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Predictors of diabetes foot complications among patients with diabetes in Saudi Arabia
DIAB-6109; No. of Pages 9 diabetes research and clinical practice xxx (2014) xxx–xxx
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Predictors of diabetes foot complications among patients with diabetes in Saudi Arabia Yang Hu a, Balkees A. Bakhotmah b,c, Owiss H. Alzahrani b, Dong Wang e, Frank B. Hu e,f,*, Hasan A. Alzahrani b,d,** a
Division of Rheumatology, Immunology and Allergy, Brigham & Women’s Hospital, Boston, MA, United States The Mohammad Hussein Al Amoudi Chair for Diabetic Foot Research, Jeddah, Saudi Arabia c Department of Nutrition and Food Sciences, Jeddah, Saudi Arabia d Department of Surgery, King Abdulaziz University (KAU), Jeddah, Saudi Arabia e Department of Nutrition and Epidemiology, Harvard School of Public Health, Boston, MA, United States f The Channing Division for Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States b
article info
abstract
Article history:
Aims: To identify risk factors and clinical biomarkers of prevalent diabetes foot complica-
Received 1 January 2014
tions, including foot ulcers, gangrene and amputations among patients with diabetes in
Received in revised form
Jeddah, Saudi Arabia.
11 May 2014
Methods: 598 diabetes patients from Jeddah participated in the current study. Patients were
Accepted 21 July 2014
considered to have diabetes foot complications if they reported diagnosis of foot ulcers or
Available online xxx
gangrene or amputations in a questionnaire administered by a physician and confirmed by
Keywords:
by patients, and several clinical markers were assessed following standard procedures.
Diabetes foot complications
Results: The prevalence of diabetes foot complications in this population was 11.4%. In the
clinical exams. Information on socio-demographic and lifestyle variables was self-reported
Foot ulcers
multivariable model without adjustment for PAD (peripheral artery disease) and DPN
Foot gangrene
(diabetes peripheral neuropathy), non-Saudi nationality, longer diabetes duration and
Amputations
insulin use was significantly associated with higher diabetes foot complications prevalence.
Diabetes
Each 1 g/L increase of hemoglobin was associated with 2.8% lower prevalence of diabetes
Saudi Arabia
foot complications. In the multivariable model adjusting for PAD and DPN, the previously observed associations except for nationality were no longer significant. Patients with both DPN and PAD had 9.73 times the odds of diabetes foot complications compared to the patients with neither condition. Conclusion: In this population, longer diabetes duration, insulin use, lower hemoglobin levels and non-Saudi nationality were associated with higher prevalence of foot complications. These associations were largely explained by the presence of DPN and PAD except for non-Saudi nationality. Diabetes patients with both DPN and PAD had nearly 10-fold increased risk of foot complications than those with neither condition. # 2014 Elsevier Ireland Ltd. All rights reserved.
* Corresponding author at: 665 Huntington Avenue, Boston, MA 02115, United States. Tel.: +1 617 432 0113; fax: +1 617 432 2435. ** Corresponding author at: The Vascular Surgery Division, Department of Surgery, King Abdulaziz University (KAU), P.O. Box 80215, Jeddah 21589, Saudi Arabia. Tel.: +966 02 6408346; fax: +966 02 6408346. E-mail addresses: [email protected], [email protected], [email protected] (F.B. Hu), [email protected] (H.A. Alzahrani). http://dx.doi.org/10.1016/j.diabres.2014.07.016 0168-8227/# 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Hu Y, et al. Predictors of diabetes foot complications among patients with diabetes in Saudi Arabia. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.07.016
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1.
Introduction
Diabetes foot complications including foot ulcers, foot gangrene and amputation are among the most serious complications among diabetic patients and cause substantial economical and psychological burden to the patients and society at large. It is estimated that the average lifetime risk of developing foot ulcers among patients with diabetes is 15% [1], and in some populations, the prevalence could be as high as 25% [2]. Ulceration of the foot among patients with diabetes is common, and one study reported 85% of diabetic lower-limb amputations were preceded by non-healing foot ulcers [3]. Some studies reported that patients with chronic foot ulcers had very poor quality of life, which was worsened after amputation [4,5]. Several prospective cohort studies have identified foot insensitivity, history of foot ulcers or amputation, insulin use, Charcot deformity, lower dorsal foot transcutaneous O2 tension, poor vision, orthostatic hypotension, abnormal ankle reflexes and age as independent predictors for incident foot ulcers [6,7]. In addition, longer duration of diabetes, poor glycemic control measured by HbA1c and reduced joint mobility were found to be significant predictors of foot ulcers, although the results are not entirely consistent [6,8,9]. Among these established risk factors, PAD (peripheral artery disease) as reflected by foot ischemia alone with DPN (diabetes peripheral neuropathy) as reflected by impaired peripheral sensation are two most important risk factors that play critical roles in diabetes foot ulcer etiology [2]. According to the latest 2013 International Diabetes Federation report, among the top five Middle Eastern and North African countries for the number of people with diabetes (20– 79 years), Saudi Arabia ranks number 4 with 3.6 million diabetes cases, with the highest diabetes prevalence (23.9%) [10]. The high prevalence of diabetes and accompanying complications leads to a great burden to the health care system and creates a major challenge to diabetes management [11,12]. Therefore, from a public health perspective, it is critical to identify risk factors for foot complications in order to develop preventive strategies [13]. To the best of our knowledge, no previous study has examined risk factors for foot complications in Saudi patients. We therefore conducted this study to investigate the association between demographic, lifestyle, and clinical risk factors and prevalence of diabetes foot complications, including foot ulcers, gangrene, and amputations, in a Saudi population.
2.
Subjects, materials and methods
The study population was recruited by advertisement from Jeddah Governance between June 2009 and May 2010. The inclusion criteria were age of 30 years and older, diagnosed with diabetes for at least 2 years and without current diabetes ulcers. 598 participants were included in the current analysis. The study was approved by the King Abdulaziz University Hospital (KAUH) Ethical Committee. Study protocols, benefits, adverse reactions, and objectives were explained to all participants. Written consent was obtained from all participants. The diagnosis of diabetes mellitus was first self-
reported by patients and then confirmed by physicians through reviewing medical records. Nationality, age, smoking status, personal income level, educational attainment, current medication use and duration of diabetes were self-reported. Nationality was classified as Saudi and non-Saudi. Smoking status was dichotomized as ever smoker and non-smoker. Personal income level was categorized as <3000, 3000–10,000 and >10,000 Saudi riyal (SR)/month (1 USD = 3.75 SR). We categorized educational attainment as illiterate, high school, and university. Duration of diabetes was categorized into <5, 5–10, 10.1–20 and >20 years. The participant’s body weight was measured to the nearest of 0.1 kg by an electronic weighing scale (Seca, Birmingham, United Kingdom). Height was measured without shoes to the nearest of 0.5 cm by a stadiometer (Seca, Birmingham, United Kingdom). Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared (kg/m2). Waist circumference was measured as the smallest circumference between the rib margin and iliac crest. Blood pressure was measured by an electronic vital signs monitor (Suresigns VS3, Philips medical system, Andover, MA, USA). Two consecutive readings of blood pressure were taken in the right arm of participants in a seated position after 5 min of rest, and the mean of the 2 measures was used for analysis. In the current analysis, participants were considered to have hypertension if they had systolic blood pressure (SBP) 140 mmHg and/or diastolic blood pressure (DBP) 90 mmHg according to the Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines [14], and/or using blood-pressure-lowering drugs. DPN was defined as reduced vibration perception and/or reduced light touch perception in either foot of a patient with the following symptoms: loss of sensations, tingling, and deformed foot. Vibration perception was assessed over bony prominences on the dorsal aspect of the 1st and 5th metatarsal heads using the Horwell Neurothesiometer (Scientific Laboratory Supplies, Nottingham, United Kingdom). Reduced vibration perception was defined by a vibration perception threshold 25 V in either foot [15]. Light touch perception was evaluated using a 10-g Semmes-Weinstein monofilament (Huntleigh Diagnostics, Cardiff, United Kingdom) at the plantar aspect of 1st and 5th metatarsal heads [16]. Loss of sensations at these areas in either foot was defined as reduced light touch perception. PAD was diagnosed as ankle–brachial index (ABI) < 0.9. Diagnosis of PAD followed the American College of Cardiology (ACC) and American Heart Association (AHA) Practice Guidelines for the Management of Patients With PAD [17]. All the assessments were conducted by an assessor first and then confirmed by a second assessor independently. Participants were instructed to fast and abstain from vigorous exercise for 12 h prior to medical examination and blood draw. Fasting venous blood samples (10 ml) were taken from the antecubital vein by the laboratory staff and sent to the KAUH’s accredited central laboratory for daily assay. Fasting blood glucose, HbA1c, lipids profile (high-density lipoproteins (HDL), low-density lipoproteins (LDL), triglycerides (TG)), homocysteine, creatinine, high sensitivity C-reactive protein (CRP), serum urea nitrogen, hemoglobin, and complete blood count were measured using standard methods.
Please cite this article in press as: Hu Y, et al. Predictors of diabetes foot complications among patients with diabetes in Saudi Arabia. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.07.016
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Because foot gangrene and amputation are usually the ultimate consequences of foot ulcers, we used foot complications as a composite outcome in the current study. Patients were considered to have foot complications if they had one of the following diagnosed conditions: foot ulcer, gangrene and amputation. Patients were considered to have foot ulcer if they reported to have past history of foot ulcer or surgical debridement or have purulent discharge. Patients who reported to have PAD history (color change blackish) or vascular examination were regarded as foot gangrene cases. The identification of foot amputation was based on selfreported toes or mid tarsal amputation or below-knee amputation (BKA) or above-knee amputation (AKA). All categorical variables were presented as number and percentage, and all the continuous variables were shown as mean standard deviation. x2 test with n 1 degree of freedom was used to compare the distribution of categorical variables with n levels between foot complication cases and non-cases. Two-sample t-test with equal or unequal variance was used to compare the continuous variables between foot complication cases and non-cases. We employed a 2-step method for variable selection. First, we used multivariable logistic regression to estimate the odds ratio and 95% confidence interval (CI) between each risk factor and risk of foot complications with adjustment for age, sex and nationality. Second, variables that reached significant level of 0.10 were included into the final model. To assess whether selected variables were associated with the risk of foot complications independent of DPN and PAD, 2 separate models were run: one without adjustment for DPN and PAD and the other adjusted for the two conditions. Since both DPN and PAD were strong predictors of foot complications, we quantified the odds ratio of foot complications according to the presence of PAD and DPN among patients with diabetes: no DPN and PAD, PAD and no DPN, and both DPN and PAD. Continuous variables were included in all models as quartiles, and the p for trend was estimated from the linear trend test using the median value of each category. All statistical analysis was conducted using SAS 9.3 software (SAS Institute, Cary, NC). All P values were 2-tailed (a = 0.05).
3.
Results
Table 1 shows the distribution of foot ulcers, gangrene, amputations and total foot complications according to sex and age groups. Among 598 participants, 11.4% of the patients had diagnosed foot complications. The prevalence of foot ulcers, gangrene and amputations were 7.9%, 1.8% and 3.5% respectively. The prevalence of each outcome was similar between males and females, and the prevalence tended to increase with age. The characteristics of the patients organized according to foot complication status are presented in Table 2. There were significantly more foot complications cases among non-Saudi nationalities, insulin users and Clopidogrel users. Moreover, patients with foot complications were more likely to be older, have lower income, have longer diabetes duration and have lower hemoglobin levels. The association between each risk factor and prevalence of foot complications is shown in Table 3. Diabetes duration (OR20+vs.2–5years = 10.09, 95% CI: 3.51–28.94) and insulin use (OR = 3.60, 95% CI: 2.10–6.17) were significantly associated with increased risk of foot complications, while oral hypoglycemic drug use (OR = 0.45, 95% CI: 0.25–0.81) and hemoglobin levels (ORQ4vs.Q1 = 0.23, 95% CI: 0.08–0.64, P for trend 0.005) were inversely associated with foot complications. The significant predictors from Table 3 were mutually adjusted in 2 separate multivariable logistic models. The results are shown in Table 4. In the model without adjustment for DPN and PAD, non-Saudi nationality (OR = 2.80, 95% CI: 1.61–4.85), insulin use (OR = 2.10, 95% CI: 1.08–4.09), and diabetes duration (OR20+vs.2–5years = 5.70, 95% CI: 1.80–18.11) were independently and significantly associated with higher odds of foot complications, whereas higher hemoglobin levels (ORQ4vs.Q1 = 0.31, 95% CI: 0.11–0.89, P for trend 0.024) were associated with reduced odds of foot complications. In the model adjusting for DPN and PAD, the associations for insulin use, diabetes duration and hemoglobin level were no longer significant. Patients with DPN had 3.21 times (OR = 3.21, 95% CI: 1.69–6.10) the odds of foot complications than those without the condition, and patients with PAD had nearly 3 fold
Table 1 – Distribution of foot ulcers, gangrene, amputations and total foot complications according to age and sex.a Gender Male Foot ulcer 342 (92.2) No 29 (7.8) Yes Foot gangrene No 363 (97.8) 8 (2.2) Yes Foot amputation 357 (96.2) No 14 (3.8) Yes Foot complicationsb No 330 (88.9) 41 (11.1) Yes a b
Age (years)
Total
Female
45
45.1–55
55.1–65
>65.0
209 (92.1) 18 (7.9)
118 (95.9) 5 (4.1)
232 (91.7) 21 (8.3)
140 (90.9) 14 (9.1)
61 (89.7) 7 (10.3)
551 (92.1) 47 (7.9)
224 (98.7) 3 (1.3)
122 (99.2) 1 (0.8)
247 (97.6) 6 (2.4)
151 (98.1) 3 (1.9)
67 (98.5) 1 (1.5)
587 (98.2) 11 (1.8)
220 (96.9) 7 (3.1)
119 (96.7) 4 (3.3)
248 (98.0) 5 (2.0)
148 (96.1) 6 (3.9)
62 (91.2) 6 (8.8)
577 (96.5) 21 (3.5)
200 (88.1) 27 (11.9)
114 (92.6) 9 (7.4)
224 (88.5) 29 (11.5)
133 (86.4) 21 (13.6)
59 (86.8) 9 (13.2)
530 (88.6) 68 (11.4)
n (%) for all such values. Foot complications include foot ulcers, foot gangrene, and foot amputations.
Please cite this article in press as: Hu Y, et al. Predictors of diabetes foot complications among patients with diabetes in Saudi Arabia. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.07.016
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Table 2 – Characteristics of 598 participants according to foot complications status. Foot complication cases
Pa
330 (62.3) 200 (37.7) 503 (94.9)
41 (60.3) 42 (61.8) 64 (94.1)
0.753 <0.001 0.783 0.152
201 (37.9) 138 (26.0) 154 (29.1) 37(7.0)
34 (50.0) 18 (26.5) 14 (20.6) 2(2.9)
222 181 127 106
39 24 5 13
No foot complications b
Sex, male Nationality, non-Saudi Diabetes type, type 2 diabetes Education Illiterate High school University Post graduate Income level (SR/month) <3000 3000–10,000 >10,000 Smoking status, ever smoker Duration of DM (years) <5 5–10 10.1–20 >20 Hypertension Insulin Oral hypoglycemic Aspirin Clopidogrel Statins Age (years) c BMI (kg/m2) Fasting blood glucose (mmol/L) HbA1c (mmol/mol) HbA1c (%) HDL (mmol/L) LDL (mmol/L) Triglyceride (mmol/L) Homocysteine (mmol/L) Creatinine (mmol/L) CRP (mmol/L) Serum urea nitrogen (mmol/L) Hemoglobin (g/L) White blood cell (106/L)) Platelet (109/L))
0.004 (41.9) (34.2) (24.0) (20.0)
155 (29.2) 128 (24.2) 161 (30.4) 86 (16.2) 343 (64.7) 176 (33.2) 434 (81.9) 302 (57.0) 35 (6.6) 202 (38.1) 53.2 10.6 31.4 6.9 10.5 4.1 76.9 24.3 9.2 2.2 1.2 0.3 3.1 1.0 1.7 1.2 8.5 4.3 81.3 28.3 6.8 7.3 5.7 4.4 137.8 21.1 7.8 3.3 255.6 79.0
(57.4) (35.3) (7.4) (19.1)
5 (7.4) 11 (16.2) 28 (41.2) 24 (35.3) 45 (66.2) 43 (63.2) 47 (69.1) 42 (61.8) 9 (13.2) 28 (41.2) 55.4 9.3 30.0 6.3 10.7 4.2 76.5 24.1 9.2 2.2 1.2 0.3 3.2 1.1 1.7 1.6 9.1 4.4 95.3 58.7 8.9 11.6 7.3 8.0 130.6 18.2 7.8 3.0 262.3 94.9
0.885 <0.001
0.812 <0.001 0.013 0.453 0.049 0.625 0.010 0.138 0.626 0.903 0.897 0.609 0.347 0.788 0.328 0.069 0.190 0.129 0.012 0.880 0.603
Abbreviations: SR, Saudi riyal (currency unit of Saudi Arabia); HbA1c, glycated hemoglobin; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; CRP, C-reactive protein. a P-values were calculated from x2 test for categorical variables or two-sample t-test for continuous variables. b n (%) for all such values. c Mean standard deviation for all such values.
(OR = 2.80, 95% CI: 1.56–5.01) odds of foot complications than those without the condition. Patients with both DPN and PAD had 9.73 times (OR = 9.73, 95% CI: 4.10–23.11) the odds of foot complications than those with neither of them (Fig. 1).
4.
Discussion
In this study, we found that non-Saudi nationality, insulin use, longer diabetes duration and lower hemoglobin levels were associated with higher prevalence of foot complications in a Saudi population. The associations for insulin use, diabetes duration and hemoglobin levels were attenuated after further adjustment for DPN and PAD, both of which are strong risk factors of foot complications. Patients with both DPN and PAD were at dramatically increased odds of having foot complications than those without either of them.
The prevalence of foot ulcers and amputations in this Saudi population was 9.9%, which was higher than that of several previous reports. In a previous study of 375 diabetic patients in Riyadh, Saudi Arabia, the prevalence of foot ulcers and amputation was only 3% [18]. A study conducted in Bahrain reported a prevalence of 5.9% for foot ulcers [19], which was slightly lower than the current study population (7.9% for foot ulcer). This could be explained by the relatively higher BMI (mean 31.2 kg/m2) and longer duration of diabetes (median 11.25 years, mean 11.28 6.43 years) in this study population compared to the Riyadh study (mean BMI, 26.8 kg/m2; median duration of diabetes, 9.8 years) and the Bahrain population (mean BMI, 27.9 kg/m2; mean duration of diabetes, 9.5 8.40 years). Another reason is the large number of non-Saudi participants in our study, who have much high prevalence of foot complications. The non-Saudi nationalities represent almost one third of the total population and their number is
Please cite this article in press as: Hu Y, et al. Predictors of diabetes foot complications among patients with diabetes in Saudi Arabia. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.07.016
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Table 3 – Association between risk factors and prevalence of foot complications among individuals with diabetes.a Risk factors
Odds ratio
95% Confidence interval
Pb
Type 2 diabetes vs. Type 1 diabetes Education Illiterate High school University Post graduate Income level (SR/month) <3000 3000–10,000 >10,000 BMI (kg/m2) Smoking, ever-smoker vs. never-smoker Duration of diabetes (years) <5 5–10 10.1–20 >20 Hypertensive vs. normotensive Insulin, user vs. non-user Oral hypoglycemic, user vs. non-user Aspirin, user vs. non-user Clopidogrel, user vs. non-user Statins, user vs. non-user Fasting blood glucose (mmol/L) <7.5 7.5–9.4 9.4–12.8 12.8 HbA1c (% (mmol/mol)) <7.8 (<62) 7.8–9.0 (62–75) 9.0–11.0 (75–97) 11.0 (97) HDL (mmol/L) <1.0 1.0–1.1 1.1–1.3 1.3 LDL (mmol/L) <2.4 2.4–3.0 3.0–3.7 3.7 Triglyceride (mmol/L) <1.0 1.0–1.5 1.5–2.1 2.1 Homocysteine (mmol/L) <6.0 6.0–7.7 7.7–10.0 10.0 Creatinine (mmol/L) <65.0 65.0–78.0 78.0–92.0 92.0 CRP (mmol/L) <3.2 3.2–3.3 3.3–8.2 8.2 Serum urea nitrogen (mmol/L) <4.0
0.57
0.18–1.77
0.330 0.522
Reference 0.93 0.70 0.39
Reference 0.48–1.82 0.35–1.40 0.09–1.78
Reference 1.07 0.38 0.97 1.24
Reference 0.58–1.98 0.13–1.10 0.92–1.01 0.62–2.47
Reference 2.92 5.61 10.09 0.96 3.60 0.45 1.19 2.01 1.08
Reference 0.98–8.72 2.07–15.20 3.51–28.94 0.55–1.67 2.10–6.17 0.25–0.81 0.69–2.04 0.90–4.51 0.64–1.83
Reference 1.80 0.97 1.78
Reference 0.83–3.89 0.41–2.52 0.80–3.94
Reference 1.14 1.36 1.01
Reference 0.51–2.57 0.66–2.83 0.45–2.27
Reference 1.96 1.44 1.18
Reference 0.89–4.33 0.63–3.31 0.50–2.79
Reference 1.64 1.40 1.82
Reference 0.73–3.70 0.59–3.32 0.81–4.13
Reference 0.85 0.75 0.70
Reference 0.41–1.76 0.35–1.59 0.32–1.50
Reference 0.90 1.18 1.00
Reference 0.35–2.31 0.48–2.92 0.40–2.53
Reference 1.02 0.57 1.42
Reference 0.46–2.24 0.22–1.44 0.63–3.22
Reference 2.22 1.90 2.80
Reference 0.88–5.61 0.72–4.99 1.10–7.12 0.319 Reference
0.132
0.118 0.537 <0.001
0.885 <0.001 0.007 0.528 0.090 0.766 0.314
0.861
0.951
0.223
0.337
0.843
0.356
0.139
Reference
Please cite this article in press as: Hu Y, et al. Predictors of diabetes foot complications among patients with diabetes in Saudi Arabia. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.07.016
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Table 3 (Continued ) Risk factors
Odds ratio
95% Confidence interval
4.0–5.0 5.0–6.4 6.4 Hemoglobin (g/L) <125 125–138 138–149 149 White blood cell (106/L)) <5.9 5.9–7.1 7.1–8.9 8.9 Platelet (109/L)) <212 212–253 253–301 301
1.35 0.87 1.56
0.61–2.98 0.36–2.11 0.70–3.47
Reference 0.63 0.54 0.23
Reference 0.30–1.33 0.24–1.22 0.08–0.64 0.704 Reference 0.63–2.87 0.47–2.32 0.42–2.16 0.694 Reference 0.48–2.29 0.60–2.66 0.35–1.86
Pb
0.005
Reference 1.34 1.04 0.96 Reference 1.04 1.27 0.81
Abbreviations: SR, Saudi riyal (currency unit of Saudi Arabia); HbA1c, glycated hemoglobin; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; CRP, C-reactive protein. a Logistic regression model adjusted for sex, age (continuous) and nationality (Saudi, non-Saudi). b For ordinal variables, P-value was estimated by a linear trend test using the median value of each category using complete data.
almost 10 million [20]. Unlike most of previous studies, our study did not exclude the non-Saudi population and that is considered as strength of this study as it reflects the full picture of this clinical problem in the Saudi population. Our results suggest that the non-Saudi nationality be considered as a vulnerable group for diabetes-related foot complications. The multivariable analyses showed that non-Saudi nationality, longer duration of diabetes and insulin use were associated with significantly higher odds of foot complications. Our data suggested that most of the non-Saudi patients (72.7%) had income less than 3000 SR/month, while only 23.9% of the Saudi patients were below this income level. This income disparity might reflect the different socio-economic status between Saudi and non-Saudi patients, and patients with low socio-economic status were less likely to get timely and adequate medical care and diabetes treatment. Diabetes duration was an indicator of the severity of diabetes and was frequently related to the development of DPN and PAD [21,22], but findings were inconsistent for foot ulcers. A matched casecontrol study found that a long duration of having diabetes (>10 years) was associated with 3 times increased risk of foot
ulcers [9]. A cross-sectional study in Bahrain reported an odds ratio of 1.32 for patients with diabetes duration greater than 5 years [19]. However, one prospective cohort study did not observe a significant association between diabetes duration and foot ulcers [6]. The discrepancy might result from the adjustment for DPN or PAD in the model because both of them were potent indicators of diabetes severity, and they are strongly correlated with longer diabetes duration. Similarly, insulin therapy is typically correlated with a longer diabetes duration and greater severity of diabetes. Thus, it was not surprising that the insulin users had higher odds of foot complications in our study. It is interesting that an inverse association was found between hemoglobin levels and foot complications prevalence. Anemia was found to be common among patients with diabetes, and hemoglobin levels tended to decrease while severity of diabetes increased [23]. Several studies reported a positive association between body weight and foot ulcers, and one potential mechanism was through higher plantar pressure in the heavier patients [6,24–26]. However, BMI was not significantly associated with foot complications in our study. Reverse causation could be a
Fig. 1 – Odds ratios of foot complications according to the presence of PAD and DPN among diabetes patient. Please cite this article in press as: Hu Y, et al. Predictors of diabetes foot complications among patients with diabetes in Saudi Arabia. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.07.016
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Table 4 – Multivariable logistic regression of risk factors associated with foot complications.a Risk factors Model without DPN and PAD Sex, male vs. female Age (years), every 1 year increment Nationality, non-Saudi vs. Saudi Insulin, user vs. non-user Oral hypoglycemic drug, user vs. non-user Clopidogrel, user vs. non-user Duration of diabetes (years) <5 5–10 10.1–20 >20 Hemoglobin (g/L) <125 125–138 138–149 149 Model with DPN and PAD Sex, male vs. female Age (years), every 1 year increment Nationality, non-Saudi vs. Saudi Insulin, user vs. non-user Oral hypoglycemic drug, user vs. non-user Clopidogrel, user vs. non-user DPN PAD Duration of diabetes (years) <5 5–10 10.1–20 >20 Hemoglobin (g/L) <125 125–138 138–149 149
95% CI
Pb
1.56 1.00 2.80 2.10 0.85 1.43
0.79–3.06 0.97–1.03 1.61–4.85 1.08–4.09 0.43–1.70 0.60–3.41
0.198 0.962 <0.001 0.030 0.643 0.421 0.024
Reference 2.78 4.33 5.70
Reference 0.91–8.51 1.51–12.44 1.80–18.11
Reference 0.71 0.62 0.31
Reference 0.33–1.54 0.26–1.46 0.11–0.89
1.28 0.99 2.47 1.73 0.97 1.39 3.21 2.80
0.64–2.58 0.96–1.02 1.39–4.38 0.86–3.48 0.46–2.02 0.55–3.52 1.69–6.10 1.56–5.01
Reference 2.70 3.70 3.60
Reference 0.88–8.34 1.26–10.84 1.09–11.89
Reference 0.96 0.72 0.42
Reference 0.42–2.19 0.29–1.76 0.14–1.27
Odds ratio
0.024
0.486 0.383 0.002 0.125 0.929 0.486 <0.0001 <0.001 0.123
0.120
a Logistic regression model adjusted for sex, age (continuous), nationality (Saudi Arabia, non-Saudi Arabia), insulin (user, non-user), duration of DM (<5, 5–10, 10.1–20, >20, years) and hemoglobin (<125.0, 125–138, 138–149, 149, g/L. b For ordinal variables, P-value was estimated by a linear trend test using the median value of each category using complete data.
possible explanation, as patients with foot complications were in very bad physical and psychological condition, and they tended to lose weight. The associations for insulin use, diabetes duration and hemoglobin levels were no longer significant after additional adjusting for DPN and PAD, suggesting these associations were largely mediated by these two conditions. Both DPN and PAD have long been recognized as important risk factors that contribute to the pathogenesis of foot complications such as foot ulcers, gangrene, and amputation. Foot neuropathies usually result in the loss of protective sensation, precipitating a break in the skin or impaired healing and thus lead to foot ulceration. Ischemia is usually the result of macrovascular disease that causes protective sweating loss, dryness in feet, and nail dystrophy [2,27], which put feet in a vulnerable position for ulceration. In our study, diabetes patients with the presence of DPN or PAD had substantially elevated risk of foot complications than those without these conditions. Our findings are consistent with several previous studies. A prospective cohort study found that the foot sensory neuropathy measured by 5.07 monofilament was associated
with 2.17 times (95% CI: 1.52–3.08) the risk of foot ulcers, and higher dorsal foot skin oxygenation (TcPO2) was associated with 20% reduced foot ulcer risk (RR = 0.8, 95% CI: 0.69–0.93) after adjusting for other risk factors [6]. One case-control study reported adjusted ORs for insensate to 5.07 monofilament and TcPO2 < 30 mmHg of 18.42 (95% CI: 3.83–88.87) and 57.87 (95% CI: 5.08–658.96) respectively [28]. A recent systematic review concluded that diabetes neuropathy and peripheral vascular diseases were the most common variables included in a risk stratification system and were consistently associated with diabetes foot ulceration development [29]. Our study also suggested that although DPN and PAD were independent risk factors for foot complications, they might have synergic effects on foot complications development because diabetes patients with both conditions had dramatically elevated risk of developing foot complications. The strengths of this study include a large sample size that included the Saudis and non-Saudis, detailed assessment of foot complications, and comprehensive measures of clinical and biochemical markers. Our study also had several limitations. First, the cross-sectional study design limits our ability
Please cite this article in press as: Hu Y, et al. Predictors of diabetes foot complications among patients with diabetes in Saudi Arabia. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.07.016
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to establish cause-effect relationships between risk factors and foot complications. Therefore, more prospective studies are needed to confirm our results. Second, the case number was relatively small, which leads to limited statistical power. Third, the participants in our study were recruited through advertisement. Thus, participants with severe conditions might not be able or willing to participate in this study. Finally, our study population might not be representative for the Saudi population because the patients were recruited from single city of Saudi Arabia and non-Saudi patients were also included. In conclusion, our study identified several risk factors for foot complications, including longer diabetes duration, insulin use, lower hemoglobin levels and non-Saudi nationality. These associations were largely mediated through the effect of DPN and PAD. The presence of both DPN and PAD was associated with a dramatically elevated risk of foot complications among patients with diabetes.
Conflict of interest
[6]
[7]
[8] [9]
[10]
[11] [12]
None known or perceived. [13]
Author contributions YH analyzed the data and wrote the manuscript. BB, OA and DW contributed to the discussions and revisions of the manuscript. HA and FH contributed to the study design, supervision of this work and the discussions and revision of the final manuscript. All authors read and approved the final version.
[14]
[15]
Funding sources
[16]
Mohammad Hussein Al-Amoudi Chair for Diabetic Foot Research, Saudi Arabia.
[17]
Acknowledgement This research is supported by Mohammad Hussein Al-Amoudi Chair for Diabetic Foot Research, Saudi Arabia.
references
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[20] Latest statistical release. Cent Dep Stat Inf; 2013. [21] Mørkrid K, Ali L, Hussain A. Risk factors and prevalence of diabetic peripheral neuropathy: a study of type 2 diabetic outpatients in Bangladesh. Int J Diabetes Dev Ctries 2010;30:11–7. [22] Al-Delaimy WK, Merchant AT, Rimm EB, Willett WC, Stampfer MJ, Hu FB. Effect of type 2 diabetes and its duration on the risk of peripheral arterial disease among men. Am J Med 2004;116:236–40. [23] Thomas MC, MacIsaac RJ, Tsalamandris C, Power D, Jerums G. Unrecognized anemia in patients with diabetes: a crosssectional survey. Diabetes Care 2003;26:1164–9. [24] Veves A, Murray HJ, Young MJ, Boulton AJ. The risk of foot ulceration in diabetic patients with high foot pressure: a prospective study. Diabetologia 1992;35:660–3.
[25] Stess RM, Jensen SR, Mirmiran R. The role of dynamic plantar pressures in diabetic foot ulcers. Diabetes Care 1997;20:855–8. [26] Ctercteko GC, Dhanendran M, Hutton WC, Le Quesne LP. Vertical forces acting on the feet of diabetic patients with neuropathic ulceration. Br J Surg 1981;68:608–14. [27] Jeffcoate WJ, Harding KG. Diabetic foot ulcers. Lancet 2003;361:1545–51. [28] McNeely MJ, Boyko EJ, Ahroni JH, Stensel VL, Reiber GE, Smith DG, et al. The independent contributions of diabetic neuropathy and vasculopathy in foot ulceration. How great are the risks? Diabetes Care 1995;18:216–9. [29] Monteiro-Soares M, Boyko EJ, Ribeiro J, Ribeiro I, DinisRibeiro M. Predictive factors for diabetic foot ulceration: a systematic review. Diabetes Metab Res Rev 2012;28:574–600.
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9
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Predictors of diabetes foot complications among patients with diabetes in Saudi Arabia Yang Hu a, Balkees A. Bakhotmah b,c, Owiss H. Alzahrani b, Dong Wang e, Frank B. Hu e,f,*, Hasan A. Alzahrani b,d,** a
Division of Rheumatology, Immunology and Allergy, Brigham & Women’s Hospital, Boston, MA, United States The Mohammad Hussein Al Amoudi Chair for Diabetic Foot Research, Jeddah, Saudi Arabia c Department of Nutrition and Food Sciences, Jeddah, Saudi Arabia d Department of Surgery, King Abdulaziz University (KAU), Jeddah, Saudi Arabia e Department of Nutrition and Epidemiology, Harvard School of Public Health, Boston, MA, United States f The Channing Division for Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States b
article info
abstract
Article history:
Aims: To identify risk factors and clinical biomarkers of prevalent diabetes foot complica-
Received 1 January 2014
tions, including foot ulcers, gangrene and amputations among patients with diabetes in
Received in revised form
Jeddah, Saudi Arabia.
11 May 2014
Methods: 598 diabetes patients from Jeddah participated in the current study. Patients were
Accepted 21 July 2014
considered to have diabetes foot complications if they reported diagnosis of foot ulcers or
Available online xxx
gangrene or amputations in a questionnaire administered by a physician and confirmed by
Keywords:
by patients, and several clinical markers were assessed following standard procedures.
Diabetes foot complications
Results: The prevalence of diabetes foot complications in this population was 11.4%. In the
clinical exams. Information on socio-demographic and lifestyle variables was self-reported
Foot ulcers
multivariable model without adjustment for PAD (peripheral artery disease) and DPN
Foot gangrene
(diabetes peripheral neuropathy), non-Saudi nationality, longer diabetes duration and
Amputations
insulin use was significantly associated with higher diabetes foot complications prevalence.
Diabetes
Each 1 g/L increase of hemoglobin was associated with 2.8% lower prevalence of diabetes
Saudi Arabia
foot complications. In the multivariable model adjusting for PAD and DPN, the previously observed associations except for nationality were no longer significant. Patients with both DPN and PAD had 9.73 times the odds of diabetes foot complications compared to the patients with neither condition. Conclusion: In this population, longer diabetes duration, insulin use, lower hemoglobin levels and non-Saudi nationality were associated with higher prevalence of foot complications. These associations were largely explained by the presence of DPN and PAD except for non-Saudi nationality. Diabetes patients with both DPN and PAD had nearly 10-fold increased risk of foot complications than those with neither condition. # 2014 Elsevier Ireland Ltd. All rights reserved.
* Corresponding author at: 665 Huntington Avenue, Boston, MA 02115, United States. Tel.: +1 617 432 0113; fax: +1 617 432 2435. ** Corresponding author at: The Vascular Surgery Division, Department of Surgery, King Abdulaziz University (KAU), P.O. Box 80215, Jeddah 21589, Saudi Arabia. Tel.: +966 02 6408346; fax: +966 02 6408346. E-mail addresses: [email protected], [email protected], [email protected] (F.B. Hu), [email protected] (H.A. Alzahrani). http://dx.doi.org/10.1016/j.diabres.2014.07.016 0168-8227/# 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Hu Y, et al. Predictors of diabetes foot complications among patients with diabetes in Saudi Arabia. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.07.016
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1.
Introduction
Diabetes foot complications including foot ulcers, foot gangrene and amputation are among the most serious complications among diabetic patients and cause substantial economical and psychological burden to the patients and society at large. It is estimated that the average lifetime risk of developing foot ulcers among patients with diabetes is 15% [1], and in some populations, the prevalence could be as high as 25% [2]. Ulceration of the foot among patients with diabetes is common, and one study reported 85% of diabetic lower-limb amputations were preceded by non-healing foot ulcers [3]. Some studies reported that patients with chronic foot ulcers had very poor quality of life, which was worsened after amputation [4,5]. Several prospective cohort studies have identified foot insensitivity, history of foot ulcers or amputation, insulin use, Charcot deformity, lower dorsal foot transcutaneous O2 tension, poor vision, orthostatic hypotension, abnormal ankle reflexes and age as independent predictors for incident foot ulcers [6,7]. In addition, longer duration of diabetes, poor glycemic control measured by HbA1c and reduced joint mobility were found to be significant predictors of foot ulcers, although the results are not entirely consistent [6,8,9]. Among these established risk factors, PAD (peripheral artery disease) as reflected by foot ischemia alone with DPN (diabetes peripheral neuropathy) as reflected by impaired peripheral sensation are two most important risk factors that play critical roles in diabetes foot ulcer etiology [2]. According to the latest 2013 International Diabetes Federation report, among the top five Middle Eastern and North African countries for the number of people with diabetes (20– 79 years), Saudi Arabia ranks number 4 with 3.6 million diabetes cases, with the highest diabetes prevalence (23.9%) [10]. The high prevalence of diabetes and accompanying complications leads to a great burden to the health care system and creates a major challenge to diabetes management [11,12]. Therefore, from a public health perspective, it is critical to identify risk factors for foot complications in order to develop preventive strategies [13]. To the best of our knowledge, no previous study has examined risk factors for foot complications in Saudi patients. We therefore conducted this study to investigate the association between demographic, lifestyle, and clinical risk factors and prevalence of diabetes foot complications, including foot ulcers, gangrene, and amputations, in a Saudi population.
2.
Subjects, materials and methods
The study population was recruited by advertisement from Jeddah Governance between June 2009 and May 2010. The inclusion criteria were age of 30 years and older, diagnosed with diabetes for at least 2 years and without current diabetes ulcers. 598 participants were included in the current analysis. The study was approved by the King Abdulaziz University Hospital (KAUH) Ethical Committee. Study protocols, benefits, adverse reactions, and objectives were explained to all participants. Written consent was obtained from all participants. The diagnosis of diabetes mellitus was first self-
reported by patients and then confirmed by physicians through reviewing medical records. Nationality, age, smoking status, personal income level, educational attainment, current medication use and duration of diabetes were self-reported. Nationality was classified as Saudi and non-Saudi. Smoking status was dichotomized as ever smoker and non-smoker. Personal income level was categorized as <3000, 3000–10,000 and >10,000 Saudi riyal (SR)/month (1 USD = 3.75 SR). We categorized educational attainment as illiterate, high school, and university. Duration of diabetes was categorized into <5, 5–10, 10.1–20 and >20 years. The participant’s body weight was measured to the nearest of 0.1 kg by an electronic weighing scale (Seca, Birmingham, United Kingdom). Height was measured without shoes to the nearest of 0.5 cm by a stadiometer (Seca, Birmingham, United Kingdom). Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared (kg/m2). Waist circumference was measured as the smallest circumference between the rib margin and iliac crest. Blood pressure was measured by an electronic vital signs monitor (Suresigns VS3, Philips medical system, Andover, MA, USA). Two consecutive readings of blood pressure were taken in the right arm of participants in a seated position after 5 min of rest, and the mean of the 2 measures was used for analysis. In the current analysis, participants were considered to have hypertension if they had systolic blood pressure (SBP) 140 mmHg and/or diastolic blood pressure (DBP) 90 mmHg according to the Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines [14], and/or using blood-pressure-lowering drugs. DPN was defined as reduced vibration perception and/or reduced light touch perception in either foot of a patient with the following symptoms: loss of sensations, tingling, and deformed foot. Vibration perception was assessed over bony prominences on the dorsal aspect of the 1st and 5th metatarsal heads using the Horwell Neurothesiometer (Scientific Laboratory Supplies, Nottingham, United Kingdom). Reduced vibration perception was defined by a vibration perception threshold 25 V in either foot [15]. Light touch perception was evaluated using a 10-g Semmes-Weinstein monofilament (Huntleigh Diagnostics, Cardiff, United Kingdom) at the plantar aspect of 1st and 5th metatarsal heads [16]. Loss of sensations at these areas in either foot was defined as reduced light touch perception. PAD was diagnosed as ankle–brachial index (ABI) < 0.9. Diagnosis of PAD followed the American College of Cardiology (ACC) and American Heart Association (AHA) Practice Guidelines for the Management of Patients With PAD [17]. All the assessments were conducted by an assessor first and then confirmed by a second assessor independently. Participants were instructed to fast and abstain from vigorous exercise for 12 h prior to medical examination and blood draw. Fasting venous blood samples (10 ml) were taken from the antecubital vein by the laboratory staff and sent to the KAUH’s accredited central laboratory for daily assay. Fasting blood glucose, HbA1c, lipids profile (high-density lipoproteins (HDL), low-density lipoproteins (LDL), triglycerides (TG)), homocysteine, creatinine, high sensitivity C-reactive protein (CRP), serum urea nitrogen, hemoglobin, and complete blood count were measured using standard methods.
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Because foot gangrene and amputation are usually the ultimate consequences of foot ulcers, we used foot complications as a composite outcome in the current study. Patients were considered to have foot complications if they had one of the following diagnosed conditions: foot ulcer, gangrene and amputation. Patients were considered to have foot ulcer if they reported to have past history of foot ulcer or surgical debridement or have purulent discharge. Patients who reported to have PAD history (color change blackish) or vascular examination were regarded as foot gangrene cases. The identification of foot amputation was based on selfreported toes or mid tarsal amputation or below-knee amputation (BKA) or above-knee amputation (AKA). All categorical variables were presented as number and percentage, and all the continuous variables were shown as mean standard deviation. x2 test with n 1 degree of freedom was used to compare the distribution of categorical variables with n levels between foot complication cases and non-cases. Two-sample t-test with equal or unequal variance was used to compare the continuous variables between foot complication cases and non-cases. We employed a 2-step method for variable selection. First, we used multivariable logistic regression to estimate the odds ratio and 95% confidence interval (CI) between each risk factor and risk of foot complications with adjustment for age, sex and nationality. Second, variables that reached significant level of 0.10 were included into the final model. To assess whether selected variables were associated with the risk of foot complications independent of DPN and PAD, 2 separate models were run: one without adjustment for DPN and PAD and the other adjusted for the two conditions. Since both DPN and PAD were strong predictors of foot complications, we quantified the odds ratio of foot complications according to the presence of PAD and DPN among patients with diabetes: no DPN and PAD, PAD and no DPN, and both DPN and PAD. Continuous variables were included in all models as quartiles, and the p for trend was estimated from the linear trend test using the median value of each category. All statistical analysis was conducted using SAS 9.3 software (SAS Institute, Cary, NC). All P values were 2-tailed (a = 0.05).
3.
Results
Table 1 shows the distribution of foot ulcers, gangrene, amputations and total foot complications according to sex and age groups. Among 598 participants, 11.4% of the patients had diagnosed foot complications. The prevalence of foot ulcers, gangrene and amputations were 7.9%, 1.8% and 3.5% respectively. The prevalence of each outcome was similar between males and females, and the prevalence tended to increase with age. The characteristics of the patients organized according to foot complication status are presented in Table 2. There were significantly more foot complications cases among non-Saudi nationalities, insulin users and Clopidogrel users. Moreover, patients with foot complications were more likely to be older, have lower income, have longer diabetes duration and have lower hemoglobin levels. The association between each risk factor and prevalence of foot complications is shown in Table 3. Diabetes duration (OR20+vs.2–5years = 10.09, 95% CI: 3.51–28.94) and insulin use (OR = 3.60, 95% CI: 2.10–6.17) were significantly associated with increased risk of foot complications, while oral hypoglycemic drug use (OR = 0.45, 95% CI: 0.25–0.81) and hemoglobin levels (ORQ4vs.Q1 = 0.23, 95% CI: 0.08–0.64, P for trend 0.005) were inversely associated with foot complications. The significant predictors from Table 3 were mutually adjusted in 2 separate multivariable logistic models. The results are shown in Table 4. In the model without adjustment for DPN and PAD, non-Saudi nationality (OR = 2.80, 95% CI: 1.61–4.85), insulin use (OR = 2.10, 95% CI: 1.08–4.09), and diabetes duration (OR20+vs.2–5years = 5.70, 95% CI: 1.80–18.11) were independently and significantly associated with higher odds of foot complications, whereas higher hemoglobin levels (ORQ4vs.Q1 = 0.31, 95% CI: 0.11–0.89, P for trend 0.024) were associated with reduced odds of foot complications. In the model adjusting for DPN and PAD, the associations for insulin use, diabetes duration and hemoglobin level were no longer significant. Patients with DPN had 3.21 times (OR = 3.21, 95% CI: 1.69–6.10) the odds of foot complications than those without the condition, and patients with PAD had nearly 3 fold
Table 1 – Distribution of foot ulcers, gangrene, amputations and total foot complications according to age and sex.a Gender Male Foot ulcer 342 (92.2) No 29 (7.8) Yes Foot gangrene No 363 (97.8) 8 (2.2) Yes Foot amputation 357 (96.2) No 14 (3.8) Yes Foot complicationsb No 330 (88.9) 41 (11.1) Yes a b
Age (years)
Total
Female
45
45.1–55
55.1–65
>65.0
209 (92.1) 18 (7.9)
118 (95.9) 5 (4.1)
232 (91.7) 21 (8.3)
140 (90.9) 14 (9.1)
61 (89.7) 7 (10.3)
551 (92.1) 47 (7.9)
224 (98.7) 3 (1.3)
122 (99.2) 1 (0.8)
247 (97.6) 6 (2.4)
151 (98.1) 3 (1.9)
67 (98.5) 1 (1.5)
587 (98.2) 11 (1.8)
220 (96.9) 7 (3.1)
119 (96.7) 4 (3.3)
248 (98.0) 5 (2.0)
148 (96.1) 6 (3.9)
62 (91.2) 6 (8.8)
577 (96.5) 21 (3.5)
200 (88.1) 27 (11.9)
114 (92.6) 9 (7.4)
224 (88.5) 29 (11.5)
133 (86.4) 21 (13.6)
59 (86.8) 9 (13.2)
530 (88.6) 68 (11.4)
n (%) for all such values. Foot complications include foot ulcers, foot gangrene, and foot amputations.
Please cite this article in press as: Hu Y, et al. Predictors of diabetes foot complications among patients with diabetes in Saudi Arabia. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.07.016
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Table 2 – Characteristics of 598 participants according to foot complications status. Foot complication cases
Pa
330 (62.3) 200 (37.7) 503 (94.9)
41 (60.3) 42 (61.8) 64 (94.1)
0.753 <0.001 0.783 0.152
201 (37.9) 138 (26.0) 154 (29.1) 37(7.0)
34 (50.0) 18 (26.5) 14 (20.6) 2(2.9)
222 181 127 106
39 24 5 13
No foot complications b
Sex, male Nationality, non-Saudi Diabetes type, type 2 diabetes Education Illiterate High school University Post graduate Income level (SR/month) <3000 3000–10,000 >10,000 Smoking status, ever smoker Duration of DM (years) <5 5–10 10.1–20 >20 Hypertension Insulin Oral hypoglycemic Aspirin Clopidogrel Statins Age (years) c BMI (kg/m2) Fasting blood glucose (mmol/L) HbA1c (mmol/mol) HbA1c (%) HDL (mmol/L) LDL (mmol/L) Triglyceride (mmol/L) Homocysteine (mmol/L) Creatinine (mmol/L) CRP (mmol/L) Serum urea nitrogen (mmol/L) Hemoglobin (g/L) White blood cell (106/L)) Platelet (109/L))
0.004 (41.9) (34.2) (24.0) (20.0)
155 (29.2) 128 (24.2) 161 (30.4) 86 (16.2) 343 (64.7) 176 (33.2) 434 (81.9) 302 (57.0) 35 (6.6) 202 (38.1) 53.2 10.6 31.4 6.9 10.5 4.1 76.9 24.3 9.2 2.2 1.2 0.3 3.1 1.0 1.7 1.2 8.5 4.3 81.3 28.3 6.8 7.3 5.7 4.4 137.8 21.1 7.8 3.3 255.6 79.0
(57.4) (35.3) (7.4) (19.1)
5 (7.4) 11 (16.2) 28 (41.2) 24 (35.3) 45 (66.2) 43 (63.2) 47 (69.1) 42 (61.8) 9 (13.2) 28 (41.2) 55.4 9.3 30.0 6.3 10.7 4.2 76.5 24.1 9.2 2.2 1.2 0.3 3.2 1.1 1.7 1.6 9.1 4.4 95.3 58.7 8.9 11.6 7.3 8.0 130.6 18.2 7.8 3.0 262.3 94.9
0.885 <0.001
0.812 <0.001 0.013 0.453 0.049 0.625 0.010 0.138 0.626 0.903 0.897 0.609 0.347 0.788 0.328 0.069 0.190 0.129 0.012 0.880 0.603
Abbreviations: SR, Saudi riyal (currency unit of Saudi Arabia); HbA1c, glycated hemoglobin; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; CRP, C-reactive protein. a P-values were calculated from x2 test for categorical variables or two-sample t-test for continuous variables. b n (%) for all such values. c Mean standard deviation for all such values.
(OR = 2.80, 95% CI: 1.56–5.01) odds of foot complications than those without the condition. Patients with both DPN and PAD had 9.73 times (OR = 9.73, 95% CI: 4.10–23.11) the odds of foot complications than those with neither of them (Fig. 1).
4.
Discussion
In this study, we found that non-Saudi nationality, insulin use, longer diabetes duration and lower hemoglobin levels were associated with higher prevalence of foot complications in a Saudi population. The associations for insulin use, diabetes duration and hemoglobin levels were attenuated after further adjustment for DPN and PAD, both of which are strong risk factors of foot complications. Patients with both DPN and PAD were at dramatically increased odds of having foot complications than those without either of them.
The prevalence of foot ulcers and amputations in this Saudi population was 9.9%, which was higher than that of several previous reports. In a previous study of 375 diabetic patients in Riyadh, Saudi Arabia, the prevalence of foot ulcers and amputation was only 3% [18]. A study conducted in Bahrain reported a prevalence of 5.9% for foot ulcers [19], which was slightly lower than the current study population (7.9% for foot ulcer). This could be explained by the relatively higher BMI (mean 31.2 kg/m2) and longer duration of diabetes (median 11.25 years, mean 11.28 6.43 years) in this study population compared to the Riyadh study (mean BMI, 26.8 kg/m2; median duration of diabetes, 9.8 years) and the Bahrain population (mean BMI, 27.9 kg/m2; mean duration of diabetes, 9.5 8.40 years). Another reason is the large number of non-Saudi participants in our study, who have much high prevalence of foot complications. The non-Saudi nationalities represent almost one third of the total population and their number is
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Table 3 – Association between risk factors and prevalence of foot complications among individuals with diabetes.a Risk factors
Odds ratio
95% Confidence interval
Pb
Type 2 diabetes vs. Type 1 diabetes Education Illiterate High school University Post graduate Income level (SR/month) <3000 3000–10,000 >10,000 BMI (kg/m2) Smoking, ever-smoker vs. never-smoker Duration of diabetes (years) <5 5–10 10.1–20 >20 Hypertensive vs. normotensive Insulin, user vs. non-user Oral hypoglycemic, user vs. non-user Aspirin, user vs. non-user Clopidogrel, user vs. non-user Statins, user vs. non-user Fasting blood glucose (mmol/L) <7.5 7.5–9.4 9.4–12.8 12.8 HbA1c (% (mmol/mol)) <7.8 (<62) 7.8–9.0 (62–75) 9.0–11.0 (75–97) 11.0 (97) HDL (mmol/L) <1.0 1.0–1.1 1.1–1.3 1.3 LDL (mmol/L) <2.4 2.4–3.0 3.0–3.7 3.7 Triglyceride (mmol/L) <1.0 1.0–1.5 1.5–2.1 2.1 Homocysteine (mmol/L) <6.0 6.0–7.7 7.7–10.0 10.0 Creatinine (mmol/L) <65.0 65.0–78.0 78.0–92.0 92.0 CRP (mmol/L) <3.2 3.2–3.3 3.3–8.2 8.2 Serum urea nitrogen (mmol/L) <4.0
0.57
0.18–1.77
0.330 0.522
Reference 0.93 0.70 0.39
Reference 0.48–1.82 0.35–1.40 0.09–1.78
Reference 1.07 0.38 0.97 1.24
Reference 0.58–1.98 0.13–1.10 0.92–1.01 0.62–2.47
Reference 2.92 5.61 10.09 0.96 3.60 0.45 1.19 2.01 1.08
Reference 0.98–8.72 2.07–15.20 3.51–28.94 0.55–1.67 2.10–6.17 0.25–0.81 0.69–2.04 0.90–4.51 0.64–1.83
Reference 1.80 0.97 1.78
Reference 0.83–3.89 0.41–2.52 0.80–3.94
Reference 1.14 1.36 1.01
Reference 0.51–2.57 0.66–2.83 0.45–2.27
Reference 1.96 1.44 1.18
Reference 0.89–4.33 0.63–3.31 0.50–2.79
Reference 1.64 1.40 1.82
Reference 0.73–3.70 0.59–3.32 0.81–4.13
Reference 0.85 0.75 0.70
Reference 0.41–1.76 0.35–1.59 0.32–1.50
Reference 0.90 1.18 1.00
Reference 0.35–2.31 0.48–2.92 0.40–2.53
Reference 1.02 0.57 1.42
Reference 0.46–2.24 0.22–1.44 0.63–3.22
Reference 2.22 1.90 2.80
Reference 0.88–5.61 0.72–4.99 1.10–7.12 0.319 Reference
0.132
0.118 0.537 <0.001
0.885 <0.001 0.007 0.528 0.090 0.766 0.314
0.861
0.951
0.223
0.337
0.843
0.356
0.139
Reference
Please cite this article in press as: Hu Y, et al. Predictors of diabetes foot complications among patients with diabetes in Saudi Arabia. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.07.016
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Table 3 (Continued ) Risk factors
Odds ratio
95% Confidence interval
4.0–5.0 5.0–6.4 6.4 Hemoglobin (g/L) <125 125–138 138–149 149 White blood cell (106/L)) <5.9 5.9–7.1 7.1–8.9 8.9 Platelet (109/L)) <212 212–253 253–301 301
1.35 0.87 1.56
0.61–2.98 0.36–2.11 0.70–3.47
Reference 0.63 0.54 0.23
Reference 0.30–1.33 0.24–1.22 0.08–0.64 0.704 Reference 0.63–2.87 0.47–2.32 0.42–2.16 0.694 Reference 0.48–2.29 0.60–2.66 0.35–1.86
Pb
0.005
Reference 1.34 1.04 0.96 Reference 1.04 1.27 0.81
Abbreviations: SR, Saudi riyal (currency unit of Saudi Arabia); HbA1c, glycated hemoglobin; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; CRP, C-reactive protein. a Logistic regression model adjusted for sex, age (continuous) and nationality (Saudi, non-Saudi). b For ordinal variables, P-value was estimated by a linear trend test using the median value of each category using complete data.
almost 10 million [20]. Unlike most of previous studies, our study did not exclude the non-Saudi population and that is considered as strength of this study as it reflects the full picture of this clinical problem in the Saudi population. Our results suggest that the non-Saudi nationality be considered as a vulnerable group for diabetes-related foot complications. The multivariable analyses showed that non-Saudi nationality, longer duration of diabetes and insulin use were associated with significantly higher odds of foot complications. Our data suggested that most of the non-Saudi patients (72.7%) had income less than 3000 SR/month, while only 23.9% of the Saudi patients were below this income level. This income disparity might reflect the different socio-economic status between Saudi and non-Saudi patients, and patients with low socio-economic status were less likely to get timely and adequate medical care and diabetes treatment. Diabetes duration was an indicator of the severity of diabetes and was frequently related to the development of DPN and PAD [21,22], but findings were inconsistent for foot ulcers. A matched casecontrol study found that a long duration of having diabetes (>10 years) was associated with 3 times increased risk of foot
ulcers [9]. A cross-sectional study in Bahrain reported an odds ratio of 1.32 for patients with diabetes duration greater than 5 years [19]. However, one prospective cohort study did not observe a significant association between diabetes duration and foot ulcers [6]. The discrepancy might result from the adjustment for DPN or PAD in the model because both of them were potent indicators of diabetes severity, and they are strongly correlated with longer diabetes duration. Similarly, insulin therapy is typically correlated with a longer diabetes duration and greater severity of diabetes. Thus, it was not surprising that the insulin users had higher odds of foot complications in our study. It is interesting that an inverse association was found between hemoglobin levels and foot complications prevalence. Anemia was found to be common among patients with diabetes, and hemoglobin levels tended to decrease while severity of diabetes increased [23]. Several studies reported a positive association between body weight and foot ulcers, and one potential mechanism was through higher plantar pressure in the heavier patients [6,24–26]. However, BMI was not significantly associated with foot complications in our study. Reverse causation could be a
Fig. 1 – Odds ratios of foot complications according to the presence of PAD and DPN among diabetes patient. Please cite this article in press as: Hu Y, et al. Predictors of diabetes foot complications among patients with diabetes in Saudi Arabia. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.07.016
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Table 4 – Multivariable logistic regression of risk factors associated with foot complications.a Risk factors Model without DPN and PAD Sex, male vs. female Age (years), every 1 year increment Nationality, non-Saudi vs. Saudi Insulin, user vs. non-user Oral hypoglycemic drug, user vs. non-user Clopidogrel, user vs. non-user Duration of diabetes (years) <5 5–10 10.1–20 >20 Hemoglobin (g/L) <125 125–138 138–149 149 Model with DPN and PAD Sex, male vs. female Age (years), every 1 year increment Nationality, non-Saudi vs. Saudi Insulin, user vs. non-user Oral hypoglycemic drug, user vs. non-user Clopidogrel, user vs. non-user DPN PAD Duration of diabetes (years) <5 5–10 10.1–20 >20 Hemoglobin (g/L) <125 125–138 138–149 149
95% CI
Pb
1.56 1.00 2.80 2.10 0.85 1.43
0.79–3.06 0.97–1.03 1.61–4.85 1.08–4.09 0.43–1.70 0.60–3.41
0.198 0.962 <0.001 0.030 0.643 0.421 0.024
Reference 2.78 4.33 5.70
Reference 0.91–8.51 1.51–12.44 1.80–18.11
Reference 0.71 0.62 0.31
Reference 0.33–1.54 0.26–1.46 0.11–0.89
1.28 0.99 2.47 1.73 0.97 1.39 3.21 2.80
0.64–2.58 0.96–1.02 1.39–4.38 0.86–3.48 0.46–2.02 0.55–3.52 1.69–6.10 1.56–5.01
Reference 2.70 3.70 3.60
Reference 0.88–8.34 1.26–10.84 1.09–11.89
Reference 0.96 0.72 0.42
Reference 0.42–2.19 0.29–1.76 0.14–1.27
Odds ratio
0.024
0.486 0.383 0.002 0.125 0.929 0.486 <0.0001 <0.001 0.123
0.120
a Logistic regression model adjusted for sex, age (continuous), nationality (Saudi Arabia, non-Saudi Arabia), insulin (user, non-user), duration of DM (<5, 5–10, 10.1–20, >20, years) and hemoglobin (<125.0, 125–138, 138–149, 149, g/L. b For ordinal variables, P-value was estimated by a linear trend test using the median value of each category using complete data.
possible explanation, as patients with foot complications were in very bad physical and psychological condition, and they tended to lose weight. The associations for insulin use, diabetes duration and hemoglobin levels were no longer significant after additional adjusting for DPN and PAD, suggesting these associations were largely mediated by these two conditions. Both DPN and PAD have long been recognized as important risk factors that contribute to the pathogenesis of foot complications such as foot ulcers, gangrene, and amputation. Foot neuropathies usually result in the loss of protective sensation, precipitating a break in the skin or impaired healing and thus lead to foot ulceration. Ischemia is usually the result of macrovascular disease that causes protective sweating loss, dryness in feet, and nail dystrophy [2,27], which put feet in a vulnerable position for ulceration. In our study, diabetes patients with the presence of DPN or PAD had substantially elevated risk of foot complications than those without these conditions. Our findings are consistent with several previous studies. A prospective cohort study found that the foot sensory neuropathy measured by 5.07 monofilament was associated
with 2.17 times (95% CI: 1.52–3.08) the risk of foot ulcers, and higher dorsal foot skin oxygenation (TcPO2) was associated with 20% reduced foot ulcer risk (RR = 0.8, 95% CI: 0.69–0.93) after adjusting for other risk factors [6]. One case-control study reported adjusted ORs for insensate to 5.07 monofilament and TcPO2 < 30 mmHg of 18.42 (95% CI: 3.83–88.87) and 57.87 (95% CI: 5.08–658.96) respectively [28]. A recent systematic review concluded that diabetes neuropathy and peripheral vascular diseases were the most common variables included in a risk stratification system and were consistently associated with diabetes foot ulceration development [29]. Our study also suggested that although DPN and PAD were independent risk factors for foot complications, they might have synergic effects on foot complications development because diabetes patients with both conditions had dramatically elevated risk of developing foot complications. The strengths of this study include a large sample size that included the Saudis and non-Saudis, detailed assessment of foot complications, and comprehensive measures of clinical and biochemical markers. Our study also had several limitations. First, the cross-sectional study design limits our ability
Please cite this article in press as: Hu Y, et al. Predictors of diabetes foot complications among patients with diabetes in Saudi Arabia. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.07.016
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to establish cause-effect relationships between risk factors and foot complications. Therefore, more prospective studies are needed to confirm our results. Second, the case number was relatively small, which leads to limited statistical power. Third, the participants in our study were recruited through advertisement. Thus, participants with severe conditions might not be able or willing to participate in this study. Finally, our study population might not be representative for the Saudi population because the patients were recruited from single city of Saudi Arabia and non-Saudi patients were also included. In conclusion, our study identified several risk factors for foot complications, including longer diabetes duration, insulin use, lower hemoglobin levels and non-Saudi nationality. These associations were largely mediated through the effect of DPN and PAD. The presence of both DPN and PAD was associated with a dramatically elevated risk of foot complications among patients with diabetes.
Conflict of interest
[6]
[7]
[8] [9]
[10]
[11] [12]
None known or perceived. [13]
Author contributions YH analyzed the data and wrote the manuscript. BB, OA and DW contributed to the discussions and revisions of the manuscript. HA and FH contributed to the study design, supervision of this work and the discussions and revision of the final manuscript. All authors read and approved the final version.
[14]
[15]
Funding sources
[16]
Mohammad Hussein Al-Amoudi Chair for Diabetic Foot Research, Saudi Arabia.
[17]
Acknowledgement This research is supported by Mohammad Hussein Al-Amoudi Chair for Diabetic Foot Research, Saudi Arabia.
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