Örebro University
School of Medical Sciences Degree project, 30 ECTS May 2016
Risk factors to major lower extremity
amputation in type 2 diabetes mellitus
Version 2
Author: Emma Melander, Bachelor of Medicine Supervisor: Stefan Jansson, MD, PhD, University Health Care Research Center, Region Örebro County. School of Medical Sciences, Örebro University, Sweden.
Abstract
BackgroundAccording to national surveys Örebro County Council have higher frequency of amputations among type 2 diabetes mellitus (T2DM) patients compared with other county councils. The aim of this study was to identify risk factors that contributed to the endpoint major lower extremity amputation (LEA) among patients with T2DM in Region Örebro County compared to a control group. A second aim was to examine the amount of health care patients with diabetes and foot ulcers utilize between baseline and endpoint.
Material and Methods
A retrospective study in which the medical records of all patients with T2DM that underwent major lower extremity amputation at Örebro University Hospital between 1 January 2012 and 31 December 2014 were scrutinized.
Results
A total of 55 patients were amputated during the study and a majority were men.
Out of those 55, 17 were matched to controls. Compared to the control group patients with an amputation had non-significant trends towards a higher age (P=0.09) and a longer diabetes duration (P=0.24). Patients with an amputation spent an average of 151.8 (±149.7) days as outpatients regarding the foot ulcer leading to amputation. The corresponding number among the non-amputated patients was 471.1 (±769.5) days. A higher percentage of the patients in the non-amputated group had lipid lowering medication.
Conclusion
The findings in this study indicate trends towards that age and diabetes duration are risk factors to major LEA. It also infers that patients with diabetes and foot ulcers are a patient group that requires a lot of health care in general.
Contents
Abbreviations ... 1
Introduction ... 2
Material and Methods ... 4
Statistics ... 6 Ethical considerations ... 6 Results ... 7 Discussion ... 12 Acknowledgements ... 15 References ... 16
Abbreviations
T2DM Type 2 Diabetes Mellitus CVD Cardiovascular Disease PAD Peripheral Arterial Disease
LEA Lower Extremity Amputation
HRQoL Health Related Quality of Life PHCC Primary Health Care Center
BMI Body Mass Index
HbA1c Haemoglobin A1c
LDL-cholesterol Low Density Lipoprotein cholesterol eGFR Estimated Glomerular Filtration Rate
CRP C-Reactive Protein
DVT Deep Vein Thrombosis
SGLT-2 Sodium-Glucose Cotransporter 2 inhibitors GLP-1 Glucagon Like Peptide 1
DPP4 Dipeptidyl Peptidase 4
RAAS Renin Angotensin Aldosterone System ACE Angiotensinogen Converting Enzyme ARB Angiotensinogen Receptor Blockers
ABI Ankle Brachial Index
PTA Percutaneous Trans luminal Angioplasty NDR National Diabetes Register
Introduction
With a prevalence in Sweden of 5 percent, Type 2 Diabetes Mellitus (T2DM) is considered a national disease [1]. T2DM is a metabolic disease where the metabolism of fats, proteins and carbohydrates is altered [2]. Defects in insulin secretion and/or increased insulin resistance lead to elevated plasma glucose levels [3]. People with T2DM often suffer from hypertension, dyslipidaemia and hyperglycaemia, which in turn increase the risk of cardiovascular diseases (CVD) [2-4]. Another important risk factor for CVD among T2DM-patients is smoking since smoking enhances dyslipidaemia and affects the lipid deposit in arterial walls [5].
Hyperglycaemia contributes to the development of microvascular complications such as retinopathy, nephropathy and diabetic neuropathy. Diabetic neuropathy is implied to have a complex pathogenesis and the level of hyperglycaemia is thought to have great significance [3]. Neuropathy in sensorineural nerves is associated to defects in the sensation of
temperature, pressure, and proprioception. This makes the diabetic foot susceptible to pressure and/or mechanical trauma from e.g. ill-fitting shoes. Small foot trauma and deformity together with neurological abnormalities such as peripheral neuropathy and vascular disease with decreased tissue perfusion are important factors to the development of foot ulcers [6]. Healing rates of foot ulcers are lower in patients with peripheral arterial disease (PAD) and it has been implied that healing predictors diverges between T2DM-patients with and without PAD. It has been adverted that infection, a central predictor to ulcer healing, is only prognostic in patients with PAD. Hence, PAD and infection are suggested as two major predictors of foot ulcer healing [7]. A foot ulcer that progresses into severe infection or gangrene precedes 85% of all amputations among patients with diabetes [6]. Patients with diabetes have higher amputation levels compared to individuals without diabetes and the amputation rate is higher among men compared to women [8]. Suggested as
independent predictors of amputation are depth of ulcer, gangrene, limb ischemia and osteomyelitis [9].
Studies have suggested that multidisciplinary teams are valuable in optimizing treatment and screening for diabetes complications [8]. To prevent complications such as diabetic foot ulcers, nurse-based foot care programmes have been suggested as a valuable component [10]. Suggested as important risk factors that prevention strategies should aim are foot mycoses, peripheral vascular disease and previous foot ulcers [11]. Against diabetic foot ulcers have the
usage of statins shown protective effects [12]. Statins has also indicated positive effects on amputation-free survival and lower risk of lower extremity amputation (LEA) [13].
Prescription and usage of orthoses is suggested an important component in preventing foot ulcers [14]. In reducing relapse of plantar ulcers have patient-specific orthoses constructed from bare-foot plantar pressure and foot shape been suggested to be superior orthoses constructed after clinic and foot shape. They have however not been implied to reduce the occurrence of nonulcerative lesions [15]. To significantly reduce the risk for ulceration it has been implied to be of great importance that the patient-specific offloading improved footwear is worn as recommended when compared to footwear without offloading improvement [16]. Interventions regarding foot self-care have indicated effectiveness in avoiding incidence of minor foot problems [17].
Foot ulcers are implied to be associated with a low health-related quality of life (HRQoL). To improve HRQoL treatment should, beyond wound care, PAD and infection, also be focused on pain medication, moderation of long periods of mobility restriction, physiotherapy to improve motility and offloading with the lowest negative effect on motility [18]. It is indicated that walking performance, function and physical fitness declines together with progression of foot ulcers [19]. Foot ulceration could be initiated by changed plantar pressure due to altered gait and amount of walking, it is hence suggested to be of great importance to protect the surviving foot after LEA [20]. It has been implied that improving patient illness beliefs could improve foot self-care and ulcer outcomes [21].
According to The National Board of Health and Welfare’s surveys Örebro County Council have higher frequency of amputations among T2DM-patients compared with other county councils [22]. The aim of this study was to identify factors that contributed to the end point major LEA among T2DM-pateints in Örebro County Council, compared to control cases. A second aim was to examine the amount of health care patients with diabetes and foot ulcers utilize between baseline and endpoint.
Material and Methods
In this study patients with diabetes that underwent LEA between 1 January 2012 and 31 December 2014 in Region Örebro County were found using the Swedish Classification of Health Interventions (KVÅ) codes. KVÅ codes for exarticulation in knee joint (NGQ09), transtibial amputation (NGQ19), other amputation or related surgery of knee or lower limb (NGQ99), exarticulation in hip joint (NFQ09), transfemoral amputation (NFQ19) and other amputation or related surgery of hip or upper leg (NFQ99) was chosen. These KVÅ codes together with the International Statistical Classification of Diseases and Related Health Problems (ICD-10) codes for diabetes (E10-E14) and amputation indications such as
atherosclerosis in extremity arteries (I70.2) other indications was embolus and thrombosis in lower extremity arteries (I74.3), cellulitis, unspecified (L03.9) and infection and inflammation caused by internal joint prosthesis (T84.5) were used to find the patients from the orthopaedic records at Örebro University Hospital, Karlskoga Hospital and Lindesbergs Hospital. To not miss any individuals, all patients that underwent LEA during the study time were double checked if having a diabetes diagnosis by controlling their primary health care centre (PHCC) and/or hospital records. A total of 98 patients with a diabetes diagnosis that had undergone LEA were found. Since the study took place in Örebro, the patients amputated at Örebro University Hospital were chosen, a total of 70 patients. Out of these, 15 patientswere
excluded. Exclusion criteria was having type1 diabetes, having the T2DM diagnosis later than the foot ulcer leading to amputation, having a false T2DM diagnosis from the orthopaedics and amputation due to an ill functioning arthrodesis. A total of 55 patients remained.
Baseline variables
Baseline was set as the date with the first written notation in medical records, at hospital or PHCC, regarding beginning of the foot ulcer, or ischemia, leading to the end point LEA. A majority was found in PHCC´s records. Ischemia was defined as sudden critical ischemia, changed patterns of earlier ischaemic pain that made the patient search health care and/or when stronger pain medications were prescribed.
For each patient, records from hospital clinics and PHCC were controlled and baseline data about gender, age, type of diabetes, diabetes duration, earlier foot wounds defined as any earlier medical record regarding earlier foot ulcers and debut date of foot ulcer, or ischemia, leading to amputation. Risk factors at baseline such as smoking, weight, length, Body Mass Index (BMI) and blood pressure were assembled. Baseline laboratory data such as Hb,
HbA1c, Low Density Lipoprotein (LDL) cholesterol, estimated Glomerular Filtration Rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) equation, creatinine, albumin/creatinine-index and C-Reactive Protein (CRP), were collected. Records were searched for comorbidities at baseline such as hypertonia, earlier cerebral vascular lesions, ischemic heart disease, undergone coronary artery bypass grafting or percutaneous coronary intervention and retinopathy.
Medical treatment and utilized health care
Medical treatment at baseline regarding lipid lowering medication, diabetes medications, antihypertensive treatment, diuretics and anti-coagulants was collected. Data regarding if any antibiotics courses were prescribed together with whether any microbiological samples were taken at baseline was noted.
The latest values of ankle brachial index (ABI) and toe pressure before amputation was collected together with data whether any vascular surgery was performed between baseline and endpoint, or earlier.
Number of doctors and nurse visits in PHCC, number of visited doctors and number of visited nurses in PHCC, number of doctors and nurse visits at hospital, number of visited doctors and nurses at hospital, number of hospitalizations, number of days as an inpatient and number of days as an outpatient were noted. Data about which medical specialists was visited/consulted regarding dermatologists, cardiologist, orthopaedist, infection specialist, thoracic and vascular surgeons and orthopaedic technicians that were visited/consulted because of the foot
ulcer/ischemia during the study time was collected.
Control patients
Controls were found using the Swedish National Diabetes Register (NDR). They were found using the NDR´s search function and searches were made regarding each PHCC with
amputated patients. Variables were set to T2DM and risk category foot, which was set to earlier diabetic foot wound or on-going severe foot disease. Control patients were matched to the index patients regarding which PHCC they belonged to, gender and occurrence of foot ulcers. Baseline was set to debut date of foot ulcer that healed and end point was set to the last written record about the wound that healed. They were then checked for the same data as the index patients.
We created a risk score to do comparisons between the groups. One point for each: Diabetes duration >15 years, HbA1c >55 mmol/mol, systolic blood pressure >140 mmHg, LDL-cholesterol >2.5 mmol/L, smoking habits (never smoker 0p, former smoker 1p and current smoker 2p), CVD (earlier myocardial infarction, cerebrovascular lesion, retinopathy or albumin-creatinine-ratio >2.5 g/mol), lipid lowering medication and age >75 years. Statistics
All data were analysed using SPSS version 22 (IBM, Armonk, NY, USA). Simple statistics, such as mean values and standard deviations, was used to describe the patient groups. Logistic regression was used to perform comparisons regarding the created risk score. To enable statistical calculations regarding the risk factor smoking, former and current smokers were put together and counted as one group. Chi-Square test was used to perform calculations regarding lipid-lowering medication and T-Test was used to perform calculations regarding differences in age and diabetes duration. P-values below 0.05 were regarded as statistically significant.
Ethical considerations
The Regional Ethical Review Board in Uppsala, Dnr 2016/035, approved the study. This study is a retrospective record review and hence no patients were contacted, the study is also a part of the internal work to improve medical quality.
Results
A total of 55 patients underwent major LEA during the study. Twice as many men as women were amputated during the studied time. Women and men had a mean age of 79.5 and 74.6 years respectively, a non-significant age differences (P=0.051). Women and men had mean diabetes duration of 19.5 and 15.9 years, respectively, but when comparing differences in diabetes duration between the groups the results were non-significant (P=0.24). Baseline data is shown in Table 1. Out of these, 16 were amputated due to ischemia and 39 due to a foot ulcer. The group amputated due to ischemia spent an average of 40.1 (± 19.5) days as
inpatients and 41.7 (±72.0) days as outpatients. The group amputated due to a foot ulcer spent an average of 50.6 (±40.2) as inpatients and 167.8 (±163.2) days as outpatients.
Seventeen control patients were matched to the patients amputated due to a foot ulcer. Baseline data for amputated patients and non-amputated patients is shown in Table 2. The patients in the amputated group were non-significantly (P=0.09) older than the patients in the non-amputated group, 78.5 years and 73.5 years respectively. The patients in the amputated group had a non-significant (P=0.24) longer diabetes duration compared to the patients in the non-amputated group, 15.8 years compared to 12.1 years respectively. As also seen in this table, a non-significant (P=0.11) higher percentage of the patients in the non-amputated group had lipid lowering medication compared to the patients in the amputated group. The LDL-cholesterol values were however the same between the two groups.
The non-amputated patients spent more than three times as much time as outpatients and visited nurses at PHCC twice as much as the amputated group. Number of hospital and PHCC visits, visited staff and time spent as an out- and inpatient is shown in Table 3.
Among the patients in the amputated group, 12 (70.6%) (one missing) had have foot ulcers before the ulcer related to this study. The corresponding number among non-amputated patients was 14 (82.4%) (three missing). ABI was found in eight amputated patients and the mean value was 0.38 (±0.20) compared to six of the non-amputated patients with a mean value of 0.67 (±0.19). Among the amputated patients, 15 had their toe pressure measured and their mean value was 34.1 (±20.5) mmHg compared to 66.5 (±39.5) mmHg among the 12 non-amputated patients that had been measured. Among the amputated patients, eight (47.1%) had vascular surgery done between baseline and endpoint. Among the non-amputated
patients, three (17.6%) hade some kind of vascular surgery done due to the foot ulcer between baseline and endpoint and three (17.6%) had gone through vascular surgery before the
beginning of the foot ulcer in this study. In both groups, the majority of performed surgeries were PTA.
Of the amputated patients, five (29.4%) had a microbiological sample taken at baseline and among the non-amputated this number was three (17.6%). Of the amputated patients, 16 (94.1%) had at least one cure of antibiotics prescribed and among the non-amputated, 11 (64.7%) had at least one antibiotics cure prescribed. Among the amputated patients, four had
a CRP taken at baseline, mean value 43.5 (±48.5) mg/L and among the non-amputated patients one had a CRP taken and it was 200 mg/L.
In both groups, one (5.9%) patient was examined by a dermatologist between baseline and endpoint. An infection specialist examined 15 (88.2%) of the amputated patients and eight (47.1%) of the non-amputated patients. Among the amputated individuals, 15 (88.2%) were examined by a vascular surgeon and the corresponding number among the non-amputated individuals was eight (47.1%). A cardiologist examined four (23.5%) of the amputated patients, compared to one (5.9%) among the non-amputated patients. Among the amputated individuals, 17 (100%) were examined by an orthopedic surgeon compared to three (17.6%) among the non-amputated individuals. In both groups eight (47.1%) patients were examined by an orthopedic engineer at some point between baseline and endpoint.
Risk score for the two groups is shown in Table 4. More patients in the amputated group were above 75 years of age, the group also had more patients with CVD. The only current smokers were in the non-amputated group. Statistical calculations regarding comparisons between the groups are shown in Table 5. This shows a trend towards that age is an important risk factor. Multivariable statistical analyses were performed but none of them showed significant results.
Discussion
The findings in this study indicate non-significant trends towards that age and diabetes
duration are risk factors to major LEA. It also infers that patients with diabetes and foot ulcers are a patient group that requires a lot of health care in general. The study furthers implies a trend towards that lipid lowering medication lowers the risk for LEA but neither these results were significant.
This study showed that LEA is more common among male T2DM-patients, which is also suggested by other studies [23]. In our study the men that underwent amputation have had a shorter T2DM-duration and they were also younger than the women that underwent
amputation. Age, HbA1c and systolic blood pressure are indicated to be important risk factors for LEA for both men and women according to earlier studies [24]. Studies have implied that it is not always “the lower the better” that applies regarding e.g. blood pressure and HbA1c. Lower values might result in fewer micro- and macrovascular complications but on the other hand risk more falls due to hypotension and more hypoglycaemias due to glucose lowering agents. Hence, individual goals should be considered [4].
When comparisons are made between the patients in the amputated and non-amputated groups it is indicated that the individuals in the amputated group are older and had longer diabetes duration. Increased duration of T2DM is implied to increase the risk for amputation in both men and women according to earlier studies [24]. Earlier studies have also implied that inpatients with diabetes and PAD have a bad prognosis regarding LEA and the prognosis is suggested to be especially bad for the patients with diabetic foot syndrome [25] . Our study points in the same direction since the amputated group spent more time as inpatients than the non-amputated group. These data should be considered with the knowledge that this data also contains days as an inpatients after the amputation until discharge from the hospital. The patients that did not get amputated spent more time as outpatients regarding their foot ulcer and they visited nurses at their PHCC more than twice as much as the patients that got amputated. This could imply that diabetes patients with foot ulcers are a patient group that requires a lot of health care in general. There are costs in resources, as in many visits at PHCC and additional work, to prevent the foot ulcer to progress to the point where major LEA is necessary. However, there are also costs for the patient since an amputation affects life quality and HRQoL. Other studies have implied that suffering from a chronic foot ulcer is associated to the same amount of impact on life quality as an amputation [26].
When the HbA1c-levels are compared between the groups it is suggested that the patients in the amputated group had lower HbA1c-levels than the patients in the control group. This could depend on the fact that in both groups a majority of the individuals had have a foot ulcer before the ulcer followed in this study which could have influenced the treatment and therapy regarding glucose metabolism among the patients. Hence it is possible that the patients in the amputated group had lower HbA1c-levels since they may have been more aggressively treated regarding this cardiovascular risk factor.
Earlier studies have shown favourable effects of lipid-lowering medication when it comes to amputation free survival and statins have been associated with lower risk of LEA [13]. Patients with a statin as their lipid-lowering medication also reach their treatment goals regarding LDL-cholesterol more frequently compared to patients with other lipid lowering medications, such as fibrates [27]. In this study there is a trend that points in the same direction since 15 of the patients in the non-amputated group had lipid-lowering treatment compared to 11 of the patients in the amputated group. Both groups have the same mean LDL-cholesterol value.
Ischemic heart disease, stroke and retinopathy are suggested to be more common in the amputated group compared to the non-amputated group. This could indicate that the amputated individuals are suffering from a more severe form of diabetes than the non-amputated group. Earlier studies have pointed in the same direction and suggested that more cardiovascular complications are associated to major LEA [28]. Other studies have also found associations between retinopathy and cardiovascular complications such as LEA [29].
The amputated group had a higher albumin-creatinine-ratio and lower eGFR than the non-amputated group. When comparing anti hypertensive treatment between the groups beta-blockers is the most common antihypertensive drug among the amputated group while Renin-Angiotensin-Aldosterone System inhibitors is the most common antihypertensive treatment among the non-amputated group. In both groups, diuretics are the second most common antihypertensive treatment. In preventing CVD among T2DM-patients have ACE-inhibitors been suggested to be superior other antihypertensive drugs, such as beta-blockers and
antihypertensive drugs, regardless of class, are effective in preventing CVD among T2DM-patients [31].
Increased levels of smoking are implied to be related with an increased risk for LEA,
especially in women, according to earlier studies [24]. The only current smokers in this study were in the non-amputated group but since they were only two people in this very little group it is impossible to make any conclusion from this finding.
Strengths and limitations
Strengths in this study are that all T2DM-patients that went through LEA during the studied time are included. We got a wide set of information due to a propitious records from hospital and PHCC. This study can be seen as a pilot study and larger studies can be made to get more reliable results. The material in this study is small and it was hard to find control patients even though the NDR was used to this purpose. Those are unfortunate limitations in this study. The fact that we couldn’t find control patients could indicate that diabetes complications, such as foot ulcers, are not registered in the NDR on a regular basis. Since only 17 controls were found the groups are to small and too diverse to be able to make any conclusions from the data and none of the statistical analyses performed showed any significance. Hence, the results should be considered with caution.
In conclusion, the findings in this study indicate non-significant trends towards age and diabetes duration as two risk factors to the endpoint major LEA among T2DM-patients. The study also infers that T2DM-patients with foot ulcers require a lot of health care. The study furthers implies a non-significant trend towards that lipid lowering medication could lower the risk for LEA. The results in this study can however hopefully be used to motivate the care staff to improve medical quality in this patient group.
Acknowledgements
I would like to thank my supervisors Peter Engfeldt and Stefan Jansson for their support and invaluable knowledge during the work with this study. I would also like to thank Susanne Collgård for her enthusiasm and help with SPSS.
References
1. Jansson SP, Fall K, Brus O, Magnuson A, Wandell P, Ostgren CJ, et al. Prevalence and incidence of diabetes mellitus: a nationwide population-based pharmaco-epidemiological study in Sweden. Diabet Med 2015 Oct;32(10):1319-1328.
2. PhD,John F et al Kremer. Guyton and Hall Textbook of Medical Physiology: With
STUDENT CONSULT Online Access. 12th ed ed. Philadelphia, PA: Saunders/Elsevier; 2011.
3. Agardh C, Berne C. Diabetes. 4., [rev.] uppl. ed. Stockholm: Liber; 2010.
4. Rutter MK, Nesto RW. Blood pressure, lipids and glucose in type 2 diabetes: how low should we go? Re-discovering personalized care. Eur Heart J 2011 Sep;32(18):2247-2255.
5. Kong C, Nimmo L, Elatrozy T, Anyaoku V, Hughes C, Robinson S, et al. Smoking is associated with increased hepatic lipase activity, insulin resistance, dyslipidaemia and early atherosclerosis in Type 2 diabetes. Atherosclerosis 2001 Jun;156(2):373-378. 6. Apelqvist J. Diagnostics and treatment of the diabetic foot. Endocrine 2012
Jun;41(3):384-397.
7. Prompers L, Schaper N, Apelqvist J, Edmonds M, Jude E, Mauricio D, et al. Prediction of outcome in individuals with diabetic foot ulcers: focus on the differences between individuals with and without peripheral arterial disease. The EURODIALE Study. Diabetologia 2008 May;51(5):747-755.
8. Rasmussen BS, Yderstraede KB, Carstensen B, Skov O, Beck-Nielsen H. Substantial reduction in the number of amputations among patients with diabetes: a cohort study over 16 years. Diabetologia 2016 Jan;59(1):121-129.
9. Yesil S, Akinci B, Yener S, Bayraktar F, Karabay O, Havitcioglu H, et al. Predictors of amputation in diabetics with foot ulcer: single center experience in a large Turkish cohort. Hormones (Athens) 2009 Oct-Dec;8(4):286-295.
10. Fujiwara Y, Kishida K, Terao M, Takahara M, Matsuhisa M, Funahashi T, et al.
Beneficial effects of foot care nursing for people with diabetes mellitus: an uncontrolled before and after intervention study. J Adv Nurs 2011 Sep;67(9):1952-1962.
11. Lauterbach S, Kostev K, Kohlmann T. Prevalence of diabetic foot syndrome and its risk factors in the UK. J Wound Care 2010 Aug;19(8):333-337.
12. Johansen OE, Birkeland KI, Jorgensen AP, Orvik E, Sorgard B, Torjussen BR, et al. Diabetic foot ulcer burden may be modified by high-dose atorvastatin: A 6-month randomized controlled pilot trial. J Diabetes 2009 Sep;1(3):182-187.
13. Sohn MW, Meadows JL, Oh EH, Budiman-Mak E, Lee TA, Stone NJ, et al. Statin use and lower extremity amputation risk in nonelderly diabetic patients. J Vasc Surg 2013 Dec;58(6):1578-1585.e1.
14. Rizzo L, Tedeschi A, Fallani E, Coppelli A, Vallini V, Iacopi E, et al. Custom-made orthesis and shoes in a structured follow-up program reduces the incidence of
neuropathic ulcers in high-risk diabetic foot patients. Int J Low Extrem Wounds 2012 Mar;11(1):59-64.
15. Ulbrecht JS, Hurley T, Mauger DT, Cavanagh PR. Prevention of recurrent foot ulcers with plantar pressure-based in-shoe orthoses: the CareFUL prevention multicenter randomized controlled trial. Diabetes Care 2014 Jul;37(7):1982-1989.
16. Bus SA, Waaijman R, Arts M, de Haart M, Busch-Westbroek T, van Baal J, et al. Effect of custom-made footwear on foot ulcer recurrence in diabetes: a multicenter randomized controlled trial. Diabetes Care 2013 Dec;36(12):4109-4116.
17. Fan L, Sidani S, Cooper-Brathwaite A, Metcalfe K. Feasibility, acceptability and effects of a foot self-care educational intervention on minor foot problems in adult patients with diabetes at low risk for foot ulceration: a pilot study. Can J Diabetes 2013 Jun;37(3):195-201.
18. Siersma V, Thorsen H, Holstein PE, Kars M, Apelqvist J, Jude EB, et al. Importance of factors determining the low health-related quality of life in people presenting with a diabetic foot ulcer: the Eurodiale study. Diabet Med 2013 Nov;30(11):1382-1387. 19. Kanade RV, van Deursen RW, Harding K, Price P. Walking performance in people with
diabetic neuropathy: benefits and threats. Diabetologia 2006 Aug;49(8):1747-1754. 20. Kanade RV, van Deursen RW, Price P, Harding K. Risk of plantar ulceration in diabetic
patients with single-leg amputation. Clin Biomech (Bristol, Avon) 2006 Mar;21(3):306-313.
21. Vedhara K, Dawe K, Wetherell MA, Miles JN, Cullum N, Dayan C, et al. Illness beliefs predict self-care behaviours in patients with diabetic foot ulcers: a prospective study. Diabetes Res Clin Pract 2014 Oct;106(1):67-72.
22. Socialstyrelsen. Nationella riktlinjer - Utvärdering 2015, Diabetesvård, Indikatorer och underlag för bedömningar. 2015; Available at:
http://www.socialstyrelsen.se/Lists/Artikelkatalog/Attachments/19697/2015-2-6.pdf. Accessed 05/24, 2016.
23. Hamalainen H, Ronnemaa T, Halonen JP, Toikka T. Factors predicting lower extremity amputations in patients with type 1 or type 2 diabetes mellitus: a population-based 7-year follow-up study. J Intern Med 1999 Jul;246(1):97-103.
24. Hippisley-Cox J, Coupland C. Development and validation of risk prediction equations to estimate future risk of blindness and lower limb amputation in patients with diabetes: cohort study. BMJ 2015 Nov 11;351:h5441.
25. Malyar NM, Freisinger E, Meyborg M, Luders F, Gebauer K, Reinecke H, et al.
Amputations and mortality in in-hospital treated patients with peripheral artery disease and diabetic foot syndrome. J Diabetes Complications 2016 Apr 4.
26. Boutoille D, Feraille A, Maulaz D, Krempf M. Quality of life with diabetes-associated foot complications: comparison between lower-limb amputation and chronic foot ulceration. Foot Ankle Int 2008 Nov;29(11):1074-1078.
27. Eliasson B, Svensson AM, Miftaraj M, Jonasson JM, Eeg-Olofsson K, Sundell KA, et al. Clinical use and effectiveness of lipid lowering therapies in diabetes mellitus--an
observational study from the Swedish National Diabetes Register. PLoS One 2011 Apr 29;6(4):e18744.
28. Gershater MA, Londahl M, Nyberg P, Larsson J, Thorne J, Eneroth M, et al. Complexity of factors related to outcome of neuropathic and neuroischaemic/ischaemic diabetic foot ulcers: a cohort study. Diabetologia 2009 Mar;52(3):398-407.
29. Leveziel N, Ragot S, Gand E, Lichtwitz O, Halimi JM, Gozlan J, et al. Association Between Diabetic Macular Edema and Cardiovascular Events in Type 2 Diabetes Patients: A Multicenter Observational Study. Medicine (Baltimore) 2015
Aug;94(33):e1220.
30. Niskanen L, Hedner T, Hansson L, Lanke J, Niklason A, CAPPP Study Group. Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/beta-blocker-based treatment regimen: a subanalysis of the Captopril Prevention Project. Diabetes Care 2001 Dec;24(12):2091-2096.
31. Turnbull F, Neal B, Algert C, Chalmers J, Chapman N, Cutler J, et al. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med 2005 Jun 27;165(12):1410-1419.
