Diabetic foot ulcer is a major complication in patients with diabetes. Platelet-lymphocyte ratio (PLR) has been reported to have a predictive effect to some diabetic complications in recent years. However, it has not been fully elucidated about the relationship between diabetic foot risk or diabetic foot ulcer and PLR in patients with type 2 diabetes. Therefore, we aimed to evaluate this relationship. In this cross-sectional study, we evaluated the relationships between patient’s diabetic foot risk with the criteria of the International Working Group on the Diabetic Foot (IWGDF) and prevalent foot ulcer, and PLR in 453 consecutive patients with type 2 diabetes. Propensity score analysis was used to adjust the difference of covariates; age, sex, duration of diabetes, body mass index (BMI), HbA1c, current smoking, hypertension, dyslipidemia, neuropathy, PAD, foot deformity and history of foot ulcers. PLR was higher in patients with high risk diabetic foot or foot ulcer (117 ± 40 vs. 107 ± 31, p = 0.003 and 148 ± 65 vs. 113 ± 56, p < 0.001). A receiver-operating characteristic curve demonstrated that PLR of 130.6 constitutes the cut-off value for prevalent foot ulcer with sensitivity 0.85 and specificity 0.70. Multivariate logistic regression analysis revealed that PLR was positively correlated with prevalent foot ulcer (odds ratio, 1.02; 95% confidence interval 1.01–1.04, p = 0.003) after adjusted for several variables with propensity score analysis. Our results demonstrated that PLR can be a marker for high risk diabetic foot and diabetic foot ulcer in patients with type 2 diabetes.

DIABETIC FOOT ULCER is a major complication in patients with diabetes [1]. The lifetime risk of foot ulceration is 7–20% in these patients [2, 3] and ulcers can lead to infection and amputation of the lower extremity if appropriate care is not provided [4]. Risk factors for foot ulceration in diabetes include male gender, poor glycemic control, long duration of diabetes, peripheral neuropathy, peripheral artery disease (PAD), foot deformity and history of foot ulcers or amputation [4-9]. To prevent diabetic foot ulcer, recognition of these risk factors especially for diabetic neuropathy and PAD is needed [3, 10]. The foot risk classification of the International Working Group on the Diabetic Foot (IWGDF) is widely recognized to predict the ulceration and amputation of patients with diabetes [11].

Hematological parameters have been investigated in recent years about the relationship between endothelial dysfunction and inflammation in diabetes region, for example, white blood cell count (WBC), platelet mean volume (MPV), platelet distribution width (PDW), platelet crit (PCT), platelet count, platelet to lymphocyte ratio (PLR) [12-16]. PLR which calculated easily using the platelet lymphocyte ratio in peripheral blood count has been reported to have predictive effect about cancer, cardiovascular disease, diabetes mellitus and diabetic complications in recent years [17-19]. To our best of knowledge, it has not been fully elucidated about the relationship between patient’s diabetic foot risk or diabetic foot ulcer and PLR in patients with type 2 diabetes mellitus. Therefore, in this cross-sectional study, we investigated the relationship.

We included the patients who visited the outpatient clinic of Otsu City Hospital (Otsu, Japan) from April 2012 to December 2014 and who received foot examination in this cross-sectional study. Subjects were classified as current smokers or not according to self administered questionnaire. Patients were excluded if they had an acute inflammatory or infectious disease such as pneumonia, urinary tract infection and tissue abscess. Severe tissue damages including renal or liver failure were excluded. Patients who had the history of thyroid disease, autoimmune disease, acute massive hemorrhage, malignancies or blood diseases which affect platelet and lymphocyte counts were also excluded. This study was conducted in accordance with the Declaration of Helsinki and informed consent was obtained from all subjects. The Ethics Committee of Otsu City Hospital gave approval for this study.

All patients provided details of their demographics, medical history and medication usage. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Type 2 diabetes was diagnosed according to the Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus [20].

The IWGDF classification was used to categorized the risk of diabetic foot: group 0 (no neuropathy), group 1 (neuropathy), group 2 (neuropathy, vascular disease or deformity), and group 3 (previous ulcer) [21]. As previously reported, we thought patients in group 0 to be at “low risk” for foot ulceration, whereas those in groups 1–3 to be at “high risk” [22, 23]. Foot ulcer was defined as a full-thickness skin defect associated with neuropathy and/or peripheral arterial disease (PAD) of the lower limbs that required >14 days for healing [21, 24, 25]. A physical examination of the lower extremities was performed by a diabetologist, a certified diabetes nurse, or a certified diabetes educator.

Neuropathy was defined using the diagnostic criteria for diabetic neuropathy proposed by the Diagnostic Neuropathy Study Group [26]. In brief, in the absence of peripheral neuropathies, diabetic neuropathy is diagnosed by two or more abnormalities of three examination items: neuropathic symptoms such as neuropathic pain, paresthesia and numbness, decreased or absent ankle reflex (bilateral) and decreased distal sensation assessed by C128 Hz tuning fork without evident non-diabetic peripheral neuropathy.

Examination for foot deformity and musculoskeletal abnormalities were performed to identify such as hallux valgus deformity, hammer/claw toes deformity and hallux limitus (limited motion at the metatarsophalangeal joint). PAD was diagnosed if at least one of the following was confirmed: ankle brachial pressure index (ABI) <0.9 or absence of two or more pedal pulses on palpation [27, 28].

Blood samples were drawn in the morning after an overnight fast for measurement of glycated hemoglobin (HbA1c), total cholesterol (TC), triglycerides (TG), and creatinine. Complete blood count and examinations were performed using a Bio Majesty JCA-BM 6050 (JEOL, Tokyo, Japan). Urinary albumin and creatinine concentrations were measured in spot urine collected in the early morning. Urinary albumin was determined by a turbidimetric immunoassay (SRL Laboratories, Tokyo, Japan). Hypertension was defined as systolic blood pressure (SBP) >140 mmHg, diastolic blood pressure (DBP) >90 mmHg, and/or having received treatment for hypertension. Dyslipidemia was defined as TC concentration >5.69 mmol/L, TG concentration >1.70 mmol/L, and/or having received treatment for dyslipidemia.

The estimated glomerular filtration rate (eGFR) was used to estimate kidney function and was calculated as follows [29]:

Male: eGFR (mL·min^–1·1.73 m^–2) = 0.741 × 175 × age^–0.203 × (serum creatinine)^–1.154.

Female: eGFR = 0.741 × 175 × age^–0.203 × (serum creatinine)^–1.154 × 0.742.

Statistical analyses were performed using JMP v. 9.0 and v. 11 (SAS Institute Inc., Cary, NC). A p value <0.05 was considered significant. Continuous variables are presented as the mean value ± 1 SD. Categorical variables are presented as a number (percentage). The significance of differences between groups was evaluated by unpaired Student t-test or analyses of variance. Data were analyzed by cross-tabulation, and significance was calculated by Pearson χ² test. Pearson’s correlation analyses were used to assess the relationships between variables. Receiver-operating characteristic (ROC) curve analysis was performed to calculate sensitivity, specificity and the area under the curve to select the cut-off value of PLR for prevalent foot ulcer. Univariate and multivariate logistic regression analyses were used to adjust factors of relationship between high risk diabetic foot or prevalence of diabetic foot ulcer and PLR. We selected covariates which were known factors for multivariate analysis; age, sex, duration of diabetes, BMI, HbA1c, current smoking, hypertension, dyslipidemia, neuropathy, PAD, foot deformity and history of foot ulcers. These covariates were examined by propensity score analysis to reduce the influence of cofounders and selection bias. We conducted multivariate logistic regression analysis with calculated propensity scores of combined covariates and PLR as predictor variables and diabetic foot ulcer as dependent variable (C statistic was 0.964).

In this study, 503 consecutive patients with type 2 diabetes were enrolled. Among them, 50 patients were excluded because of acute inflammatory or infectious disease (n = 3), severe tissue damage (n = 12), thyroid disease (n = 4), autoimmune disease (n = 2), acute massive hemorrhage (n = 2), and malignancies or blood diseases (n = 27) (Fig. 1). A total of 453 patients with type 2 diabetes were included in this study. Foot ulcers were found in 17 patients. The clinical characteristics of patients (273 male and 180 female) are shown according to the IWGDF criteria and the presence of foot ulcer (Table 1). PLR in patients with group 0, 1, 2, 3 of IWGDF category was 107 ± 31, 110 ± 35, 117 ± 49 and 125 ± 58, respectively (p = 0.029). In Table 2, clinical characteristics of 436 patients excluding 17 diabetic foot ulcers are compared according to low or high risk of IWGDF criteria.

Fig. 1

Inclusion and exclusion flow

There was significant difference in value of lymphocytes between groups of IWGDF, whereas no significant difference was found in value of platelet. PLR was higher in patients with high risk diabetic foot (Table 2). Moreover, PLR was higher in patients with presence of foot ulcer (Table 3).

In multivariate logistic regression analysis, PLR was significant determinant for high risk diabetic foot after adjusted several covariates (Table 4). The results of univariate analysis between PLR and other variables are shown in Table 5. PLR was positively correlated with duration of diabetes and triglyceride whereas inversely correlated with BMI (Table 5). Univariate logistic regression analysis revealed that prevalent foot ulcer was positively correlated with PLR (OR, 1.02; 95% CI, 1.01–1.03 p < 0.0001) (Table 6). In addition, prevalent foot ulcer was positively correlated with PLR after adjusting for propensity score, including age, sex, duration of diabetes, BMI, HbA1c, current smoking, hypertension, dyslipidemia, neuropathy, PAD, foot deformity and history of foot ulcers (OR, 1.02; 95% CI, 1.01–1.04, p < 0.0001).

To evaluate the usefulness of PLR as a method to detect diabetic foot ulcer, we calculated the area under the ROC curve. The area under the ROC curve was 0.78 with p < 0.0001. The analysis determined that PLR of 130.6 constitutes the cut-off value for prevalent foot ulcer with sensitivity 0.85 and specificity 0.70.

In this cross-sectional study, we revealed the relationship between high risk diabetic foot or foot ulcers and PLR in patients with type 2 diabetes. This relation remained significant in multivariate logistic regression analysis adjusted for several factors. To our best of knowledge, this is the first report investigate the relationship between high risk diabetic foot or foot ulcers and PLR.

Foot ulcers and amputations reduce quality of life and increase morbidity and mortality of patients with diabetes [30, 31]. Furthermore, the economic burden of treatment for complications is so high [31]. In the several risk factors for foot ulceration with diabetes [4-9, 22], recognition of diabetic neuropathy and PAD is especially important to prevent diabetic foot ulcer [3, 10]. Early recognition and management of risk factors can prevent or delay adverse outcomes of diabetic foot [32]. However, such approaches are not always implemented in practice [33]. Therefore, simple method is needed to indicate the risk of diabetic foot or diabetic foot ulcers.

PLR is calculated easily using the platelet lymphocyte ratio in peripheral blood count which can be measured in daily outpatient clinic and is reported to have predictive effect about diabetes mellitus and diabetic complications in recent years [17-19]. PLR which combines the predictive risk of platelet and lymphocyte count is also reported to be a prognostic marker of inflammation for many types of cardiovascular disease, including PAD and hypertension [34, 35]. In diabetic patients with albuminuria, PLR was higher and was found to be a predictor of albuminuria. This relationship was thought to be increased inflammation and impaired endothelial dysfunction in diabetic patients with albuminuria [18]. Other study indicated the significant difference about the levels of lymphocyte counts in patients with and without diabetic neuropathy [36]. In this study, the rate of patients with neuropathy was similar to other previous study [37] but was higher compared with recent Japanese study included large number of patients [38]. The proportion of neuropathy was higher in patients with prevalent foot ulcer. Higher level of PLR was found in patients with foot ulcer and high risk diabetic foot. Multivariate logistic regression analysis indicated that high risk diabetic foot and foot ulcer were correlated with PLR after adjusted for several factors. As previously reported, platelet can interact with a variety of different type of cells, which initiate the inflammation in the arterial wall [39], and thought to be the pathogenetic mechanism of atherosclerosis [40]. Other studies demonstrated the role of activated platelet which might be an important role of increased atherogenesis [41, 42], whereas lymphocyte indicates the protective component of inflammation [43]. In this study, patients with foot ulcer had significantly lower lymphocyte counts. However, multivariate logistic regression analysis did not reach statistical significance when lymphocyte was included as a covariate instead of PLR (p = 0.053). Our findings suggested that PLR might be useful to predict low extremities atherosclerosis leading to assess diabetic foot ulcer in patients with type 2 diabetes mellitus.

This study has some limitations. First, the number of patients available for analysis was not large, they were all Japanese, and the prevalence of diabetic foot ulcer and previous history of foot ulcers in our study were lower than other studies [7, 8, 44], whereas higher than recent large cohort study in Japan [45]. Second, the prevalence of PAD, diabetic neuropathy and glycemic control in this study is lower compared with other studies [46], although these control levels were comparable to recent Japanese study [38]. These might be contributed to the lower rate of foot ulcer. Therefore, it is uncertain if this finding is general. Third, patients using sodium glucose transporter 2 (SGLT2) inhibiter were not included in this study. Therefore, we could not evaluate the effect of SGLT2 inhibiter on foot ulcer. However, it is not fully elucidated about the relationship between SGLT2 inhibiters and the incidence of foot ulcer [47]. Finally, the cross-sectional design only permits inference of the causal relationships between high risk diabetic foot or foot ulcers and PLR. Further study is needed to evaluate the application for PLR to predict diabetic foot ulcers in patients with type 2 diabetes. In a clinical situation, it is important to assess PAD and DPN, as established risk factors for concomitant cardiovascular diseases or diabetic foot ulcers. PLR is simple, inexpensive and is a useful marker for assessment of high risk diabetic foot and foot ulcers in patients with type 2 diabetes.

In conclusion, PLR can be a useful marker for assessment of high risk diabetic foot and foot ulcers in patients with type 2 diabetes.

We thank all staff members of the diabetes team in Otsu City Hospital for their assistance.

Yoshitaka Hashimoto has received grants from Asahi Kasei Pharma. Michiaki Fukui has received grants, honoraria and research supports from AstraZeneca plc., Astellas Pharma Inc., Nippon Boehringer Ingelheim Co., Ltd., Daiichi Sankyo Co., Ltd., Eli Lilly Japan K.K., Kyowa Hakko Kirin Company Ltd., Kissei Pharmaceutical Co., Ltd., MSD K.K., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Pharma Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Sanofi K.K., Ono Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. The sponsors were not involved in the study design; in the collection, analysis, interpretation of data; in the writing of this manuscript; or in the decision to submit the article for publication. The authors, their immediate families, and any research foundations with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article. The authors declare that although they are affiliated with a department that is supported financially by pharmaceutical company, the authors received no current funding for this study and this does not alter their adherence to all the journal policies on sharing data and materials. The other authors have nothing to disclose.

YM contributed to the conception and design, wrote the manuscript, and researched and analyzed data. MI contributed to acquisition of data, critical revision of the manuscript, and analysis and interpretation of data, and approved the final version of the manuscript. YH contributed to critical revision of the manuscript, and to analysis and interpretation of data. AY contributed to research data and discussion. NN contributed to revision of the manuscript. MF contributed to critical revision of the manuscript.

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