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Comorbidities in the diabetic patient with foot problems

Neil Baker, Stephan Morbach, Vilma Urbancic-Rovan, Kristien Van Acker
The main causes of diabetic foot problems are neuropathy and peripheral vascular disease, in tandem with trauma and infection. The cornerstones of diabetic foot ulcer treatment are pressure relief, control of infection and maintenance of adequate blood supply to the affected limb. The course and outcome of diabetic foot complications, particularly ulceration, are strongly influenced by comorbidities, such as kidney disease, arterial hypertension, dyslipidaemia, congestive heart failure and mental illness. A holistic patient approach by a well-coordinated and skilled interdisciplinary team is mandatory if successful outcomes are to be consistently achieved.

Diabetes mellitus is complex to manage as it is a disease that is commonly concomitant with other comorbid conditions. As type 2 diabetes is predominantly a disease of middle-aged, overweight and older individuals, many individuals will have one or more concomitant illnesses, e.g. arterial hypertension and dyslipidaemia, heart failure, renal impairment due to diabetic nephropathy, poor eyesight, psychological problems and polypharmacy (Alonso-Morán, 2014). The significant impact of multi-morbidity, defined as presence of two or more long-term health conditions, has become widely recognised in recent years, warranting a specially dedicated issue of a NICE guideline dedicated to this in 2016 (Farmer et al, 2016; NICE, 2016).

Patients with diabetic foot problems are a particularly vulnerable group. For a decade, the diabetic foot has been considered the “cancer of diabetes”, since the mortality of diabetic patients with foot ulceration is comparable to the mortality of patients with various malignancies (Armstrong et al, 2007). Due to the multifactorial aetiology of diabetic foot ulceration (DFU), the diabetic foot lies between specialties and requires management by a finely-tuned and skilled interdisciplinary team (Barshes et al, 2013). The interrelation between the comorbid conditions is complex and almost never unidirectional. There is no simple answer to the question which is the cause and which is the consequence. Multi-morbidities in patients with diabetic foot problems have been  investigated in many studies (Prompers et al, 2007; Apelqvist et al, 2011; Morbach et al, 2012; Bruun et al, 2013; Choi et al, 2014; Hoffstad et al, 2015; Begun et al, 2016). Most of them have demonstrated that renal failure has a significant influence on the course and outcome of the diabetic foot, but have also confirmed the significant impact of other comorbid conditions.

This paper is an attempt to summarise the evidence for the influence of renal failure, congestive heart failure, dyslipidaemia, neurological disorders and mental illness on the outcome of diabetic foot disease, and to suggest the potential windows of opportunity to improve these outcomes.

Diabetic foot and the kidney
The lower-limb amputation rate among people with end-stage renal disease (ESRD) on dialysis therapy is high in the general population. On its own, ESRD increases the risk for lower-extremity amputation equivalent to three or more other comorbidities (including diabetes) (Tseng et al, 2005; Goldberg et al, 2012). However, the combination of diabetes and ESRD represents one of the strongest risk factors for lower-extremity amputation (Kaminski et al, 2015; Gilhotra et al, 2016). Elevated urinary albumin excretion predicts peripheral arterial disease in type 1 diabetes patients independently of the conventional atherogenic risk factors of duration and control of diabetes (Deckert et al, 1996). Thus, chronic renal failure has been named a “vasculopathic state” (Luke, 1998; McGrath and Curran, 2000), since impaired renal function is associated with an increased prevalence of peripheral arterial disease (O’Hare et al, 2002). Rates of contralateral limb amputation are high both after minor and major amputation, and predicted by renal disease, atherosclerosis, and atherosclerosis with diabetic neuropathy (Glaser et al, 2013).

Due to various pathologies, e.g. uraemia, arterial medial wall calcification, etc, the results of the revascularisation procedures in patients with diabetes and ESRD are generally poor (Jaar et al, 2004). The association between renal failure and foot complications is so strong that Foster and co-workers have even used the term “renal foot” (Figures 1 and 2) (Foster et al, 1995).

There are multiple possible mechanisms for the association between diabetes mellitus, renal failure and the progression of macrovascular disease, including altered function of the renin-angiotensin system, arterial hypertension and hyperlipidaemia (Hinchliffe et al, 2006). Activation of the RANKL/NF-kappaB pathway may be involved in the development of medio-calcinosis of the arterial wall (Jeffcoate, 2004), which leads to reduced vessel compliance. Large fluid shifts in patients on dialysis might lead to fluctuations in blood pressure and oedema formation altering tissue perfusion. Haemodialysis induces changes in tissue haemoglobin concentrations and microvascular compliance and may significantly affect toe pressure of the lower extremities in people with diabetes (De Blasi et al, 2009; Kay et al, 2011). Haemodialysis leads to a transient fall in transcutaneous oxygen tension in the feet (Hinchliffe et al, 2006), which might become critical in those with established PAD.

Practical tip: Bearing this in mind, great care must be taken of patients’ heels when receiving dialysis as they are often lying still on firm couches for up to 4–6 hours. Try to make it routine for patients to have their feet examined during their dialysis sessions.

Morbach et al (2001) have demonstrated that the coincidence of neuropathy and peripheral vascular disease was more common in diabetic patients on dialysis than in patients without renal impairment. This leads to higher risk of unrecognised non-healing foot lesions. Chronic non-healing foot ulcers create a state of permanent inflammation with elevated circulating levels of various inflammatory cytokines, which could contribute to the progression of kidney failure (Game et al, 2013).

Clinical tip: Ensure that all foot ulcer patients have renal function tests at least once a year.

Diabetic foot and arterial hypertension
Most of the available papers addressing the issue of arterial hypertension and its impact on diabetic foot ulcer/amputation have confirmed a negative influence of arterial hypertension on the course of diabetic foot ulceration. Arterial hypertension is reportedly associated with an increased risk for diabetic microvascular complications (Tracey et al, 2016) and has been recognised as a risk factor for lower-extremity amputation in people with diabetes (Lee et al, 1993; Zubair et al, 2012; Jeon et al, 2017). However, one study from Brazil demonstrated a lower risk for foot ulcer and amputation in those with arterial hypertension (Parisi et al, 2016). The study of Budiman-Mak et al (2016) was the first to confirm the negative influence of systolic pressure variability on the course and outcome of diabetic foot disease.

The potential mechanisms through which arterial hypertension may exert influence on foot ulcer and gangrene development may be multiple — through the influence on arterial wall stiffness (Magalháes et al, 2011), inflammatory induced intimal thickening, altered rheology and plaque formation in the lower extremities or through negative impact on renal function.

Specific evidence for the target values of blood pressure in the patients with critical limb ischaemia is lacking. Good control of hypertension is necessary to avoid the progression of macrovascular complications (stroke, myocardial infarction and congestive heart failure). Overly aggressive antihypertensive treatment, however, may decrease limb perfusion and worsen the symptoms of claudication or critical limb ischaemia, therefore, great care must be taken to ensure that the rate of blood pressure fall is controlled. Acute drops in blood pressure can even lead to the need for amputation (Gardner and Afaq, 2008; Lambert and Belch, 2013). In the retrospective study by Im et al (2016), amputation rates at 12 months after below-knee arteries interventions in patients with critical limb ischaemia were higher in those with controlled hypertension.

Clinical tip: Ensure that hypertension is optimally managed pharmacologically, give lifestyle advice and routinely take blood pressures on those attending clinics with foot ulceration and those stratified at moderate/high ulcer risk.

Diabetic foot and dyslipidaemia
Hyperlipidaemia is a significant risk factor for the progression of atherosclerosis (Beckman et al, 2002). Its role in the pathogenesis of diabetic foot complications has also been confirmed in many clinical trials and meta-analyses (Zubair et al, 2012; Pei et al, 2014). A recent publication from Japan identified high-density lipoprotein (HDL) cholesterol levels as a predictor for lower-extremity amputation in patients with diabetes and foot ulcers. The contemplation of HDL cholesterol levels as a simple marker of the nutritional status was invalidated by the fact that neither triglyceride levels nor low-density lipoprotein (LDL) cholesterol levels were predicting this endpoint (Ikura et al, 2015). Pleiotropic effects of HDL, such as anti-oxidant and anti-inflammatory properties, may play a role (Tabet and Rye, 2009). Accordingly, the study by Sohn et al (2013), which included 83,593 cholesterol drug-naive patients with type 1 or 2 diabetes, was able to demonstrate a significant association between statin use and diminished amputation risk among patients with diabetes (Sohn et al, 2013). In the patients with critical limb ischaemia, statin use after angiography or endovascular intervention was associated with decreased mortality, improved patency of the target vessels and increased likelihood of amputation-free survival (Westin et al, 2014).

Clinical tip: Ensure all patients with foot ulcers are on lipid-lowering agents and monitor their effects. Additionally, check that lifestyle education has been given and understood.

Diabetic foot and cardiovascular disease/heart failure
Patients with diabetic foot ulcers are at higher risk of all-cause mortality compared with patients with diabetes without a history of DFU. This risk is attributable, to a large extent, to a greater burden of cardiovascular disease (Brownrigg et al, 2012). DFU patients not only have a higher prevalence of previous cardiovascular morbidity than their ulcer-free counterparts, they also show a higher incidence of new onset vascular events on a 5-year follow-up (Pinto et al, 2008). Together with the high frequency of cardiovascular disease, recent reports indicate that the presence of QT interval prolongation might contribute to the increased mortality rates in patients with diabetes and foot ulcers (Fagher and Löndahl, 2013) and those suffering above-ankle amputation (Fagher et al, 2015). Many investigators claim that diabetic foot disease can be regarded as an important cardiovascular risk marker (Löndahl et al, 2008; Tuttolomondo et al, 2015). Congestive heart failure is associated with lower ulcer healing rates, as well as with lower probability of healing overall (Rhou et al, 2015), probably due to lower perfusion and oxygenation in the extremities (Figure 3). A study from China demonstrated that the prevalence of congestive heart failure in diabetic foot ulcer patients was higher than in diabetic patients without foot ulceration. Furthermore, it was worse in those with higher Wagner grade ulcers (Xu et al, 2013).

Additionally, the presence of heart failure conferred a greater increased relative risk of a worse prognosis, slower healing rates and all-cause mortality was higher in those without heart failure (Xu et al, 2013). Aggressive cardiovascular risk management has been demonstrated to reduce mortality of diabetic patients with foot ulceration (Young et al, 2008).

The mechanisms through which congestive heart failure may exert adverse effect on wound healing are unclear. Tissue ischaemia may play an important role. Congestive heart failure may act at least partly through peripheral ischaemia. Oedema associated with congestive heart failure may also be a potential contributing mechanism as it may precipitate tissue ischaemia and impair healing by increasing the distance required for diffusion of oxygen from capillaries to the ulcer, and it may reduce clearance of ulcer metabolites and degradation products from the ulcer site. Another possible mechanism contributing to the association between comorbid chronic heart failure (CHF) and ulcer healing may be renal insufficiency (Rhou et al, 2015).

Clinical tip: Patients with heart failure and lower-limb oedema should be advised to rest with elevated legs and to exercise the calf muscle pump to reduce oedema.

Diabetic foot and cerebrovascular disease
Diabetic foot problems are closely associated with cerebrovascular events. A history of cerebrovascular disease has been identified as an independent baseline predictor of diabetes-related lower-extremity amputation in a phase 1 Fremantle study (Davis et al, 2006). Transient ischaemic attacks (TIA) and ischaemic stroke are more prevalent before the onset of foot problems and on prospective evaluation (Tuttolomondo et al, 2015).

Clinical tip: Optimise protective footwear in this group of patients. Ensure that any protective footwear or insoles are regularly reviewed. This must include those with ulcers, but also moderate- to high-risk patients. Particular attention should be paid to the foot margins.

Diabetic foot and mental disorders
Foot problems are significantly associated with mental health symptoms in diabetic patients and caregivers. This may affect treatment in the foot clinic, outcome and quality of life (Hoban et al, 2015). The relationship between mental disorders and diabetic foot problems has been investigated by many. Williams et al have demonstrated that major depression is associated with a two-fold higher risk of incident diabetic foot ulcers and with a 33% higher risk of incident major lower-limb amputation in veterans with diabetes (Williams et al, 2010; 2011). In addition, Iversen et al (2015) confirmed a substantially increased risk of developing a foot ulcer in patients with symptoms of depression. In Ismail et al’s study (2007), depression was present in one third of patients with diabetes and new foot ulceration. Minor and major depressive disorders were associated with an approximately threefold hazard risk for mortality compared with no depression.

The adverse effect of depression on outcomes in patients with diabetes may not be attributed to poorer glycemic, blood pressure, or lipid control (Heckbert et al, 2010). The biologic effects of depression are multifaceted: there is evidence for a neuroendocrine link between stress, depression and diabetes mellitus — depression has been linked to hypothalamic-pituitary-adrenal axis dysregulation and sympathetic nervous system activation (Golden, 2007; Lustman et al, 2008; Lin et al, 2010). Activation of the hypothalamic–pituitary–adrenal and sympathetic–adrenal medullary axes can modulate levels of matrix metalloproteinases and, thereby, wound healing (Yang et al, 2002).

Lastly, coping style and depression influence the healing of diabetic foot ulcers and there is also a significant independent effect of patients’ illness beliefs on survival in patients with diabetic foot ulcers (Vedhara et al, 2010; 2016).

Clinical tip: Try to create a positive and friendly atmosphere in the foot ulcer clinic and use humour where possible. Patients should be treated as people not foot ulcers. Screening for depression with a simple tool is recommended.

Diabetic foot and palliative care
Comorbidities affect medicine and other treatment choices, functional status, surgical risk and quality of life. Foot ulcers and gangrene are no exception in end-of-life patients. The basic strategy in these patients must be to improve their quality of life, mainly by controlling wound-related symptoms (pain, exudate, odour and infection), providing psychological support and avoiding unnecessary procedures. Open empathic discussion with the patient and his relatives is mandatory to understand their views about the condition.

Early consultation with palliative care and pain specialists is highly recommended. Palliative care is a philosophy and a system for deciding care. In those patients where healing is unlikely, palliation can be the primary focus and can be used alone or integrated with usual chronic disease care. However, it should not be forgotten that patients who are likely to heal could still benefit from integrated palliative care (Chrisman, 2010; Dunning, 2016).

Body height, although not a comorbidity, is an independent predictor of lower-extremity amputation among patients with type 1 and type 2 diabetes (Tseng, 2006). Anaemia in patients with any condition, including diabetic foot ulceration, is associated with higher mortality, predominantly from infections (Almoznino-Sarafian et al, 2010), although not substantially proven may affect tissue oxygenation.

The role of nutrition in wound healing deserves special attention, since poor/malnutrition may affect immune system, collagen synthesis and wound tensile strength. Good quality randomised studies addressing this topic are scarce and direct benefit of use of nutritional supplements in human wound healing is not evidence based. Nevertheless, evaluation of patient’s nutritional status is recommended and a balanced diet providing sufficient caloric (30–35 or even 40 kcal/kg) and fluid intake, as well as vitamins and minerals should be given (Maier et al, 2013; Quain and Khardori, 2015; Molnar et al, 2016).

Obesity in diabetic patients is associated with increased prevalence of foot ulcers (Vela et al, 1998; Sohn et al, 2011), the mechanism is unclear. In contrast to this, the risk of amputation is higher for non-elderly male patients with body mass index (BMI) <25 kg/m2 compared to overweight individuals (BMI 25–29.9 kg/m2), and lower for those with BMI ≥30 kg/m2. While the amputation risk continues to decrease for higher BMI, amputation-free survival shows a slight upturn at BMI >40 kg/m2 (Sohn et al, 2012). A more recent study investigated the effect of limb preservation status and BMI on the survival of patients with limb-threatening diabetic foot ulcers. Median survival time had positive correlation with BMI levels for patients with limb-preserved and minor lower-extremity amputation, but not for those with major LEA (Lin et al, 2017).

Finally, a study from Canada demonstrated that obesity does not appear to significantly impact inpatient amputation rehabilitation outcomes and, as such, should not be a deciding factor as to whether a patient is offered rehabilitation or not (Vivas et al, 2017). This association between obesity and amputation risk, amputation rehabilitation outcome and survival of patients with limb-threatening diabetic foot ulcers shows a pattern consistent with the ‘obesity paradox’ — fitness beats fatness — observed in many other health conditions.

Untreated severe obstructive sleep apnea has been demonstrated to delay ulcer healing due to prolonged overnight hypoxemia (Vas et al, 2016).

A problem that is all too often overlooked are polypharmacy and drug interactions, in particular, between antibiotics, anticoagulants and statins. These may result either in increased activity of the latter with bleeding complications or in diminished activity with resulting thrombo-embolic complications.

Conclusions and recommendations
Management of patients with diabetes and foot ulceration is a demanding task requiring a dedicated, well-coordinated and skilled interdisciplinary team. Special attention should be paid to the patients with renal impairment, in particular, to those with ESRD on haemodialysis and renal transplant patients. Foster et al have demonstrated decreased prevalence of gangrene and a fall in amputation rate in renal transplant patients after the introduction of a special foot clinic (Foster et al, 1995). Marn Pernat et al (2016) have demonstrated improved outcomes after implementation of routine foot check in patients with diabetes on haemodialysis. Good glycaemic regulation, treatment of hypertension and dyslipidaemia are the cornerstones of the holistic approach to the patient. Psychological problems should not be overlooked, and patient preferences and priorities never be neglected. Thus, clinicians should remember to ‘treat the whole patient not just the hole in the patient’.


Almoznino-Sarafian D, Shteinshnaider M, Tzur I et al (2010) Anemia in diabetic patients at an internal medicine ward: clinical correlates and prognostic significance. Eur J Intern Med 21(2): 91–6 
Alonso-Morán E, Orueta JF, Fraile Esteban JI et al (2014) The prevalence of diabetes-related complications and multimorbidity in the population with type 2 diabetes mellitus in the Basque Country. BMC Public Health 14: 1059
Apelqvist J, Elgzyri T, Larsson J et al (2011) Factors related to outcome of neuroischemic / ischemic foot ulcer in diabetic patients. J Vasc Surg 53(6): 1582–8
Armstrong DG, Wrobel J, Robbins JM (2007) Guest Editorial: are diabetes-related wounds and amputations worse than cancer? Int Wound J 4(4): 286–7
Barshes NR, Sigireddi M, Wrobel JS et al (2013) The system of care for the diabetic foot: objectives, outcomes, and opportunities. Diabet Foot Ankle 10: 4 doi: 10.3402/dfa.v4i0.21847
Beckman JA, Creager MA, Libby P (2002) Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA287(19): 2570–81
Begun A, Morbach S, Rümenapf G, Icks A (2016) Study of Disease Progression and Relevant Risk Factors in Diabetic Foot Patients Using a Multistate Continuous-Time Markov Chain Model. PLoS One 11(1): e0147533
Brownrigg JR, Davey J, Holt PJ et al (2012) The association of ulceration of the foot with cardiovascular and all-cause mortality in patients with diabetes: a meta-analysis. Diabetologia 55(11): 2906–12
Bruun C, Siersma V, Guassora AD et al (2013) Amputations and foot ulcers in patients newly diagnosed with type 2 diabetes mellitus and observed for 19 years. The role of age, gender and co-morbidity. Diabet Med 30(8): 964–72
Budiman-Mak E, Epstein N, Brennan M et al (2016) Systolic blood pressure variability and lower extremity amputation in a non-elderly population with diabetes. Diabetes Res Clin Pract 114: 75–82
Choi MS, Jeon SB, Lee JH (2014) Predictive factors for successful limb salvage surgery in diabetic foot patients. BMC Surg 14: 113
Chrisman CA (2010) Care of chronic wounds in palliative care and end-of-life patients. Int Wound J 7(4): 214–35
Davis WA, Norman PE, Bruce DG, Davis TM (2006) Predictors, consequences and costs of diabetes-related lower extremity amputation complicating type 2 diabetes: the Fremantle Diabetes Study. Diabetologia 49(11): 2634–41
De Blasi RA, Luciani R, Punzo G et al (2009) Microcirculatory changes and skeletal muscle oxygenation measured at rest by non-infrared spectroscopy in patients with and without diabetes undergoing haemodialysis. Crit Care 13(Suppl 5): S9
Deckert T, Yokoyama H, Mathiesen E et al (1996) Cohort study of predictive value of urinary albumin excretion for atherosclerotic vascular disease in patients with insulin dependent diabetes. BMJ 312(7035): 871–4
Dunning T (2016) Integrating palliative care with usual care of diabetic foot wounds. Diabetes Metab Res Rev 32(Suppl 1): 303–10
Fagher K, Löndahl M (2013) The impact of metabolic control and QTc prolongation on all-cause mortality in patients with type 2 diabetes and foot ulcers. Diabetologia 56(5): 1140–7
Fagher K, Nilsson A, Löndahl M (2015) Heart rate-corrected QT interval prolongation as a prognostic marker for 3-year survival in people with Type 2 diabetes undergoing above-ankle amputation. Diabet Med 32(5): 679–85
Farmer C, Fenu E, O’Flynn N, Guthrie B (2016) Clinical assessment and management of multimorbidity: summary of NICE guidance. BMJ 354: i4843
Foster AV, Snowden S, Grenfell A et al (1995) Reduction of gangrene and amputations in diabetic renal transplant patients: the role of a special foot clinic. Diabet Med 12(7): 632–5
Game FL, Selby NM, McIntyre CW (2013) Chronic kidney disease and the foot in diabetes–is inflammation the missing link? Nephron Clin Pract 123(1-2): 36–40
Gardner AW, Afaq A (2008) Management of lower extremity peripheral arterial disease. J Cardiopulm Rehabil Prev 28(6): 349–57
Gilhotra RA, Rodrigues BT, Vangaveti VN, Malabu UH (2016) Prevalence and Risk Factors of Lower Limb Amputation in Patients with End-Stage Renal Failure on Dialysis: A Systematic Review. Int J Nephrol 2016: 4870749
Glaser JD, Bensley RP, Hurks R et al (2013) Fate of the contralateral limb after lower extremity amputation. J Vasc Surg 58(6): 1571–7
Goldberg JB, Goodney PP, Cronenwett JL, Baker F (2012) The effect of risk and race on lower extremity amputations among Medicare diabetic patients. J Vasc Surg 56(6): 1663–8
Golden SH (2007) A review of the evidence for a neuroendocrine link between stress, depression and diabetes mellitus. Curr Diabetes Rev 3(4): 252–9
Heckbert SR, Rutter CM, Oliver M et al (2010) Depression in relation to long-term control of glycemia, blood pressure, and lipids in patients with diabetes. J Gen Intern Med 25(6): 524–9
Hinchliffe RJ, Kirk B, Bhattacharjee D et al (2006) The effect of haemodialysis on transcutaneous oxygen tension in patients with diabetes-a pilot study. Nephrol Dial Transplant 21(7): 1981–3
Hoban C, Sareen J, Henriksen CA et al (2015) Mental health issues associated with foot complications of diabetes mellitus. Foot Ankle Surg 21(1): 49–55
Hoffstad O, Mitra N, Walsh J, Margolis DJ (2015) Diabetes, lower-extremity amputation, and death. Diabetes Care 38(10): 1852–7
Hinchliffe RJ, Jeffcoate WJ, Game FL (2006) Diabetes, established renal failure and the risk to the lower limb. Practical Diabetes Int 23(1): 28–32
Ikura K, Hanai K, Shinjyo T, Uchigata Y (2015) HDL cholesterol as a predictor for the incidence of lower extremity amputation and wound-related death in patients with diabetic foot ulcers. Atherosclerosis 239(2): 465–9
Im SI, Rha SW, Choi BG et al (2016) Impact of uncontrolled hypertension on 12-month clinical outcomes following below-the-knee arteries (BTK) interventions in patients with critical limb ischemia. Clin Hypertens 22: 9
Ismail K, Winkley K, Stahl D et al (2007) A cohort study of people with diabetes and their first foot ulcer: the role of depression on mortality. Diabetes Care 30(6): 1473–9
Iversen MM, Tell GS, Espehaug B et al (2015) Is depression a risk factor for diabetic foot ulcers? 11-years follow-up of the Nord-Trøndelag Health Study (HUNT). J Diabetes Complications 29(1): 20–5
Jaar BG, Astor BC, Berns JS, Powe NR (2004) Predictors of amputation and survival following lower extremity revascularization in hemodialysis patients. Kidney Int 65(2): 613–20
Jeffcoate W (2004) Vascular calcification and osteolysis in diabetic neuropathy-is RANK-L the missing link? Diabetologia 47(9): 1488–92
Jeon BJ, Choi HJ, Kang JS et al (2017) Comparison of five systems of classification of diabetic foot ulcers and predictive factors for amputation. Int Wound J 14(3): 537–45
Kaminski MR, Raspovic A, McMahon LP et al (2015) Risk factors for foot ulceration and lower extremity amputation in adults with end-stage renal disease on dialysis: a systematic review and meta-analysis. Nephrol Dial Transplant 30(10): 1747–66
Kay DB, Ray S, Haller NA, Hewit M (2011) Perfusion pressures and distal oxygenation in individuals with diabetes undergoing chronic hemodialysis. Foot Ankle Int 32(7): 700–3
Lambert MA, Belch JJ (2013) Medical management of critical limb ischaemia: where do we stand today? J Intern Med 274(4): 295–307
Lee JS, Lu M, Lee VS et al (1993) Lower-extremity amputation. Incidence, risk factors, and mortality in the Oklahoma Indian Diabetes Study. Diabetes 42(6): 876–82
Lin EH, Rutter CM, Katon W et al (2010) Depression and advanced complications of diabetes: a prospective cohort study. Diabetes Care 33(2): 264–9
Lin CW, Hsu BR, Tsai JS et al (2017) Effect of limb preservation status and body mass index on the survival of patients with limb-threatening diabetic foot ulcers. J Diabetes Complications 31(1): 180–5
Löndahl M, Katzman P, Fredholm O et al (2008) Is chronic diabetic foot ulcer an indicator of cardiac disease? J Wound Care17(1): 12–6
Luke RG (1998) Chronic renal failure — a vasculopathic state. N Engl J Med 339(12): 841–3
Lustman PJ, Penckofer SM, Clouse RE (2008) Recent advances in understanding depression in adults with diabetes. Curr Diab Rep 7(2): 114–22
Magalhães P, Capingana DP, Silva AB et al (2011) Arterial stiffness in lower limb amputees. Clin Med Insights Circ Respir Pulm Med 5: 49–56
Maier HM, Ilich JZ, Kim JS, Spicer MT (2013) Nutrition supplementation for diabetic wound healing: a systematic review of current literature. Skinmed 11(4): 217–24
Marn Pernat A, Peršič V, Usvyat L et al (2016) Implementation of routine foot check in patients with diabetes on haemodialysis: associations with outcomes. BMJ Open Diabetes Res Care 4(1): e000158
McGrath NM, Curran BA (2000) Recent commencement of dialysis is a risk factor for lower-extremity amputation in a high-risk diabetic population. Diabetes Care 23(3): 432–3
Molnar JA, Vlad LG, Gumus T (2016) Nutrition and Chronic Wounds: Improving Clinical Outcomes. Plast Reconstr Surg 138(3 Suppl): 71S–81S
Morbach S, Quante C, Ochs HR et al (2001) Increased risk of lower-extremity amputation among Caucasian diabetic patients on dialysis. Diabetes Care 24(9): 1689–90
Morbach S, Furchert H, Gröblinghoff U et al (2012) Long-term prognosis of diabetic foot patients and their limbs: amputation and death over the course of a decade. Diabetes Care 35(10): 2021–7
NICE (2016) Multimorbidity: Clinical Assessment and Management (NICE guideline NG56). Available at: (accessed 16.10.2017)
O’Hare AM, Hsu CY, Bacchetti P, Johansen KL (2002) Peripheral vascular disease risk factors among patients undergoing haemodialysis. J Am Soc Nephro 13(2): 497–503
Parisi MC, Moura Neto A, Menezes FH et al (2016) Baseline characteristics and risk factors for ulcer, amputation and severe neuropathy in diabetic foot at risk: the BRAZUPA study. Diabetol Metab Syndr 8: 25
Pei E, Li J, Lu C et al (2014) Effects of lipids and lipoproteins on diabetic foot in people with type 2 diabetes mellitus: a meta-analysis. J Diabetes Complications 28(4): 559–64
Pinto A, Tuttolomondo A, Di Raimondo D et al (2008) Cardiovascular risk profile and morbidity in subjects affected by type 2 diabetes mellitus with and without diabetic foot. Metabolism 57(5): 676–82
Prompers L, Huijberts M, Apelqvist J et al (2007) High prevalence of ischaemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study. Diabetologia 50(1): 18–25
Quain AM, Khardori NM (2015) Nutrition in Wound Care Management: A Comprehensive Overview. Wounds 27(12): 327–35
Rhou YJ, Henshaw FR, McGill MJ, Twigg SM (2015) Congestive heart failure presence predicts delayed healing of foot ulcers in diabetes: An audit from a multidisciplinary high-risk foot clinic. J Diabetes Complications 29(4): 556–62
Sohn MW, Budiman-Mak E, Lee TA et al (2011) Significant J-shaped association between body mass index (BMI) and diabetic foot ulcers. Diabetes Metab Res Rev 27(4): 402–9
Sohn MW, Budiman-Mak E, Oh EH et al (2012) Obesity paradox in amputation risk among nonelderly diabetic men. Obesity (Silver Spring) 20(2): 460–2
Sohn MW, Meadows JL, Oh EH et al (2013) Statin use and lower extremity amputation risk in nonelderly diabetic patients. J Vasc Surg 58(6): 1578–85
Tabet F, Rye KA (2009) High-density lipoproteins, inflammation and oxidative stress. Clin Sci (Lond) 116(2): 87–98
Tracey ML, McHugh SM, Fitzgerald AP et al (2016) Risk factors for macro- and microvascular complications among older adults with diagnosed type 2 diabetes: findings from the Irish longitudinal study on ageing. J Diabetes Res 2016: 5975903
Tseng CL, Rajan M, Miller DR et al (2005) Use of administrative data to risk adjust amputation rates in a national cohort of medicare-enrolled veterans with diabetes. Med Care 43(1): 88–92
Tseng CH (2006) Prevalence of lower-extremity amputation among patients with diabetes mellitus: is height a factor? CMAJ174(3): 319–23
Tuttolomondo A, Maida C, Pinto A (2015) Diabetic foot syndrome as a possible cardiovascular marker in diabetic patients. J Diabetes Res 2015: 268390
Vas PR, Ahluwalia R, Manas AB et al (2016) Undiagnosed severe sleep apnoea and diabetic foot ulceration – a case series based hypothesis: a hitherto under emphasized factor in failure to heal. Diabet Med 33(2): e1–4
Vedhara K, Miles JN, Wetherell MA et al (2010) Coping style and depression influence the healing of diabetic foot ulcers: observational and mechanistic evidence. Diabetologia 53(8): 1590–8
Vedhara K, Dawe K, Miles JN et al (2016) Illness beliefs predict mortality in patients with diabetic foot ulcers. PLoS One 11(4): e0153315
Vela SA, Lavery LA, Armstrong DG, Anaim AA (1998) The effect of increased weight on peak pressures: implications for obesity and diabetic foot pathology. J Foot Ankle Surg 37(5): 416–20
Vivas LL, Pauley T, Dilkas S, Devlin M (2017) Does size matter? Examining the effect of obesity on inpatient amputation rehabilitation outcomes. Disabil Rehabil 39(1): 36–42
Westin GG, Armstrong EJ, Bang H et al (2014) Association between statin medications and mortality, major adverse cardiovascular event, and amputation-free survival in patients with critical limb ischemia. J Am Coll Cardiol 63(7): 682–90
Williams LH, Rutter CM, Katon WJ et al (2010) Depression and incident diabetic foot ulcers: a prospective cohort study. Am J Med123(8): 748–54
Williams LH, Miller DR, Fincke G et al (2011) Depression and incident lower limb amputations in veterans with diabetes. J Diabetes Complications 25(3): 175–82
Xu L, Qian H, Gu J et al (2013) Heart failure in hospitalized patients with diabetic foot ulcers: clinical characteristics and their relationship with prognosis. J Diabetes 5(4): 429–38 
Yang EV, Bane CM, MacCallum RC et al (2002) Stress-related modulation of matrix metalloproteinase expression. J Neuroimmunol 133(1-2): 144–50
Young MJ, McCardle JE, Randall LE, Barclay JI (2008) Improved survival of diabetic foot ulcer patients 1995-2008: possible impact of aggressive cardiovascular risk management. Diabetes Care 31(11): 2143–7
Zubair M, Malik A, Ahmad J (2012) Incidence, risk factors for amputation among patients with diabetic foot ulcer in a North Indian tertiary care hospital. Foot (Edinb) 22(1): 24–30

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