High Rates of Comorbid Conditions in Patients With Type 2 Diabetes and Foot Ulcers

Foot ulceration in patients with diabetes mellitus (DM) affects quality of life and creates a significant economic burden for both the patient and healthcare systems worldwide.^1–3 The annual incidence of foot ulcers is 1%–4% while the prevalence is 5%–10% in patients with DM.^1,4 The lifetime risk for foot ulcers development in patients with diabetes is nearly 15%,1 and frequently leads to disability and leg amputation.^1,2 The link between foot ulcers and leg amputations is indisputable, as diabetes is the cause of almost 50% of all nontraumatic lower extremity amputations worldwide.^1,5
Patients with diabetes and lower extremity arterial disease (LEAD) have approximately a 10-year reduction in life expectancy and a 2-fold increase in mortality compared to patients without LEAD.^6,7 Previous studies have shown consistently increased mortality rates after amputations, with cardiovascular disease to be the leading cause of death.^8,9 In addition, recent data have shown high mortality rates in patients with foot ulcers⁹— patients with ischemic ulcers have the highest mortality followed by those with neuroischemic and neuropathic ulcers.^8,9 Although it is expected that patients with peripheral vascular disease will probably develop other macrovascular complications such as coronary (CAD) and carotid artery disease,^6,7 the reason for the high mortality among patients with neuropathic foot ulcers is not known. Increased prevalence of comorbid conditions could be a possible explanation for the high mortality rates in patients with diabetes and foot ulcers; however, this hypothesis has not been examined. Therefore, the aim of this cross-sectional study was to investigate the prevalence rates of comorbid conditions in patients with both diabetes and neuropathic and neuroischemic foot ulcers.

Materials and Methods
A total of 742 patients with type 2 diabetes (234 with foot ulcers and 508 without ulcers) matched for age and sex consecutively attending the outpatient diabetes and diabetic foot clinics of the authors’ hospital were reviewed. Patients with purely ischemic ulcers were excluded because these patients were referred and managed in the vascular surgery department of the hospital. The demographic and clinical characteristics of the study subjects are shown in Table 1.

The study patients’ medical histories were reviewed with particular attention to previous CAD (myocardial infarction, stable angina, revascularization procedures at the coronary arteries, or diagnosed stenosis [> 50%] at the coronary arteries). Patients were considered to have cerebrovascular disease (CVD) when they reported a history of stroke, transient ischemic attack, revascularization procedures at the carotid arteries, or carotid artery stenosis (> 50%). LEAD was diagnosed when one of the following was present: 1) history of intermittent claudication, 2) absence of at least 2 out of 4 peripheral pulses in the feet, 3) ischemic rest pain, 4) gangrene, 5) history of revascularization procedures at the aorta or the lower leg arteries, or 6) ankle-brachial pressure index (ABI) values < 0.9.¹⁰ ABI was measured and calculated in all subjects with foot ulcers using a pulsed-continuous Doppler (Hokanson MD16, Bellevue, Wash). Diagnosis of neuropathy was based on assessment of the neuropathy symptom score (NSS), neuropathy disability score (NDS), and vibration perception threshold (VPT), as previously described.^11–13 Ulcers in patients with neuropathy but without LEAD were classified as purely neuropathic, while ulcers in patients with both neuropathy and LEAD were classified as neuroischemic.
Weight and height were measured and body mass index (BMI) was calculated in all subjects. Hypertension was defined when systolic and/or diastolic pressure exceeded 140/90 mmHg, respectively, in 3 observations or when patients were treated with antihypertensive agents. Nephropathy was defined as an estimated creatinine clearance (CrCl) < 40 mL/min using the Cockcroft and Gault formula¹⁴ in the presence of either microalbumunuria or proteinuria. Patients were considered as smokers if they were active smokers or if they had discontinued smoking during the previous year. Retinopathy was diagnosed as background or proliferative by direct fundoscopy. Dyslipidemia was diagnosed when low density lipoprotein (LDL) cholesterol levels were > 100 mg/dL and/or low high density lipoprotein (HDL) levels were < 40 mg/dL and < 50 mg/dL for men and women, respectively, and/or fasting plasma triglyceride levels were > 150 mg/dL, according to the American Diabetes Association guidelines,¹⁵ or when patients had been treated with statins or fibrates.
Serum lipids, creatinine, and HbA1c values were obtained from the medical record. Low density lipoprotein (LDL) cholesterol was calculated using the formula of Friedwald et al.¹⁶ Microalbuminuria was diagnosed in a morning urine sample when albumin/creatinine ratio was in the range of 2.5–30 mg/mmol for the men and 3.5–30 mg/mmol for the women in at least 2 urine samples over a 6 month period; values > 30 mg/mmol were diagnostic for proteinuria.

Statistical analysis
Analyses were performed using the SPSS 10.0 (SPSS, Chicago, Ill) statistical package. All variables were tested for normal distribution of data. Data are shown as mean ± SD or median (interquartile range) as appropriate. Differences between the studied groups examined using the student’s unpaired t-test or the Mann-Whitney U-test for parametric and nonparametric data, respectively, while a chi-squared test was used for categorical data. P < 0.05 (2-tailed) was considered statistically significant.

Results
Patients with diabetes with and without foot ulcers did not differ significantly in terms of age, sex, smoking habits, glycemic control, and prevalence rates of hypertension, dyslipidemia, and CVD (Table 1). The known duration of diabetes was longer (P < 0.001), while BMI (P = 0.03) and CrCl (P = 0.003) values were lower in patients with foot ulcers compared to those without ulcers. In addition, the prevalence rates of CAD (P = 0.005), LEAD (P < 0.001), retinopathy (P < 0.001), and nephropathy (P = 0.04) were higher in the patients with foot ulcers compared to those without foot ulcers (Table 1).

In the foot ulceration group, 65% of the ulcers were purely neuropathic and 35% were of mixed etiology. Patients with neuroischemic foot ulcers were older (P = 0.04), had a longer duration of diabetes (P = 0.001), a lower BMI, and were more frequently male (P = 0.001) and smokers (P = 0.001; Table 2). In addition, these patients had worse renal function (P = 0.01). Glycemic control was not significantly different between the two groups. However, both retinopathy (P < 0.001) and nephropathy (P < 0.001) were more common in the group of patients with neuroischemic than in the group with neuropathic foot ulcers; the same was true for the prevalence rates of hypertension (P < 0.001), dyslipidemia (P = 0.001), and CAD (P < 0.001). Prevalence rates of CVD were low and not significantly different between the studied groups (Table 2).

Discussion
The main finding of the present study is that the prevalence rates of comorbid conditions such as CAD, nephropathy, and retinopathy are more common in patients with diabetes with neuropathic foot ulcers than in those without ulcers. Moreover, these comorbid conditions and, additionally, prevalence rates of dyslipidemia, hypertension, and smoking are much higher in patients with diabetes who have neuroischemic ulceration, compared to patients with neuropathic foot ulceration. Furthermore, this study showed that duration of diabetes is longer in patients with either neuropathic or neuroischemic foot ulceration than in patients without foot ulcers.
Foot ulceration is a serious complication of DM that increases morbidity and mortality.^1,9 In addition, DM incurs significant financial costs for both the patient and the community.² The main risk factors for foot ulceration are diabetic neuropathy and LEAD.^4,17–20 Neuropathy is the common denominator in the vast majority of diabetes-related foot ulcers.^19,20 However, an ulcer will not develop, unless accidental trauma occurs in an area of high-pressure distribution especially due to poor-fitting footwear, in patients with either neuropathy or LEAD.^2,21,22 In addition, the wound healing process in diabetes is impaired due to reduced blood supply at the wounded area, defected leucocyte function, and abnormal expression of growth factors.²⁰ In agreement with a previous report,² the present study showed that the majority of foot ulcers in diabetes (almost 65%) were purely neuropathic.
CAD is the principal cause of death in patients with DM. Epidemiological studies have conclusively shown that in DM coexistence of various risk factors for macrovascular disease including hypertension, dyslipidemia, and smoking, doubles the risk for CAD morbidity and mortality in comparison with the nondiabetic population.²³ In the present study, the findings of increased prevalence of CAD and of risk factors for macrovascular complications among patients with neuropathic and mixed etiology ulcers suggest that these comorbid conditions in the patients with foot ulceration may be associated with high cardiovascular mortality.
Diabetic nephropathy, even in the presence of microalbuminuria, is strongly associated with the development of macrovascular complications and with increased cardiovascular mortality.^24–27 Early diabetic nephropathy predicts not only renal impairment but has been identified as a contributing factor to atherosclerosis through endothelial dysfunction,²⁸ and reflects wide vascular damage at the glomeruli, the retina, and the intima of the arteries.²⁹ In addition, nephropathy is associated with the development of hypertension and dyslipidemia, both well known factors for CAD.²⁵ Moreover, patients at all stages of diabetic nephropathy are at a particularly high risk for foot ulceration, as neuropathy is particularly common in the early stages of nephropathy.^30,31 In addition, diabetes is the most significant risk factor for foot amputation among patients with chronic kidney disease.³² In the present study, nephropathy was more common in the patients with either neuropathic and neuroischemic foot ulcers and most likely contributes to the high prevalence of macrovascular complications and mortality in the patients with foot ulcers through the aforementioned mechanisms.
Diabetic retinopathy is a common complication of diabetes. Previous studies have shown the close relationship between retinopathy and foot ulceration—this relationship reflects a widespread microangiopathy.^33,34 Moreover, poor vision may interfere with a patient’s ability to detect early foot lesions.³⁴ The association between nephropathy and retinopathy has been described in previous studies and seems to start at the level of microalbuminuria.²⁸ Additionally, patients with proteinuria have much higher rates of retinopathy compared to those without proteinuria.³⁵ It is noteworthy that in the present study the prevalence rates of diabetic retinopathy were almost double in the participants with foot ulcers in comparison with those without foot ulcers (35% versus 19%). In addition, diabetic retinopathy affected 56% of the patients with neuroischemic foot ulcers.
Beyond DM, duration of glycemic exposure, male gender, advanced age, hypertension, dyslipidemia, and smoking are risk factors for the development of LEAD.¹⁰ In the present study, the authors found that patients with neuroischemic foot ulceration had higher prevalence rates in all of these conditions and a longer duration of diabetes, corroborating previous findings.^4,5 Diabetes control was not significantly different between patients with and without foot ulcers or between patients with neuropathic and neuroischemic ulcers. However, a robust relationship between glycemic control and LEAD has not been established. The UK Prospective Diabetes Study (UKPDS) and other data show that improvement in glycemic control does not prevent the development of LEAD or reduce amputations due to LEAD.^34,36
The present study did not assess quality of life (QoL) in the patients with foot ulcers. Previous studies have shown that patients with DM face multiple emotional issues related to the course of their disease, as it requires significant lifestyle changes.³⁷ It is considered that uncomplicated DM, per se, does not affect QoL.³⁸ However, foot ulceration has a strong detrimental impact on QoL and affects a patient’s ability to perform simple daily tasks and leisure activities.^39–42 Thus, patients with foot ulcers more often suffer from depression and have poorer QoL than those without ulcers.^39–42 Additionally, patients with nonhealing foot ulcers may have infection-related complications, gangrene, or amputation, which are often associated with depression and further compromise QoL.^40,41 Moreover, QoL is compromised not only from foot ulcers and their complications but, in addition, from the comorbidity particularly CAD⁴³ and renal impairment.^44,45 It has been demonstrated that both depression and impaired QoL are strongly associated with high mortality rates.^46,47 Therefore, aside from the comorbid conditions in the patients with foot ulcers, QoL issues are equally important and may be associated with high mortality rates.
The present study is cross-sectional and cannot establish a cause and effect relationship between the comorbid conditions and mortality in patients with foot ulcers. However, the authors have shown high prevalence rates of diseases and conditions associated with worse outcomes in patients with foot ulcers.

Conclusion
The present study has shown that the prevalence rates of comorbid conditions such as CAD, nephropathy, and retinopathy are more common in patients with diabetes with neuropathic foot ulcers in comparison to those without ulcers. Moreover, these comorbid conditions and additionally, prevalence rates of dyslipidemia, hypertension, and smoking are much higher in patients with diabetes who have neuroischemic ulcers, compared to patients with neuropathic foot ulceration.
The incidence of diabetes in the general population is expected to rise. Thus, a subsequent increase in prevalence of diabetic foot complications is expected to follow. Physicians should pay special attention to recognize patients who are at risk for foot ulceration to help prevent foot problems. Comorbid conditions must also be recognized and managed aggressively. Since DM is one of the most common chronic diseases worldwide, focusing on the prevention and proper management of the diabetic foot problems will decrease not only amputations, but will preserve QoL and may provide longer survival rates among patients with diabetes.