les groupes TIR <70 % contre >70 %). Le Les résultats suggèrent que le TIR est inversement associé à la présence et à la gravité de la neuropathie autonome cardiaque chez les patients diabétiques de type 2 et Il existe également un lien potentiel entre la gravité du TIR et celle du CAN.
Mots-clés: Neuropathie autonome cardiaque, surveillance continue de la glycémie, temps au-dessus de la plage, temps en dessous de la plage, temps dans la plage, type 2 diabète sucré
INTRODUCTION
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and relative insulin deficiency. It affects millions of people worldwide and is associated with various complications, including microvascular and macrovascular diseases. Among the microvascular complications, cardiac autonomic neuropathy (CAN) is a significant concern.[1]
Cardiac autonomic neuropathy is a progressive disorder that affects the autonomic nervous system’s control over the heart and blood vessels. It is characterized by impaired regulation of heart rate, blood pressure, and vascular tone, leading to a higher risk of cardiovascular morbidity and mortality.[2] CAN often remains undiagnosed until the late stages when symptoms become apparent or when cardiovascular complications arise.
Continuous glucose monitoring (CGM) has emerged as a valuable tool in the management of diabetes. It provides real-time glucose measurements, allowing individuals with diabetes and their health-care providers to monitor glucose levels continuously and make timely therapeutic adjustments. CGM also provides additional metrics beyond traditional glycemic measures, such as time in range (TIR).[3]
TIR is a CGM metric that reflects the amount of time a person’s glucose levels remain within a target range. While the specific target range may vary depending on individual factors and treatment goals, TIR generally represents the proportion of time spent within a desired glycemic range (e.g., 70–180 mg/dL or 3.9–10.0 mmol/L). TIR has gained attention as a meaningful glycemic control metric because it provides a comprehensive assessment of glucose fluctuations, including both hypo and hyperglycemia.[4]
The association between TIR and various diabetes-related outcomes has been extensively studied. Higher TIR has been linked to a reduced risk of hypoglycemia, improved glycemic control, and a lower incidence of macrovascular complications in individuals with T2DM.[4,5,6] However, the relationship between TIR and CAN in patients with T2DM remains relatively unexplored.
To date, only a limited number of studies have investigated the relationship between TIR and CAN in T2DM patients. However, these studies have shown promising results. Previous studies demonstrated that higher TIR was associated with improved heart rate variability, an important marker of cardiac autonomic function.[7] Similarly, another study found that patients with more severe CAN were found to have lower TIR[8], and a 10% increase in the TIR was significantly inversely associated with the severity of CAN.[9]
Understanding the potential association between TIR and CAN is crucial, as it may provide insights into the role of glycemic control in preventing or delaying the development of cardiac autonomic neuropathy. These initial findings highlight the need for further investigation to establish a more robust understanding of the association between TIR and CAN. Moreover, elucidating the potential mechanisms underlying this association will be crucial for identifying therapeutic targets and developing interventions to mitigate the risk of CAN in patients with T2DM.
However, the literature on the correlation between TIR and its association with CAN in type 2 diabetic patients is limited and there has been no such study in the Indian population. Hence, this study aims to evaluate the relationship between TIR and CAN in type 2 diabetic patients in an Indian setting with the aim of improving management strategies and patient outcomes in high-risk populations.
MATERIALS AND METHODS
Study design
The study design involves prospective study.
Objective
The objective of this study is to determine TIR through 3-day CGM and evaluate its association with cardiac autonomic neuropathy in type 2 diabetic patients.
Study population
A total of 42 individuals (age ≥18 years) with T2DM who visited the endocrinology department of the hospital, from July 15, 2022 to September 13, 2022, were recruited. The exclusion criteria included those with a severe medical illness such as severe liver disease (Child–Pugh score >7), thyroid disease (either hypothyroidism or hyperthyroidism), malignancy; those with a past medical history of cardiovascular diseases such as myocardial infarction, stroke, coronary, carotid, or lower limb revascularization, those with an estimated glomerular filtration rate calculated by the Chronic Kidney Disease Epidemiology Collaboration formula of <30 ml/min/1.73 m2, pregnant women, and those who were clinically diagnosed with type 1 diabetes. Clinical data and other relevant laboratory data were collected from the patients after taking their consent. Institutional ethical committee clearance was taken MSRMC/EC/SP-07/07-2022.
Assessment of metrics of glycemic variability
All metrics of glycemic variability were obtained using the “FreeStyle Libre Pro Flash Glucose Monitoring System Sensor” manufactured by Abbott Diabetes Care Ltd. Based on the original blood glucose data recorded by this system, 3-day average blood glucose levels were calculated. TIR was assessed as the time percent during a 24-h period when the glucose is in the range of 70–180 mg/dL. Time above range (TAR) was defined as the time percent during a 24-h period when the glucose is above 180 mg/dL, and time below range (TBR) was defined as the time percent during a 24-h period when the glucose is below 70 mg/dL.
CGM-based times-in-ranges targets were defined based on American Diabetes Association Guidelines,[4]
TIR: (70–180 mg/dL [3.9–10.0 mmol/L]) – >70% of CGM readings
-
TBR
Level 1: (<70 mg/dL [3.9 mmol/L]) – <4% of CGM readings
Level 2: (<54 mg/dL [3.0 mmol/L]) – <1% of CGM readings.
-
TAR
Level 1: (>180 mg/dL [10.0 mmol/L]) – <25% of CGM readings
Level 2: (>250 mg/dL [13.9 mmol/L]) – <5% of CGM readings.
For ease of analysis, we have assessed TIR, TBR (level 1), and TAR (level 1) readings in our study.
Assessment of cardiac autonomic neuropathy
Patients were advised to avoid smoking, alcohol, and physical activity in the 24-h period before the test and avoid intake of food and caffeine 3 h before the test. Drugs such as antihistamines, beta blockers, and acetaminophen were withheld 12 h before the examination.
The tests performed to assess cardiac autonomic neuropathy include:
-
Systolic blood pressure response to standing [Table 1]
The change in systolic blood pressure from a supine position and standing up for 2 min was measured manually.
Heart rate response to deep breathing (exhalation: inhalation ratio)[10] [Table 2]
Heart rate response to standing (30:15 ratio) [Table 3]
Heart rate response to the Valsalva maneuver (Valsalva ratio) [Table 4].
Table 1.
Grading of change in systolic blood pressure from supine to standing
| Difference in SBP (mmHg) | Grading |
|---|---|
| ≥20 | Abnormal |
| 11–19 | Borderline |
| ≤10 | Normal |
SBP=Systolic blood pressure
Table 2.
Grading according to exhalation to inhalation ratio
| E: I ratio | Grading |
|---|---|
| ≤1.10 | Abnormal |
| 1.11–1.20 | Borderline |
| ≥1.21 | Normal |
E: I=Exhalation to inhalation
Table 3.
Grading according to 30:15 ratio
| 30:15 ratio | Grading |
|---|---|
| ≤1 | Abnormal |
| 1.01–1.03 | Borderline |
| ≥1.04 | Normal |
Table 4.
Grading according to Valsalva ratio
| Valsalva ratio | Grading |
|---|---|
| ≤1.10 | Abnormal |
| 1.11–1.20 | Borderline |
| ≥1.21 | Normal |
The heart rate responses to deep breathing, standing, and Valsalva Manoeuvre were assessed using the “DIABETES RISK Profiler and Analysis Device” manufactured by Genesis Medical Systems Pvt. Ltd.
Each normal test was graded as 0, borderline test as 0.5 and each abnormal test was graded as 1. Based on this, the severity of cardiac autonomic neuropathy (CAN) was quantified using a cardiac autonomic neuropathy score which had a minimum score of 0 and a maximum score of 4.
A score of 0–0.5 was regarded as absent CAN, a score of 1–1.5 as early CAN, and a score of ≥2 was regarded as definite CAN as shown in the table below [Table 5] based on a study done by Guo et al.[8]
Table 5.
Grading of cardiac autonomic neuropathy based on cardiac autonomic neuropathy score
| CAN score | Grading |
|---|---|
| 0–0.5 | Absent CAN |
| 1–1.5 | Early CAN |
| ≥2 | Definite CAN |
CAN=Cardiac autonomic neuropathy
Statistical analysis
Data were analyzed using the IBM Corp. Released 2013. IBM SPSS Statistics for windows, version 22 (Armonk, NY:IBM Corp). Categorical variables were represented in the form of frequency with percentages. The Chi-square test was used as a test of significance for qualitative data. Continuous variables that followed a normal distribution were represented as mean and standard deviation, while continuous variables not following a normal distribution were expressed as median (interquartile range [IQR]). Independent t-test was used as a test of significance to identify the mean difference between two quantitative variables. One-way ANOVA was used to compare the continuous variables between the three groups of CAN, and the Kruskal–Wallis test was used for variables not following a normal distribution. All the statistical analyses were done at a 5% level of significance (P < 0.05).
RESULTS
Baseline characteristics
A total of 42 subjects were classified into three groups based on the tests to assess cardiovascular autonomic neuropathy. These were:
No CAN (n = 6, 14.3%)
Early CAN (n = 24, 57.1%)
Definite CAN (n = 12, 28.6%).
The mean age of all subjects was 52.3 ± 12.7 years, and out of the subjects, 52.4% were men and 47.6% were women. The median (IQR) duration of diabetes was 6 (1.9, 12.8) years. The mean TIR (percentage) was 64.4% ±23.5%. Patients with any form of CAN (early and definite CAN) tend to be older, with higher glycated hemoglobin (HbA1c) and mean glucose values as well as higher levels of total cholesterol, triglycerides, low-density lipoprotein (LDL), and very LDL (VLDL). In terms of the medications, there was no significant difference between the groups [Table 6].
Table 6.
Baseline characteristics according to the presence of cardiovascular autonomic neuropathy (n=42)
| Absent CAN (n=6; 14.3%) | Early CAN (n=24; 57.1%) | Definite CAN (n=12; 28.6%) | P | |
|---|---|---|---|---|
| Age, mean±SD | 49.83±12.79 | 49.88±12.50 | 58.33±11.95 | 0.149 |
| Sex, n (%) | ||||
| Male | 3 (13.6) | 15 (68.2) | 4 (18.2) | 0.254 |
| Female | 3 (15.0) | 9 (45.0) | 8 (40.0) | |
| HbA1c (%), mean±SD | 8.0±1.5 | 9.13±1.8 | 8.58±1.4 | 0.296 |
| Mean glucose (mg/dL), mean±SD | 179.7±42.5 | 223.6±51.9 | 202.7±47.1 | 0.145 |
| Total cholesterol (mg/dL), mean±SD | 147.1±23.7 | 180.4±44.7 | 176.3±37.7 | 0.211 |
| Triglycerides (mg/dL), mean±SD | 170.7±112.6 | 177.0±116.0 | 167.4±77.1 | 0.966 |
| LDL (mg/dL), mean±SD | 83.3±29.8 | 110.3±42.0 | 100.1±41.8 | 0.337 |
| VLDL (mg/dL), mean±SD | 25.8±11.8 | 32.3±11.2 | 32.0±10.5 | 0.558 |
| Use of oral anti-diabetic drugs, n (%) | 6 (14.3) | 24 (57.1) | 12 (28.6) | a* |
| Use of insulin, n (%) | 2 (18.2) | 4 (36.4) | 5 (45.5) | 0.250 |
*No statistics are computed because oral anti-diabetic drugs (metformin) are a constant. SD=Standard deviation, HbA1c=Glycated hemoglobin, LDL=Low-density lipoprotein, VLDL=Very LDL, CAN=Cardiac autonomic neuropathy
Association between time in range and CAN
The study participants whose blood glucose levels were within the recommended range of 70–180 mg/dl for >70% of the day, that is TIR >70%, which indicates a favorable glycemic status had a greater percentage of subjects with absent CAN (19%) when compared with those with TIR <70% (9.5%). In addition to this, in those subjects with TIR >70% had early CAN or either absent CAN as compared to those with TIR <70%. Furthermore, those with TIR >70% had lower rates of definite CAN (14.3%) as compared to those with TIR <70%(42.9%)[Table 7].
Table 7.
Association between time in range and cardiac autonomic neuropathy
| TIR | No CAN, n (%) | Early CAN, n (%) | Definite CAN, n (%) | Total, n (%) | P |
|---|---|---|---|---|---|
| <70% | 2 (9.5) | 10 (47.6) | 9 (42.9) | 21 (100) | 0.115 |
| >70% | 4 (19.0) | 14 (66.7) | 3 (14.3) | 21 (100) | |
| Total | 6 (14.3) | 24 (57.1) | 12 (28.6) | 42 (100) |
CAN=Cardiac autonomic neuropathy, TIR=Time in range
Association between time above range and CAN
Blood glucose levels >180 mg/dl for <25% of the day, that is TAR <25%, indicates a favorable glycemic status. These patients had a greater percentage of subjects with absent CAN (17.4%) when compared with those with TAR >25% (10.5%). Patients with TAR <25% were found to have a much higher rate of early CAN when compared to those with TAR >25% probably because of less number of patients and short duration of study. In addition, those with TAR >25% had a slightly higher rate of definite CAN (36.8%) as compared to those with TAR <25% (21.7%) [Table 8].
Table 8.
Association between time above range and cardiac autonomic neuropathy
| TAR | No CAN, n (%) | Early CAN, n (%) | Definite CAN, n (%) | Total, n (%) | P |
|---|---|---|---|---|---|
| >25% | 2 (10.5) | 10 (52.6) | 7 (36.8) | 19 (100) | 0.523 |
| <25% | 4 (17.4) | 14 (60.9) | 5 (21.7) | 23 (100) | |
| Total | 6 (14.3) | 24 (57.1) | 12 (28.6) | 42 (100) |
TAR=Time above range, CAN=Cardiac autonomic neuropathy
Association between time below range and CAN
Favorable glycemic status is indicated by blood glucose levels <70 mg/dl for <4% of the day, that is, TBR <4%. These participants had a greater percentage of subjects with absent CAN (18.5%) when compared with those with TBR >4% (6.7%). Patients with TBR <4% had lesser rates of early CAN and definite CAN as compared to groups with TBR >4% [Table 9].
Table 9.
Association between time below range and cardiac autonomic neuropathy
| TBR | No CAN, n (%) | Early CAN, n (%) | Definite CAN, n (%) | Total | P |
|---|---|---|---|---|---|
| >4% | 1 (6.7) | 9 (60.0) | 5 (33.3) | 15 (100) | 0.558 |
| <4% | 5 (18.5) | 15 (55.6) | 7 (25.9) | 27 (100) | |
| Total | 6 (14.3) | 24 (57.1) | 12 (28.6) | 42 (100) |
CAN=Cardiac autonomic neuropathy, TBR=Time below range
There was the clinically meaningful association between CGM metrics and CAN, in those patients who had better TIR had less prevalence of CAN. Although P values of the compared variables are not statistically probably because of the short duration of the study and small sample size.
DISCUSSION
The association between TIR, a CGM metric, and cardiac autonomic neuropathy (CAN) in patients with T2DM has been explored in this study. The findings suggest that maintaining glucose levels within the recommended range is associated with a reduced risk of CAN in this population.
In our study, encompassing 42 participants, the prevalence of early cardiac autonomic neuropathy (CAN) was evident in the majority, accounting for 57.1% of the cohort. Following this, definite CAN was detected in 28.6% of subjects, while only a modest fraction of 14.3% did not manifest with CAN.
This study delved into the correlation between distinct baseline characteristics and the severity of CAN. It was observed that patients afflicted by any form of CAN tended to be of advanced age, aligning with prior research emphasizing age-associated vulnerability to autonomic dysfunction. This underscores the imperative of routine CAN screening for elderly individuals with T2DM. Moreover, patients grappling with CAN displayed elevated levels of HbA1c and mean glucose values, signifying suboptimal glycemic control. The consistent linkage between inadequate glycemic control and CAN development accentuates the necessity for meticulous diabetes management to ameliorate autonomic neuropathy risk.
Our study also scrutinized patients’ lipid profiles, uncovering a notable link between dyslipidemia and CAN presence. Those affected by CAN exhibited escalated total cholesterol, triglycerides, LDL, and VLDL levels. These perturbations in lipid composition contribute to vascular inflammation and endothelial dysfunction, both implicated in CAN etiology.
Interestingly, despite all participants receiving oral antidiabetic agents, a larger proportion of those with CAN necessitated insulin, contrasting with their counterparts lacking CAN. This discrepancy underscores that CAN might signify an advanced T2DM stage necessitating intensified therapeutic strategies.
Consistent with previous guidelines and international consensus,[5] the study highlights the importance of glycemic control in patients with T2DM. Higher TIR, indicating a greater percentage of time spent within the target glucose range of 70–180 mg/dL, is associated with a more favorable glycemic status. This finding supports the notion that tight glucose control plays a vital role in mitigating the risk of CAN development.[11]
The current study observed distinct patterns in the association between TIR and CAN. Subjects with TIR >70% had a greater percentage of individuals with absent CAN than those with TIR <70%.[12] Furthermore, the TIR >70% group exhibited higher rates of absent CAN or early CAN, while the rates of definite CAN were lower compared to the TIR <70% group.[13] These findings suggest that maintaining glucose levels within the recommended range, as indicated by higher TIR, may confer a protective effect against the development of CAN in T2DM patients.
In addition, the relationship between TAR and CAN was examined. Patients with TAR <25%, indicating a lower percentage of time spent with blood glucose levels above 180 mg/dL, demonstrated a greater percentage of individuals with absent CAN compared to those with TAR >25% (Service, 2003). Notably, the TAR <25% group exhibited higher rates of early CAN compared to absent CAN and definite CAN.[14] These findings suggest that limiting the time spent with hyperglycemia may have a favorable impact on the development of CAN in T2DM patients.
Furthermore, the study assessed the association between TBR and CAN. Subjects with TBR <4%, indicating a lower percentage of time spent with blood glucose levels below 70 mg/dL, demonstrated a greater percentage of individuals with absent CAN than those with TBR >4%.[14] Similar to TAR, the TBR <4% group exhibited higher rates of early CAN compared to absent CAN and definite CAN.[14] Interestingly, the rates of definite CAN were comparable between the TBR <4% and TBR >4% groups.[14]
These findings suggest that maintaining glucose levels within the recommended range and avoiding both hypoglycemia and hyperglycemia are associated with a reduced risk of CAN in patients with T2DM. Consistent with previous studies,[15,16] these results emphasize the importance of glycemic stability and minimizing glucose variability in preventing the development of CAN.
Cardiovascular autonomic neuropathy (CAN), an independent predictor of serious cardiovascular events and related mortality, occurs as one of the major complications of diabetes mellitus.[17,18] Damage to the autonomic nerve fibers (that innervate the heart and blood vessels) through oxidative stress, as a result of persistent hyperglycemia and hypoglycemia in diabetics, attributes to its development.[19] Hyperglycemia through polyol pathway leads to direct neuronal damage and also leads to decreased neuronal blood flow through protein kinase C activation. Neuronal blood supply may also be affected due to the accumulation of advanced glycosylation end products, thereby leading to nerve hypoxia and altered nerve function. According to the ACCORD study, the mortality rate of diabetics with CAN was 1.55–2.14 times higher than non-CAN, thus confirming that CAN increased the mortality of T2DM. The study also established that CAN increases cardiovascular disease mortality.[10]
The mechanisms underlying the association between TIR and CAN remain to be fully elucidated. It is possible that sustained glycemic control within the recommended range mitigates the adverse effects of glucose fluctuations on the autonomic nervous system.[17,20] In addition, optimizing glycemic control may alleviate the various metabolic and vascular factors implicated in CAN pathogenesis.[7] Smoking, obesity, and lifestyle are among the risk factors associated with CAN development.
Limitations of the study should be acknowledged. The sample size was relatively small. Our 3-day-CGM monitoring may have been too short to assess the glycemic status. Future prospective studies with larger cohorts are warranted to validate these findings and explore potential confounding factors.
CONCLUSION
The study highlights the association between TIR, a CGM metric reflecting glycemic control, and the presence of CAN in patients with T2DM. Higher TIR and reduced glucose variability appear to be associated with a lower risk of CAN development. These findings emphasize the importance of CGM and maintaining glucose levels within the recommended range to mitigate the risk of developing CAN and subsequent cardiovascular complications. Further research is needed to confirm these findings, explore potential mechanisms, and guide targeted interventions for preventing and managing CAN in T2DM.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
I would like to thank ICMR – STS (Indian Council of Medical Research – Short Term Studentship) for providing the necessary support for the primary research work. I would like to acknowledge Dr. Monika Vempadapu (Pharm D), Research Associate, Division of Research and Patents at Ramaiah Medical College, for her support in formatting the manuscript.
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