Abstract
Background:
Diabetic retinopathy (DR) and diabetic peripheral neuropathy (DPN) are among the most prevalent complications of diabetes mellitus (DM), both of which stem from microvascular complications and are believed to have a shared underlying pathophysiology. A notable challenge is that patients may go unnoticed for either condition by their treating physician, given that these complications typically fall under different medical specialties. Consequently, this study aimed to investigate the clinical correlation between the severity of DR and DPN and explore their associations with glycemic variability and the levels of glycated hemoglobin (HbA1c).
Methodology:
This is a hospital-based cross-sectional observational study involving 156 patients attending the ophthalmology outpatient department and the inpatient department at a tertiary care hospital in rural South India over a period of 2 years.
Results:
There was an increase in the severity of DR with increasing duration of DM among patients (P < 0.001). The proportion of patients with DPN notably increased with increasing severity of DR among the patients (P < 0.001). Notably, the number of patients with DR and DPN changes increased with increasing glycemic values. These findings suggest a statistically significant association between DR and DPN and glycemic control.
Conclusion:
This study revealed a positive correlation between the severity of DR and the presence of DPN, along with an association with HbA1c variability. This underscores the importance of interdisciplinary collaboration for comprehensive evaluation and management.
Keywords: Diabetes mellitus, diabetic retinopathy, glycated hemoglobin, peripheral neuropathy
Résumé
Contexte:
La rétinopathie diabétique (RD) et la neuropathie périphérique diabétique (NPD) figurent parmi les complications les plus fréquentes du diabète sucré (DS). Toutes deux résultent de complications microvasculaires et partageraient une physiopathologie sous-jacente commune. Un défi majeur réside dans le fait que ces affections peuvent passer inaperçues auprès des médecins traitants, car elles relèvent généralement de spécialités médicales différentes. Par conséquent, cette étude visait à examiner la corrélation clinique entre la gravité de la RD et de la NPD et à explorer leurs associations avec la variabilité glycémique et les taux d’hémoglobine glyquée (HbA1c).
Méthodologie:
Il s’agit d’une étude observationnelle transversale menée en milieu hospitalier, auprès de 156 patients consultant le service d’ophtalmologie (ambulatoire et hospitalier) d’un hôpital de soins tertiaires situé en zone rurale du sud de l’Inde, sur une période de 2 ans.
Résultats:
La gravité de la RD augmentait avec la durée du DS chez les patients (p < 0,001). La proportion de patients atteints de neuropathie périphérique diabétique (NPD) a augmenté de façon notable avec la sévérité croissante de la rétinopathie diabétique (RD) parmi les patients (p < 0,001). De façon remarquable, le nombre de patients présentant une RD et une NPD a augmenté avec l’élévation des valeurs glycémiques. Ces résultats suggèrent une association statistiquement significative entre la RD, la NPD et le contrôle glycémique.
Conclusion:
Cette étude a révélé une corrélation positive entre la sévérité de la RD et la présence d’une NPD, ainsi qu’une association avec la variabilité de l’HbA1c. Ceci souligne l’importance d’une collaboration interdisciplinaire pour une évaluation et une prise en charge complètes.
Mots-clés: Diabète sucré, rétinopathie diabétique, hémoglobine glyquée, neuropathie périphérique
INTRODUCTION
Diabetes mellitus (DM) has become a major global health challenge. Patients with DM are prone to various complications that can pose life-threatening risks and significantly impact their quality of life. The vasa nervorum is vulnerable to damage from chronic hyperglycemia, which can result in changes, ultimately leading to microangiopathy.[1] Progressive vascular dysfunction in the retina results in DR, whereas vascular dysfunction in peripheral nerves leads to diabetic neuropathy. These chronic complications associated with the disease represent the primary causes of morbidity, mortality, and healthcare expenditure related to DM.[2]
Both DR and diabetic peripheral neuropathy (DPN) are microangiopathies sharing similar pathophysiologies.[3] Consequently, the presence and severity of one can affect the other. The eye serves as a crucial indicator of diabetic microangiopathic complications, highlighting the relationship between retinopathy and neuropathy.[,5,6] However, since these conditions are typically diagnosed and treated by different medical specialties, patients may receive care and treatment for only one aspect, potentially leading to untreated systemic complications and prolonged suffering. A deeper awareness of the interrelationship between DR and DPN underlines the importance of screening for other complications, thus enabling comprehensive management and improved outcomes.
Glycemic indices were used to determine glycemic control and to analyze the association and severity of DR and DPN. Therefore, this study was carried out with the aim of correlating the grade of DR with that of DPN and gauging their link with glycemic control.
METHODOLOGY
A total of 156 patients diagnosed with DM were included in this cross-sectional study; these patients visited the outpatient department (OPD) of ophthalmology at a tertiary care hospital in rural South India. The study was conducted over a period of 2 years. All patients who were diagnosed with diabetic retinopathy (DR) were included in the study. Patients with gestational DM and retinopathy due to other causes and patients with DPN due to other causes, such as Vitamin B12 deficiency, traumatic neuropathy, and HIV neuropathy (ruled out by examining clinical features related to the disease) were all excluded from the study. Ethical clearance prior to the commencement of the study was approved by the Ethics and Research Committee. All the patients who fulfilled the selection criteria were informed about the nature of the study, and written informed consent was obtained from all the participants before enrollment. Demographic details of patients with detailed ophthalmological examination was carried out, followed by assessment of glycemic status by fasting blood sugar (FBS), postprandial blood sugar (PPBS), and glycated hemoglobin (HbA1c) levels.
DR was determined through fundus examination and graded clinically using the “Early Treatment of Diabetic Retinopathy Study” classification for DR. Neurological examination was performed on the basis of the “Toronto clinical neurological scoring system,” which included the extent of paresthesia, tingling or numbness, the presence of burning, vibration, light touch, temperature, and relevant examination.
RESULTS
This study compared the severity of DR with the occurrence of DPN in diabetic patients. A total of 156 patients who attended the ophthalmology OPD in the setting and fulfilled the previously stated inclusion criteria were enrolled in this study.
The study included 106 (67.9%) males and 50 (32.1%) females [Graph 1].
Graph 1.
Gender distribution of patients with diabetic retinopathy
The study group had a mean age of 58.85 ± 10 years, with most of the population falling into the fifth (36%) or sixth (32%) decade in both the male and female categories [Table 1].
Table 1.
Age group distribution
| Age group | Number of patients |
|---|---|
| <31 | 1 |
| 31–40 | 5 |
| 41–50 | 25 |
| 51–60 | 56 |
| 61–70 | 49 |
| 71–80 | 17 |
| >80 | 2 |
| Total | 156 |
The majority of the patients, i.e. 152 (96.8%), had type 2 diabetes mellitus (T2DM), and the remaining patients had T1DM (3.2%) [Table 2].
Table 2.
Type of diabetes mellitus
| DM | n (%) |
|---|---|
| Type 1 DM | 5 (3.2) |
| Type 2 DM | 151 (96.8) |
DM=Diabetes mellitus
The number of years of diabetes and the severity of retinopathy were studied, and patients with mild and moderate DR had average durations of diabetes of 6 years 6 months and 8 years, respectively. Nine years in severe DR patients and a mean of 13 years were noted in both proliferative DR (PDR) patients and advanced diabetic eye disease (ADED) [Table 3]. The severity of DR increased with increasing duration of DM among patients (P < 0.001).
Table 3.
Duration of diabetes
| Grading of DR | Mean (years) |
|---|---|
| Mild DR | 6.56 |
| Moderate DR | 8.70 |
| Severe/very severe DR | 9.20 |
| PDR | 13.00 |
| ADED | 13.30 |
DR=Diabetic retinopathy, ADED=Advanced diabetic eye disease, PDR=Proliferative DR
DR severity was assessed. As shown in Table 4, most of the patients fall into the category of mild nonproliferative DR (NPDR), 45%, followed by moderate NPDR, 34%. Severe NPDR corresponds to 10%, and PDR is present in 5% of patients. ADED is observed in 6.4% of patients.
Table 4.
Frequency of severity of diabetic retinopathy
| Grading of DR | Number of patients (%) |
|---|---|
| Mild NPDR | 70 (44.9) |
| Moderate NPDR | 53 (34.0) |
| Severe/very severe NPDR | 15 (9.6) |
| PDR | 8 (5.1) |
| ADED | 10 (6.4) |
DR=Diabetic retinopathy, NPDR=Nonproliferative DR, PDR=Proliferative DR, ADED=Advanced diabetic eye disease
Our study revealed that there was a striking increase in the severity of retinopathy with increasing HbA1c levels [Graph 2] and that the HbA1c level overlapped with the severity of retinopathy. The mean HbA1c values for mild and moderate DR patients were 6.8% and 7.4%, respectively. In severe DR patients, the mean HbA1c level was 8.7%, and in PDR and ADED patients, it was 8.9% and 9.5%, respectively.
Graph 2.
Association between glycated hemoglobin values and severity of diabetic retinopathy among patients. HbA1c = Glycated hemoglobin, DR = Diabetic retinopathy, PDR = Proliferative diabetic retinopathy, ADED = Advanced diabetic eye disease
DPN was noted in 33 patients (21.2%) in the study group, with varying severity [Table 5].
Table 5.
Peripheral neuropathy
| Peripheral neuropathy | Frequency (%) |
|---|---|
| Present | 33 (21.2) |
| Absent | 123 (78.8) |
The mean HbA1c in those with DPN (n = 33) was 9.7 ± 1.6, whereas it was 6.9 ± 1.5 among patients without DPN (n = 123) (t = 9.395, P < 0.001) [Graph 3].
Graph 3.
Peripheral neuropathy and glycated hemoglobin. HbA1c = Glycated hemoglobin
FBS and PPBS were high in patients with peripheral neuropathy in comparison to patients with only DR. Our study revealed mean FBS and PPBS values of 269 (±94) and 310 (±78), respectively, in patients with DPN. The mean FBS and PPBS were significantly higher among patients with DPN compared with those with DR alone (P < 0.001) [Graph 4].
Graph 4.
Fasting blood sugar and postprandial blood sugar correlation with diabetic peripheral neuropathy (DPN) with diabetic retinopathy (DR) and DR without DPN. FBS = Fasting blood sugar, PPBS = Postprandial blood sugar, DR = Diabetic retinopathy, DPN = Diabetic peripheral neuropathy
The percentage of patients with DPN increases as the severity of DR increases as 50% of those with PDR have DPN. However, it increases to 70% in ADED patients. The proportion of patients with peripheral neuropathy increased with increasing severity of DR among the patients (P < 0.001) [Table 6].
Table 6.
Staging of diabetic retinopathy patients in comparison with that of diabetic peripheral neuropathy patients
| Grading | DPN present (%) | DPN absent (%) |
|---|---|---|
| Mild DR | 5 (7.1) | 65 (92.9) |
| Moderate DR | 10 (18.9) | 43 (81.1) |
| Severe/very severe DR | 7 (81.1) | 8 (53.3) |
| PDR | 4 (50.0) | 4 (50.0) |
| ADED | 7 (70.0) | 3 (30.0) |
| Total | 33 (21.2) | 123 (78.8) |
DR=Diabetic retinopathy, PDR=Proliferative DR, ADED=Advanced diabetic eye disease, DPN=Diabetic peripheral neuropathy
DISCUSSION
The current cross-sectional observational study was carried out in the Department of Ophthalmology at a tertiary care hospital in rural South India for a duration of 2 years with the aim of correlating the severity of DR with DPN and assessing their relationship with variations in glycemic indices and HbA1c levels. The study included 156 patients diagnosed with both T1DM and T2DM who fulfilled the selection criteria and provided written informed consent.
Two clinic-based studies revealed that the occurrence rates of DR in T2DM patients in South India were 34.1% and 37%, respectively.[7,8] Agarwal et al. in their study revealed the prevalence rate of 28.9% of DR among DM patients.[9] Another study conducted by Narendran et al. concluded a 26.2% prevalence rate of DR.[10]
Kalpana et al.[11] noted that among DR patients, males were affected more than females. A study by Sharma et al.[12] reported that the number of males with retinopathy was greater than that of females. Similarly, in our study, 67.9% of males and 32.1% of female patients were found to have retinopathy; therefore, a higher incidence of DR was noted among the male population than among the female population.
Katulanda et al.[13] reported that the occurrence of DPN was almost equal between the two sexes. Ji et al.[14] in a study conducted in 2012 reported the same occurrence of DPN in both males and females, accounting for 43.3% and 49.8%, respectively. In our study, a slightly greater male preponderance was noted than in the other studies.
The duration of DM, an essential predictor of DR, decides the contact time of other risk factors. Rema et al.,[15] in their CURES study, reported that the risk of diabetic retinopathy (DR) increased by 1.89 times for every 5-year increase in the duration of diabetes. Al-Sarraf et al.[16] detected that patients with a duration of 10-19 years of disease are twice as likely to be anticipated to have DR and approximately three times more likely to have DR when the duration of exposure is more than 20 years. Agarwal et al.’s study has shown that the maximum prevalence of DR in patients with more than 15 years of diabetes was 52.2%.[9] In our study, it was noted that overall, the severity of DR increased with increasing duration of DM among patients (P < 0.001).
Won et al.[17] and Ji et al.[14] also concluded that DPN was more common in individuals who had a longer course of disease. A study conducted by Feldman et al.,[18] Gill et al.,[19] and Ashok et al.[20] revealed that the period of diabetes was a significant determinant of neuropathy, which was similarly noted in our study.
Kumar et al.[21] reported that with increasing age, the duration of DM and increased HbA1c were common risk factors for both DR and DPN. A study conducted by Meena et al.[22] reported that an increase in the FBS, PPBS, and HbA1c biochemical parameters was associated with an increase in the degree of DR severity. In our study, the FBS average in retinopathy patients was 178 mg/dL and that of PPBS 222 mg/dL. As the levels of FBS and PPBS increased, the severity of DR and DPN increased. Kilpatrick et al.,[23] in a DCCT study, reported a significantly increased risk of retinopathy, not only with higher mean HbA1c values but also with greater fluctuations. For every increase in the SD of HbA1c by a value of one as the absolute percentage, the hazard ratio of both the development and progression of DR increased by more than 100%. In the CURES[24] Eye study, as the level of HbA1c increased by 2%, the risk of DR increased by 1.7. Another study conducted by Nanda and Mohanta[25] demonstrated that HbA1c is a strong predictor of the severity of diabetic retinopathy (DR). Our study revealed a striking increase in the severity of retinopathy with increasing HbA1c levels.
Salwa and Ayman[26] acknowledged HbA1c as a modifiable risk factor for diabetic neuropathy. In their corresponding studies, Won et al.,[17] Ji et al.,[14] and Rema et al.[15] reported that DPN is more common in diabetic patients with a higher HbA1c. The rate of increase in DPN is much greater than that in DR.
Foo et al.[27] and Takao et al.[28] reported that HbA1c variability, measured as HbA1c-standard deviation or HbA1c-coefficient of variation, was predictive of the development of DR and neuropathy. In their study, Su et al.[29] reported that the incidence of neuropathy increased with increasing variability in HbA1c.
Lee et al.[30] conducted a study which revealed that HbA1c level was a quantitative indicator of the severity of polyneuropathy and that poor glycemic control (HbA1c level > 6.5%) may increase the incidence of polyneuropathy in DM patients by more than fivefold. Their study revealed close relationships between glycemic erraticism parameters and DPN in type II diabetes patients. Raman et al.[31] reported that those with a higher coefficient of variability of fasting plasma glucose had an evidently greater risk of DPN. In our study, the FBS and PPBS were found to be high in patients with peripheral neuropathy in comparison to patients with only DR. The mean FBS and mean PPBS were significantly higher in patients with DPN than in those without DPN (P < 0.001). The mean FBS and the mean PPBS were significantly higher in the PDR group than in the other DR group (P < 0.001). Sharma et al.[12] reported that the prevalence of DPN in patients with DR was 2.75 times greater than that in patients without DR (14%). Kumar et al.[21] and Won et al.[17] reported that the incidence of DPN was increased in patients with retinopathy. Salwa and Ayman[26] and Katulanda et al.[13] reported that DR was the most significant risk factor for a patient with DPN, and their ratio of association was similar to the findings of our study. The percentage of patients suffering from both the microvascular complications was almost equal to that in our study.
Ashok et al.,[20] in a study to perceive the prevalence of neuropathy, compared the incidence of retinopathy in patients with and without neuropathy and reported a higher incidence in those with neuropathy. In our study, the percentage of patients with DPN increased as the severity of retinopathy increased. The proportion of patients with peripheral neuropathy increased significantly with increasing severity of DR in both eyes (P < 0.001).
CONCLUSION
In the present study which was conducted, it was observed that there was a clinical correlation between the severity of DR and the presence of DPN. DPN was remarkably more common in diabetic patients with retinopathy than in those without retinopathy. A statistically significant positive correlation was found between the severity of DR and the incidence of DPN. Uncontrolled DM when present for a longer duration was concluded to be a common risk factor for both DR and DPN. Higher glycemic index variability and elevated HbA1c levels were associated with both DR and DPN.
Hence, these parameters become important in the long run and further support the need for aggressive early intervention and long-term monitoring to prevent vision-threatening stages of the disease. Our findings also highlight the potential value of screening for DPN in patients with DR and vice versa. Early detection and management of one complication may offer opportunities to intervene before the other progresses, especially in resource-limited settings where access to ophthalmologic or neurologic services may be constrained.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
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