The Influence of Gender as a Risk Factor in Diabetic Foot Ulceration

Diabetic foot complications such as ulcerations are a major health problem, estimated to occur in up to 15% of patients with diabetes during their lifetime.¹ If insufficiently treated, these ulcerations can lead to lower extremity amputations and even death.^2,3 The total cost of diabetic foot complications in the United States has been projected to approach $4 billion annually, as extrapolated from the costs of ulcer care and amputations.⁴ Therefore, identification of risk factors for foot ulceration is useful in both screening and prevention of these complications in the diabetic population.
Numerous risk factors for the development of foot ulceration have been documented. These risk factors include: peripheral neuropathy, high plantar foot pressures, limited joint mobility, and peripheral vascular disease.^5–10 Reported in approximately 30% to 50% of all patients with diabetes, peripheral sensory neuropathy has been found to be the most common and sensitive predictor for foot ulceration in the diabetic patient.^11,12 In a study that specifically studied casual pathways of diabetic foot ulceration, the presence of neuropathy was reported in 78% of feet with ulcers.¹³
While peripheral neuropathy appears to be the major clinical risk factor associated with foot ulceration, socio-demographic factors also appear to influence the likelihood of foot ulceration. Socio-demographic risk factors include: race, education level, and gender.^14,15 These studies observed that foot ulcerations predominantly afflict men, with poorer outcomes such as amputations also more prevalent in men.¹⁶ While diabetic foot complications appear to demonstrate preponderance towards male gender, it remains unknown whether gender is a single, independent risk factor for diabetic foot ulceration.
In a previous large, prospective trial that the authors’ unit coordinated, 29% of all patients with diabetes, including men and women, were shown to ulcerate over a 30-month period.¹⁷ In the present study, these same data are analyzed separately for men and women. The main goal of this study is to examine whether gender influences the incidence of foot ulcers and if gender is a significant risk factor for diabetic foot ulceration.

Methods
Patients. A total of 248 patients with diabetes were included in the study. These patients were recruited from the Joslin-Beth Israel Deaconess Foot Center, a primary foot care clinic (Boston, Mass), the University of Texas Health Science Center (San Antonio, Tex), and the California College of Podiatric Medicine (San Francisco, Calif). Patients were enrolled consecutively at each clinic location. The diagnosis of diabetes had been made before enrollment and was confirmed by either communication with a primary care provider or medical record review. Patients attended the above clinics for various reasons, including regular foot care and foot care related to previous foot problems such as ulceration and peripheral vascular disease.
Data collection. All investigators met before the start of the study to discuss and review methods for data collection. The testing modalities and examination methods were demonstrated to all investigators to ensure uniformity.
All patients underwent a complete history and physical examination in addition to other modalities to assess abnormalities associated with neuropathy, peripheral vascular disease, and foot deformity. Each foot was examined and scored separately for data analysis purposes.
Neuropathy disability score. The neuropathy disability score (NDS) was used to quantify the severity of diabetic neuropathy obtained from physical examination and was based on tendon reflexes and sensory modalities as previously described.^17,18 The patella and Achilles tendon reflexes were tested. A score of 0 was given if the reflex was normal. A score of 1 was given if the reflex could be elicited with reinforcement. A score of 2 was given if the reflex was absent. The total represented the reflex score.
Sensory tests included a pinprick with a pointed metal or wooden pin, light touch with a strip of cotton ball, vibration with a tuning fork, and temperature perception using a test tube filled with cold water. A score was given according to the anatomical location in which the patient could not identify the stimuli introduced. A score of 0 was given if the patient perceived the stimulus at all levels. A score of 1 was given if the patient failed to perceive the stimulus at the base of the toe; a score of 2 was given if the patient failed to perceive the stimulus at the midfoot; a score of 3 was given if the patient failed to perceive the stimulus at the heel; a score of 4 was given if the patient failed to perceive the stimulus at the lower leg; a score of 5 was given if the patient failed to perceive the stimulus at the knee. The average score of both feet was entered as the sensory score. The summation of reflex and sensory scores for each modality was entered as the NDS. An NDS of ≥ 5 was indicative of the existence of moderate or severe neuropathy.
Vibration perception threshold. A biothesiometer (Biomedical, Newbury, Ohio) was used to test vibration perception threshold (VPT). This is a hand-held device with a rubber tractor that vibrates at 100 Hz. The hand-held unit is connected to a base unit with an electrical cord. This unit contains a linear scale that displays the applied voltage, which ranges from 0 to 50 V. The method of testing was standardized. The device was held with the tractor balanced vertically on the pulp of the toe. At this time, the voltage was increased on the base unit until the patient could perceive the vibration.¹⁹
If a patient could not detect vibration at the maximum voltage of 50 V, then a value of 51 V was assigned for statistical analysis. A mean of 3 readings in each foot was entered for final data analysis. A value of ≥ 25 V was considered indicative of a patient at risk for foot ulceration.²⁰
Semmes Weinstein Monofilaments (SWM). Eight Semmes Weinstein monofilaments were used that apply pressure from 1 g–100 g to evaluate the cutaneous perception threshold. The plantar aspect of the hallux was used for this testing. With their eyes closed, the patient indicated to the investigator when he or she could feel the filament. Inability to feel a 5.07 SWM (10 g of pressure) was considered indicative of being at high risk for foot ulceration.²¹
Maximal plantar foot pressure. The F-Scan mat system (Tekscan, Boston, Mass) was used to measure dynamic plantar foot pressures.²² The mat was calibrated for each patient by using the patient’s weight before each testing session. The patients walked without shoes over the mat, and maximal plantar foot pressure for the entire foot was obtained. Several practice runs were made to familiarize the patient with the system and to ensure the recording of a natural gait. The mean reading of 3 midgait footsteps was entered for final data analysis. Foot pressures ≥ 6 kg/cm² were considered to be indicative of patients at high risk for foot ulceration according to previously published studies.²³
Joint mobility. A goniometer was used to measure the total range of motion at the first metatarsophalangeal joint (MTPJ) and the subtalar joint (STJ).²⁴ The range of motion from maximal passive plantar flexion to maximal passive dorsiflexion was measured for the first MTPJ. The range of motion from maximal passive inversion to maximal passive eversion was measured for the STJ. The average of 3 readings in each foot was recorded.

Statistical Analysis
The Minitab statistical package Version 12.0 (Minitab, State College, Pa) for personal computers was used for statistical analysis. Comparisons between patients who developed and did not develop foot ulceration were made by using chi-squared tests for categorical variables. For individual continuous variables, comparisons were made by using the 2-tailed Student’s t-test if assumptions of normality were achieved or with Wilcoxon’s rank-sum test if nonparametric hypothesis testing was required. Univariate and multivariate logistical regression was used in a stepwise fashion to assess variables that were independently significant predictors of ulceration. Significance levels of P = 0.05 were used throughout.

Results

A total of 248 patients were included in the study and were followed for a mean period of 30 months (range 6–40). Patient characteristics are shown in Table 1. Men had higher NDS (13 ± 8 versus 8 ± 7, P < 0.0001), VPT (36 ± 17 V versus 23 ± 16, P < 0.0001), SWM (5.9 ± 1.4 versus 5.9 ± 1.3, P < 0.0001), and plantar peak foot pressures (6.4 ± 3.4 kg/cm² versus 5.0 ± 2.3, P < 0.0001), while women had higher MTPJ mobility (69 ± 24 degrees versus 77 ± 23, P < 0.0001) and STJ mobility (22 ± 10 degrees versus 26 ± 8, P < 0.0001; [Table 2]).
Plantar foot ulceration developed in 49 (40%) men compared to 24 (19%) women (P < 0.0001) during the study. When men and women were analyzed separately, univariate logistical regression analysis yielded similar odds ratios (OR) in both groups for high NDS (≥ 5) [M 6.1 (2.1–17.7), W 8.3 (2.8–24.4) (OR (95% CI)], high VPT (≥ 25 V) [M 6.0 (2.5–14.6), W 8.9 (3.7–21.6)], SWM [M 6.6 (1.9–21.9), W 3.7 (1.4–10.0)], high foot pressures (≥ 6 kg/cm²) [M 2.7 (1.5–5.0), W 3.0 (1.4–6.5)], and MTPJ mobility [(M 0.97 (0.96–0.99), W 0.98 (0.97–1.0)] (Figure 1).

Discussion
A previous large prospective study found that 29% of all patients with diabetes ulcerated over a 30-month period.¹⁷ Observations of these patients who ulcerated revealed that there was an increased frequency for men to develop a foot ulceration compared to women. Thus, 49 (40%) men developed a foot ulceration compared to 24 (19%) women.
The main finding of the present study is that men and women with diabetes and equal severity of risk factors for developing foot ulceration have similar chances to develop a foot ulcer. This finding indicates that women with diabetes are at a lower risk for foot ulceration because they have less severe neuropathy and other risk factors for foot ulceration, such as limited joint mobility. However, once neuropathy or other risk factors are present, women have the same risk as men in developing foot ulceration.
Why women with diabetes are less likely to develop neuropathy compared to men remains unclear. The exact etiology of diabetic neuropathy is under debate; however, there are a number of theories postulated. It is currently believed that diabetic peripheral neuropathy is the result of metabolic factors, such as high blood glucose, long duration of diabetes, abnormal blood fat levels, and possibly low levels of insulin.^25–28 Additional factors include neurovascular dysfunction, most notably endothelial dysfunction, leading to damage of the blood vessels that carry oxygen and nutrients to the nerves.
Previous data have suggested that men were almost twice as likely as women to develop insensate neuropathy. The reasons for this discrepancy are not clear. Previous studies have shown that height is one of the main predictors for the development of neuropathy while other predictors include age, length of time with diabetes and diabetes control.²⁹ As taller subjects have longer nerve fibers, it is believed that the increased length makes them more vulnerable to injury. As women are on average shorter than men, as was the case with the authors’ subjects, the height difference may be one of the main reasons for the development of less severe neuropathy. Furthermore, women, especially of reproductive age, have better endothelial function in both micro- and macrocirculation—this may offer additional protection.³⁰

Conclusion
The results of this study indicate that women have a lower risk than men for foot ulceration. This lower risk appears to be the result of less severe neuropathy, increased joint mobility, and lower foot pressures. However, once neuropathy or other risk factors are present, women were found to have the same risk of developing foot ulcerations as men. Therefore, women with risk factors for foot ulceration should be considered to be at an equal risk as men for developing future problems.