Prevalence and Association of Diabetic Retinopathy with Diabetic Foot Ulcer: A Cross-Sectional Observational Study

We aimed to elucidate prevalence and association of diabetic retinopathy (DR) in patients with diabetic foot ulcer (DFU) from Pakistan. In this cross-sectional study, about 225 DFU patients who underwent ophthalmic examinations within 6 months of diagnosis of foot ulceration were included. The medical records of 305 diabetic patients without DFU were included as controls. The association of DR with DFU was assessed by comparing DFU patients with proliferative DR (PDR) and DFU patients without PDR. Out of 225 DFU patients, 215 patients (95.6%) had DR and 169 patients (75.1%) had PDR. The prevalence of DFU was significantly greater (P = 0.0527) among the male diabetic patients, whereas advanced age of these patients (≥41 years) had a significant effect (P = 0.0286) on development and progression of PDR. A longer duration of diabetes (≥10 years) was identified as a significant contributing factor for the development of both DFU (P = 0.0029) and PDR (P = 0.0299). Moreover, the risk of PDR increased in diabetic patients with higher DFU grades (grade 3 and grade 4). In conclusion, retinopathy was prevalent in DFU patients. Therefore, DFU patients with advancing age and longer duration of diabetes should undergo retinal examinations for timely diagnosis and management of DR.


Introduction
Diabetes mellitus (DM) is a metabolic disease, caused by chronic hyperglycemia as a result of defects in secretion of insulin, resistance to insulin action, or a combination of the two. Type 1 and type 2 are two main types of diabetes. Type 1 diabetes mellitus (T1DM) results from absolute deficiency of insulin secretion, and type 2 diabetes mellitus (T2DM) results from combined defects in both relative deficiency of insulin secretion and insulin resistance [1]. T2DM is the dominant form of diabetes which account to approximately >85% of all diabetes cases [2]. Diabetic foot ulcer (DFU) is the most devastating complication of diabetes, with a global prevalence of 6.3%, and is more common in patients with type 2 diabetes [3].
The lifetime risk of foot ulceration in patients with diabetes lies somewhere in the range of 15 and 25% [4,5], with a yearly rate of around 2-3% [6].
Diabetic is associated with microvascular complications, including retinopathy, neuropathy, and nephropathy, and macrovascular complications, including ischemic coronary illness, stroke, and peripheral vascular disease [7]. Diabetic retinopathy (DR) is a common complication of diabetes that affects vision. DR damages the blood vessels of the light-sensitive tissue at the back of the eye (retina) that results in blindness if left undiagnosed and untreated. It is estimated that 20 years after diagnosis, those with type 1 diabetes and 60% of those with type 2 diabetes will have some level of retinopathy [8]. Approximately 4 million individuals around the globe are estimated to losing their sight from diabetic retinopathy, the main source of visual impairment in patients aged 20-74 years [9]. The risk of development and progression of DR is closely associated with the type 1 diabetes [8], longer duration of diabetes [10], advancing age [11], poor glycemic control [12], high blood pressure [13] and elevated serum lipids [14].
The descriptive analytical studies have demonstrated that diabetic retinopathy (DR) is among one of the major contributing factors in the development of foot ulceration and subsequent lower limb amputation in diabetic patients [11,[15][16][17]. Importantly, DFU patients with PAD are less likely to heal and more likely to require amputation compared to patients without PAD. Moreover, retinal screening in people with diabetic foot ulceration, followed by treatment of sight-threatening retinopathy, may prevent severe vision loss or blindness [18]. It is therefore essential that DR is diagnosed in all diabetic patients with a foot ulcer. There is a significant rise in the prevalence of diabetes and its complications in Pakistan, causing a major social and economic burden [19,20]. Therefore, this study was conducted with an aim to investigate the prevalence of DR in patients with a DFU in Pakistan and to elucidate the potential association between DR and DFU.

Materials and methods
This was a cross-sectional observational study conducted in the diabetology clinic at Pakistan Institute of Medical Sciences (PIMS), located in federal capital of Pakistan, which is the largest tertiary care referral hospital. This study was conducted between March 2017 and February 2018 as per the guidelines of the Declaration of Helsinki, and the Institutional Ethical Committee approval was obtained before initiation. The study was explained, and written informed consent of the patients was obtained before their recruitment. Inclusion criteria were as follows: (1) all type 2 diabetic patients and only those type 1 diabetes patients with diabetes duration of more than 5 years, diagnosed with foot ulcers based on the Wagner ulcer classification, were included in this study. (2) Patients were included in the study only if they underwent ophthalmic examinations particularly funduscopy of the retina within 6 months after DFU diagnosis.
Participated DFU patients were classified into Wagner's grades [21] as follows: grade 1 (superficial ulcer), grade 2 (deep ulcer), grade 3 (ulcer with osteomyelitis), grade 4 (forefoot gangrene), and grade 5 (mid foot or hind foot gangrene). Moreover, the presence and severity of DR among DFU patients were assessed based on the grading of the Global Diabetic Retinopathy Project Group [22]. A five-stage disease severity classification for DR includes no apparent retinopathy (no DR), proliferative DR (PDR), and mild, moderate, or severe non-proliferative DR (NPDR). Clinical information and demographic details were obtained from medical records of participating patients. The medical records of diabetic patients without a DFU who also visited the diabetology clinic at PIMS for a health checkup were included as control. Analysis of recruitment data was performed by using SPSS-PC version 16.0, and then tables and graphs were constructed to display characteristics of studied patients. The association between DR and DF was determined by using the Chisquare test. P-values <0.05 were considered significant.

Results
Data of patients recruited in the study was analyzed and summarized in Table 1. Among 225 patients with foot ulceration, majority of them were male (62.7%) and had type 2 (60%) diabetes. Most DFU patients were aged 41 years old and over (88.4%) and had diabetes since ≥10 years (65.8%), high HbA1c ≥ 7% (77.3%), and higher level of systolic blood pressure (72.4%). Statistically, significant differences were observed among diabetic patients with a foot ulcer or without a foot ulcer in relation to gender (P = 0.0527) and diabetes duration (P = 0.0029) only.
Additionally, DFU patients with PDR were compared with DFU patients without PDR as shown in  Table 2 and Figure 1. Moreover, the common ulcer grades were 3 (41.8%) and 4 (31.6%), among DFU patients with DR ( Table 3).

Discussion
Diabetes is a common disease, associated with microvascular and macrovascular diseases that contribute to an increased risk of foot ulcers and subsequent lower extremity amputations in diabetic patients [7]. Population-based studies identified that DR is among one of the contributing diseases that significantly increased risk for foot ulceration in diabetic populations of Saudi Arabia [23], Korea [11], Spain [15], Iran [16] and India [17]. However, data is limited about contribution of DR in development of foot ulceration in diabetic population of Pakistan.
The present study revealed that the majority (95.7%) of DFU patients had DR, with 71.9% demonstrated PDR. A similar study reported that DR was prevalent (90%) in the US diabetic patients with foot ulcers, and about more than half of these patients had PDR [11]. Pemayun et al. in a hospital-based case-control study found PAD to be a major predictive factor for poor outcome among hospitalized DFU patients [24]. Previously, Nwanyanwu et al. in a retrospective cohort study assessed that chronic foot ulcers might contribute to retinopathy progression due to the reason that a significant proportion of diabetic chronic ulcer patients with NPDR who progressed to PDR in their analysis [25]. Among DFU patients with PDR, 73.4% had advanced Wagner's grades (grades 3 and 4) of foot ulceration in the present study. Hwang et al. found association of PDR with DFU and speculated that elevated oxidative stress and endothelial dysfunction can cause PDR in the advanced stages of diabetes [11].
The cross-sectional diabetes studies reported that prevalence of foot complications increases among diabetic males with advanced age and longer duration of diabetes [10,11,19,23]. In the current study, diabetic patients with foot ulcers were compared with those without foot ulcers to find significant determinants for foot ulcer in diabetic patients, and it was found that a significant number of diabetic males were at a greater risk for the development of foot ulcers. Higher average height, higher plantar pressure, inadequate self-care practices, inappropriate shoes, and frequent exposure to traumatic events and frequently found peripheral insensate neuropathy have been identified as risk factors contributing to foot ulceration in diabetic males [26,27]. Additionally, DFU patients were classified into the PDR or NPDR group; our results showed that diabetic males with foot ulcers had a higher prevalence of PDR comparatively to females, but this difference was not significant. Similarly, a diabetes study from the United Kingdom reported that PDR was more prevalent in males than in females [28]. In contrast, a community-based study in China showed that diabetic females were associated with increased risk of PDR [29]. This gender difference observed in present and previous studies could not identify it as a risk factor contributing to PDR in diabetic patients with foot ulceration.  Importantly, advancing age has been observed as a contributing factor to foot ulceration in diabetic patients in many studies [11,23]. Although prevalence of foot ulcers was determined high among advanced age diabetic patients in current study, a statistically significant difference was not observed in terms of increasing age (≥41 years) of diabetic patients with and without foot ulceration. On the other hand, our study demonstrated statistically significant correlation between PDR and advanced age of DFU patients. In contrast to this observation, Hwang et al. [11] in a recent study failed to show a correlation between PDR and advanced age of DFU patients. Similarly, Li and Wang reported lower prevalence of DR in elderly diabetic patients and suggested that favorable control of blood glucose, blood pressure, and blood lipids effectively prevented the occurrence of DR in diabetic patients [30]. Therefore, it seems that high blood glucose levels and elevated systolic blood pressure have contributed to the developing of PDR in elderly DFU patients in current study.
Comparatively high prevalence of foot ulcers was observed among diabetic patients with diabetes duration more than 10 years in the current study, and this observation was significant. A previous study from Sudan supported our observation [10]. In two different previously conducted diabetic foot studies, the average duration of diabetes in DFU patients was 13.2 [31] and 8.2 years [32]. Based on current and previous observations, we hypothesize that the lengthy duration of diabetes is a significant risk factor for the development of diabetic foot ulceration. In addition, Chawla et al. in a study reported that chronic hyperglycemia and diabetes duration are among the main contributing factors to development and progression of DR in diabetic patients with foot ulcer [33]. The results of the present study also showed that lengthy duration of diabetes was a significant risk factor in progression of PDR among patients with DFU. In agreement with our results, Hwang et al. also reported that the foot ulcer patients with PDR had a longer duration of diabetes compared to those with NPDR [11].

Conclusion
In summary, the present study showed that a large proportion of advanced age patients with longer duration of diabetes had retinopathy and were at substantial risk of developing foot ulceration. Therefore, in advanced age DFU patients, and particularly those with longer duration of diabetes, early detection of DR and timely treatment may decrease the risk of severe vision loss or blindness.