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Prevalence, incidence and progression of peripheral arterial disease in Asian Indian type 2 diabetic patients
Prevalence, incidence and progression of peripheral arterial disease in Asian Indian type 2 diabetic patients Jayasheel Eshcol, Saravanan Jebarani, Ranjit Mohan Anjana, Viswanathan Mohan, Rajendra Pradeepa PII: DOI: Reference:
S1056-8727(14)00128-7 doi: 10.1016/j.jdiacomp.2014.04.013 JDC 6264
To appear in:
Journal of Diabetes and Its Complications
Received date: Revised date: Accepted date:
10 September 2013 24 April 2014 24 April 2014
Please cite this article as: Eshcol, J., Jebarani, S., Anjana, R.M., Mohan, V. & Pradeepa, R., Prevalence, incidence and progression of peripheral arterial disease in Asian Indian type 2 diabetic patients, Journal of Diabetes and Its Complications (2014), doi: 10.1016/j.jdiacomp.2014.04.013
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ACCEPTED MANUSCRIPT Prevalence, incidence and progression of peripheral arterial disease in Asian Indian type 2 diabetic patients
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Jayasheel Eshcol 1 Ranjit Mohan Anjana 2 Viswanathan Mohan 2
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Rajendra Pradeepa 2
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Saravanan Jebarani 2
University of Iowa Hospitals and Clinics, Iowa City, IA, USA
2
Madras Diabetes Research Foundation & Dr. Mohan’s Diabetes Specialities Centre, WHO Collaborating Centre for Non-communicable Diseases Prevention and Control & IDF Centre of Education, Chennai, India
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1
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Key words: Peripheral arterial disease, diabetes, prevalence, incidence, India, South Asians
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Running title: Incidence of peripheral arterial disease in type 2 diabetes
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Word count: 3206 Abstract: 208 No. of Tables: 2 No. of Figures: 1
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ADDRESS FOR CORRESPONDENCE Dr. V. MOHAN, M.D., FRCP (Lond, Edin, Glasg & Ire), Ph.D., D.Sc., FNASc., DIRECTOR & CHIEF OF DIABETES RESEARCH MADRAS DIABETES RESEARCH FOUNDATION & Dr. Mohan’s DIABETES SPECIALITIES CENTRE WHO Collaborating Centre for Noncommunicable Diseases Prevention & Control, 4, CONRAN SMITH ROAD, GOPALAPURAM, CHENNAI - 600 086, INDIA TEL NO: (9144) 4396 8888 FAX NO: (9144) 2835 0935 Email: [email protected] Website:www.drmohansdiabetes.com
ACCEPTED MANUSCRIPT ABSTRACT
Objective: To assess the prevalence, incidence, etiology and factors related to
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progression of peripheral arterial disease [PAD] in Asian Indian type 2 diabetic patients.
Methods: Patients with type 2 diabetes (T2DM), with multiple doppler studies done
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between 2001-2011 at a tertiary diabetes center in south India, were included. Baseline clinical and biochemical characteristics and Ankle Brachial Index [ABI] measurements
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were abstracted from the electronic medical records.
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Results: 2512 T2DM patients were followed for an average of 7 years. 7.6% of the study population had PAD in 2001 [women-11.8%, men- 5.1%] with an adjusted odds ratio (OR) of 3.09 [Confidence Interval (CI):1.9- 4.9] for women. Prevalent PAD was
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associated with increased mortality [Hazards ratio (HR) 3.3, CI:1.4-7.7]. 280 new patients of PAD were identified- crude incidence, 17/1000 patient years with higher rates
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in females [HR 1.94, CI:1.4-2.7]. Age and duration of diabetes were the other predictors of incident PAD. Progression of PAD was seen in 16.5% of patients, with age (p=0.002)
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and HbA1c (p= 0.022) being the predictors.
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Conclusions: Women had a higher prevalence of PAD. Older age, female gender and duration of diabetes were related to an increased incidence of PAD. An elevated HbA1c being associated with progression of PAD stresses the need for strict control of diabetes.
ACCEPTED MANUSCRIPT INTRODUCTION
Peripheral arterial disease (PAD) is a disease in which, atherosclerotic (AS)
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stenosis of arteries in organs other than the heart and the brain and most commonly,
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arteries in the lower extremities are involved. Since AS is a generalized disease, PAD is associated with increased mortality due to coronary artery disease (Weitz et al., 1996).
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PAD can be diagnosed noninvasively by measuring the ankle brachial index [ABI]. Diabetes is a well known risk factor for PAD and the American Diabetes Association
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[ADA] recommends screening for PAD in all patients with diabetes >50 years of age and in diabetic patients younger than age 50 with at least one other risk factor for coronary
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artery disease (American Diabetes Association.,2004).
According to the recent national Indian Council of Medical Research - India
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Diabetes [ICMR-INDIAB] study currently, in India, there are 62.4 million people with type 2 diabetes mellitus [T2DM] (Anjana et al., 2011). Furthermore, the burden of micro and
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macrovascular complications is immense since T2DM occurs at a younger age compared to an occidental population of Europe (Pradeepa et al., 2010). Overall the
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prevalence of PAD is lower in Asian Indians, but this is mainly due to the younger age at onset of T2DM. As the population ages, the prevalence of PAD will dramatically
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increase. Moreover as India’s population is currently 1.2 billion this means that already there are ~4 million people with PAD assuming the prevalence of PAD to be 6.3% (Premalatha et al., 2000). Indeed it is now known that the economic burden of PAD is equivalent to that of CVD (Mahoney et al., 2010). It is therefore crucial to understand the risk factors for PAD in the Indian diabetic population. Several studies have published information on the prevalence of PAD in the diabetic population. However, only a few studies have reported data on incident PAD or progression of PAD, and there are none from India. Hence the present study was taken up, to assess the prevalence, incidence and progression of, and factors associated with, PAD in Asian Indian T2DM patients attending a large diabetic centre in south India.
ACCEPTED MANUSCRIPT METHODS
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Study population
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Patients with T2DM, with multiple doppler studies (2001-2011) at the Dr Mohan's Diabetes Specialties Centre, a tertiary diabetes care center in Chennai city in south
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India, were included in the study. The centre has state-of-the-art facilities for diabetes and its complications at fifteen clinics in different geographical areas in southern India.
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All the clinics are linked through electronic medical records, from which baseline clinical and biochemical characteristics and Ankle Brachial Index [ABI] measurements were
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abstracted.
A total of 7,586 T2DM patients aged 20 years and above were registered in
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2001, of whom 6893 patients had ABI measurements (response rate 90.9%). Of these, 2512 patients [36.4%] had at least one follow up ABI measurement between the years
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2001 and 2011. They were termed ‘responders’ and were included in the study. The rest, i.e., 4,381 of the 6,893 were considered as ‘non-responders’. The mean number of
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ABI measurements was 3.6 ± 1.8 during the follow up period and the mean time between first and last ABI was 7.0 ± 2.8 years. There were no significant differences in and the 4,381 non-responders
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the baseline values between the 2512 responders
[responders vs non-responders: age (years) 51 10 vs 52 12, p = 0.174; fasting plasma glucose (mg/dl): 160 58 vs 163 58, p = 0.074; duration of diabetes (years) 7.8 6.7 vs 8.0 6.7, p = 0.246; systolic blood pressure (mm Hg): 131 16 vs 132 17, p = 0.128; diastolic blood pressure (mm Hg): 82 7 vs 82 8, p = 0.584)]. The exclusion criteria included patients aged <20 years, patients who had been examined earlier at the hospital, type 1 diabetes and other types of diabetes, those with any open wounds, casts, or dressings that interfered with testing or those who were not willing to undergo the Doppler test.
ACCEPTED MANUSCRIPT Approval of the Institutional Ethics Committee of Madras Diabetes Research Foundation was obtained prior to study commencement and written informed consent
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was obtained from all participants.
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Clinical and biochemical studies
Measurements of weight, height, and waist circumference were obtained using
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standardized techniques. The BMI was calculated using the following formula: weight [kg)/ height (m2)]. Blood pressure was recorded in the sitting position in the right arm
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with a mercury sphygmomanometer [Diamond Deluxe Industrial Electronics and Products, Pune, India]. The pulse pressure (pressure difference between the systolic
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and diastolic pressures) was also obtained.
A fasting blood sample was taken for estimation of fasting plasma glucose,
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serum cholesterol, serum triglycerides, high density lipoprotein [HDL] cholesterol and creatinine using a Hitachi-912 Autoanalyser [Hitachi, Mannheim, Germany]. The intra-
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and inter assay coefficient of variation for the biochemical assays ranged between 3.1% and 7.6%. Low-density lipoprotein [LDL] cholesterol was calculated using the
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Friedewald formula. Glycated hemoglobin [HbA1c] was estimated by high pressure liquid chromatography using the Variant machine [Bio-Rad, Hercules, CA, USA] certified
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by National Glycohemoglobin Standardization Program (NGSP). The intra- and interassay coefficients of variation of HbA1c nearest to 6.0% were 1.65% and 2.75% respectively for the Variant II machine which was used between 2001 and 2006 and 0.59% and 1.15% for the Variant II Turbo machine, which was used from 2007 to 2011.
Doppler studies
Blood pressure recordings were made of brachial, dorsalis pedis and posterior tibial arteries in the supine position by trained technicians by doppler probe using the KodyVaslab machine [Kody Labs, Chennai, India]. For each leg the highest pressure of the dorsalis pedis and posterior tibial arteries was used as the numerator while the higher of the brachial pressures was used as the denominator (Premalatha et al., 2000).
ACCEPTED MANUSCRIPT The lower ABI of the two legs was as defined as the ABI of the patient. The interobserver variation of the ABI measurements of two independent technicians and the intra-observer variation of the two readings measured by one technician were assessed
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by the kappa statistics [ ] in a subset of 100 patients. The unweighted
for inter-
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observer agreement was 0.756 indicating good concordance. While the unweighted
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for agreement for intra-observer variation was 0.880 indicating very good agreement.
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Electrocardiogram [ECG]
A resting 12-lead ECG was also carried out. Minnesota coding was used to
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grade the ECGs by a single trained grader who was masked to the clinical status of the patient.
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Definitions
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PAD was defined based on the American College of Cardiology/American Heart Association [ACC/AHA] 2005 guidelines (Hirsch et al., 2006) as an ABI ≤ 0.90 while an
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ABI > 1.30 was graded as unclassifiable. Progression of PAD was defined as a decrease in ABI>0.15 or a change in category of severity (Hirsch et al., 2006). For
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quantitative change the patients were grouped in 3 categories, less than −0.15, −0.15 to +0.15, and more than +0.15. The change in ABI was calculated using the first and last measurements of ABI.
Coronary artery disease [CAD] was diagnosed based on a past history of documented myocardial infarction and/or drug treatment for CAD (aspirin or nitrates) and/or electrocardiographic changes suggestive of ST segment depression and/or Qwave changes and/or T-wave changes using appropriate Minnesota codes (Rose et al., 1982).
Age was defined as the age at the time of the first examination i.e. in 2001.
ACCEPTED MANUSCRIPT Hypertension was diagnosed based on past medical history, drug treatment for hypertension, and/or if the patient had systolic blood pressure [SBP] of 140 mmHg or greater and/or diastolic blood pressure [DBP] of 90 mmHg (National High Blood
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Pressure Education Program, 2003) .
Estimated Glomerular Filtration Rate [eGFR] was estimated using the Modification of
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Diet in Renal Disease [MDRD] study equation [mL/min/1.73 m2] (Levey et al.,1999 ). The formula used for calculating the GFR was: GFR = 186 × (serum creatinine)−1.154 ×
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Age−0.203 × (0.742 if female) × (1.210 if African-American [not applicable to our population])
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Smoking: Individuals were classified as ‘never smoked’ and ‘ever smoked’.
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Statistical Analysis
All statistical analyses were performed with SAS version 9.1 [SAS Institute, Cary, North
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Carolina]. Patients with initial or final ABI values greater than >1.3 were not analyzed for incidence or progression. Baseline characteristics of the population of patients with and
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without PAD were compared by logistic regression analysis. Cox proportional hazard models were used to determine the hazard ratio for mortality, incident PAD and
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progression. For incident PAD, time was measured from the initial ABI in 2001 to the date of ABI ≤0.9 for incident cases. For mortality, time was measured from the initial ABI to the date of death and date of last visit for censored cases. To build the Cox model, we first did a univariate analysis of each variable .Categorical variables were analyzed with Kaplan-Meir curves to ensure proportionality and the variable was included in the multivariate model if the log rank test had a p-value <0.20. Cox proportional hazard model was done separately for each continuous variable and variables were included in the final model if the Chi-squared test had a p-value <0.20. The final Cox proportional hazard model for incident PAD and progression also included the first ABI to adjust for regression to the mean.
ACCEPTED MANUSCRIPT RESULTS
The study population consisting of 2512 type 2 diabetic patients [952 females
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and 1560 males] who were followed for a mean of 7.0 ± 2.8 years. Nineteen patients [3
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females] with a baseline or final ABI value >1.3 were excluded from the study. Thus, a
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total of 2493 patients were included in the study.
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Prevalence of PAD
Table 1 presents the clinical and biochemical characteristics of patients without
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PAD and those with PAD at baseline and those who developed PAD on follow up. The population with PAD at baseline were older, had a longer duration of hypertension and diabetes, higher blood pressure and pulse pressure, higher LDL cholesterol and lower
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eGFR compared to those without PAD. CAD was present in 9.3% among those without PAD, 15.2% among those with PAD at baseline and 16.4% among those who
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developed PAD during the follow up.
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The baseline prevalence of PAD was 7.6% [11.8% in women and 5.1% in men, p<0.001]. The prevalence of PAD among female patients ranged from 5.2% in patients
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under 40 years to 10.2% in those in the age group of 40-60 years and 20.2% in patients older than 60 years [trend 2 :17.99, p<0.001]. The corresponding prevalence among men were 1.7%, 3.9% and 11.1% [trend 2:27.61, p<0.001]. Thus the baseline prevalence of PAD was higher among female patients at all the age groups studied.
On multivariate analysis of prevalent PAD, female gender came out as the strongest predictor of PAD with an OR 3.09 [CI 1.96-4.89]. Other variables significantly associated with prevalent PAD were age [OR: 1.06 (CI1.04-1.09), p<0.001], duration of diabetes [OR: 1.03 (CI 1.00-1.06), p=0.04] and LDL cholesterol [OR: 1.01(CI 1.0021.013), p=0.01]. During the follow-up period, 43 patients died of whom 13 were females. Prevalent PAD was associated with higher mortality with an adjusted hazard ratio [HR] of 3.3 [CI 1.4-7.7]
ACCEPTED MANUSCRIPT Incidence of PAD
During the period of follow-up, 280 patients developed PAD, resulting in a crude
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PAD incidence rate of 17.2 per 1000 patient years. 15.3% of women compared to 8.7%
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of men developed PAD [p<0.001] [Figure 1]. On univariate analysis [Table 2], the group that developed PAD was older, had longer duration of diabetes, higher blood
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pressure, HbA1c and LDL cholesterol and the e-GFR was lower, compared to patients
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who remained free of PAD.
On multivariate analysis, the most powerful predictor of incident PAD was female
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gender with a hazard ratio of 1.94 [CI 1.4-2.7]. The only other predictors that remained significant were age [HR: 1.03 (CI 1.01- 1.05), p=0.001] and duration of diabetes [HR:
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1.03 (CI 1.01- 1.05), p=0.008].
In addition, the incidence of PAD increased with increasing age, with a crude
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incidence rate of 11.0 per 1000 patient years in the age group < 40 years, 20.3 for ages
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40-60 and 44.7 for the age group >60 years.
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Progression of PAD
There was a significant change in ABI [defined as ± 0.15] in 413 [16.5%] of patients. Of these 137 [5.5%] had a decrease and 276 [11%] had an increase in ABI. A change in ABI, was significantly associated with higher A1C compared to patients who had a stable ABI (HbA1c <7%: 14.9%; 7-8.9%: 15.7%; ≥9%: 19.1%, Trend p=0.044). Age and HbA1c were also predictors of progression in the multivariate analysis [Table 2]. There was no difference in progression between males and females. Low eGFR, pulse pressure and duration of diabetes were associated with progression on univariate, but not multivariate, analysis.
The relationship between treatment [exercise rehabilitation, anti-platelet therapy, lipid-lowering drugs] and progression of PAD was studied. Of the 191 subjects who had
ACCEPTED MANUSCRIPT PAD at baseline, PAD progression was observed in 80 subjects [41.9%]. Of the 80 subjects, 1.3% [n=1] were on exercise rehabilitation therapy, 47.5% [n=38] were on antiplatelet therapy, 36.2% [n=29] were on lipid-lowering medication and 15.0% [n=12] were
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on combination therapy of anti-platelet and lipid-lowering therapy [trend 2:6.58,
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p=0.010].”
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DISCUSSION
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This is the first study highlighting some of the factors associated with the progression of PAD in Asian Indians with T2DM. Thus, it may be possible to mitigate
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some of the complications responsible for the already huge burden of diabetes in this ethnic group (Gujral et al., 2013). The overall prevalence of PAD at baseline [2001] was similar to an earlier population based study done in our city (Premalatha et al., 2000) as
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well as data from diabetic patients in the 1999–2004 National Health and Nutrition Examination Surveys [NHANES] (Gregg et al., 2007). Earlier studies have shown a
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lower prevalence of PAD in Asian Indians compared to other ethnic groups (Premalatha & Mohan.,1995; Premaltha et al., 2000) which may be because of the lower age of the
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study participants in Indians compared to other ethnic group. It is well known that age is an important risk factor for PAD. The average age in this study was 51.5 years, which is
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much lower than most western studies of PAD in T2DM where the age is in the range of 55 -74 years (Alzamora et al., 2010).
One of the striking findings in our study is the higher prevalence and incidence of PAD in women. PAD is generally believed to equally affect men and women, although the data is primarily from the Caucasian populations (Hirsch et al., 2012). There are however some studies that show increased prevalence in women. A prospective population based study in Singapore showed that females had higher risk for PAD across three ethnic groups, with the highest in the Indian sub-group [adjusted OR 3.71] (Subramaniam et al., 2011). The Peripheral Arterial Disease in Interventional Patients Study which found 23.3% of women had ABI <0.9 compared to 11.6% of men (Moussa et al., 2009). There may indeed be ethinic differences as suggested by a recent meta-
ACCEPTED MANUSCRIPT analysis comparing PAD in different ethnic groups in America. While women in the fifth decade had a higher rates of PAD than men in all ethnic groups, among Asian American, and American Indians, prevalence of PAD was higher in women at all age
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groups (Allison et al., 2007).
There may be a physiologic basis for the difference in PAD prevalence between
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men and women and it could be related to differences in the risk factors for PAD. According to Nasir et al (2007), the gender differences in PAD may be related to
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differences in the biology between vascular beds. These authors reported that women tended to have higher thoracic aorta calcification in contrast to men who had higher
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coronary calcification. It is of interest that the prevalence rate of PAD in women was higher, despite the much lower smoking rate in women compared to men (0% vs. 12% respectively). Also, 20.2% of the female patients older than 60 years had PAD
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compared to 11.1% in men the same age group. One of the reasons for this could be that older women take poorer care of their diabetes than men. There is an obvious need
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for more studies to better understand the biology of differential susceptibility to PAD
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between women and men.
Several studies have reported both decreases as well increases in ABI. A cut-off
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value of 0.15 representing a significant change, has been used in multiple studies (Nicoloff et al., 2002) and has been found to be associated with an increase in all cause as well as CVD mortality (Criqui et al., 2008). In this study, there was a significant change in ABI (± 0.15) in over 15% of patients (<0.15: 5.5%; >0.15: 11%). However, the rate of progression as denoted by a decline in ABI is lower than that reported in other ethnic groups (Aboyans et al., 2006). This could likely be a reflection of the younger age of our patients. However, with regards to the increase in ABI observed in our study it is unclear whether this reflects an improvement or it is due to medial arterial calcification consequent to ageing which causes stiffening of the vessel wall thereby resulting in higher ABI readings. While relatively little attention has been given to a rise in ABI values, it is now being recognized that a high ABI confers a similar risk for CVD, as a low ABI (Resnick et al., 2004).
ACCEPTED MANUSCRIPT The intra- or inter observer variability of ABI measurements in this study varied from good to very good. The ABI test has been shown to have excellent reproducibility with a variation in measurements between 9-21%. de Graaf et al ( 2001 ) found that
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there was no significant intra or inter observer differences at 1 day and 1 week, with a
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repeatability coefficient of 9-27% (suggesting a difference greater than 27% is not
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related to measurement variation) and intra-class coefficient of 0.87-0.98..
There are several limitations to our study. First, as this is a retrospective chart
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review, it is subject to missing data at baseline [HbA1c values (n=585), lipids (n=72) and blood pressure (n=96) ]. Second, the study was conducted at a single private diabetes center and hence it may not be generalizable to diabetic populations of all
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socioeconomic classes or to the population of India. Third, as it is a retrospective ‘real life’ study, the number and duration between ABIs measurements varied between
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patients. Fourth, including patients with at least 2 ABI measurements may be a potential source of bias. Fifth, using only one ABI as a diagnostic tool has its own limitation
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according to the American Diabetes Association [ADA] (2004) which includes calcified or poorly compressible vessels in the elderly. Next, although there are stringent internal
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quality control measures at our centre to ensure accuracy of the ABI significant intra and inter observer variations could have occurred during the long period of the study
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due to different technicians doing the doppler study. Finally, patients with initial or final ABI values greater than >1.3 were not analyzed for incidence or progression as the measurements are less reliable, although such patients have been shown to have similar CVD risk as patients with PAD.
Conclusion Our study shows that women with T2DM had higher prevalence of PAD. Older age, female gender and duration of diabetes were related to an increased incidence of PAD. As an elevated HbA1c is associated with progression of PAD , this stresses the need for strict control of diabetes.
Conflict of interest: The authors declare that they have no conflicts of interest
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ACCEPTED MANUSCRIPT Table 1: Clinical and biochemical characteristics of the study population Characteristic
No PAD
PAD at Baseline
Developed PAD during follow-up (n = 280)
51.0 ± 9.9
57.5 ± 10*
54.7 ± 10*
112 [58.6]* 25.3 ± 5.5
25.3 ± 4.1
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(n=191)
145 [51.8]*
133 ± 16
135 ± 18**
81 ± 8*
82 ± 8
49 ± 13
52 ± 13**
53 ± 14 **
Duration of HTN (yrs)
4.8 ± 5.6
6.7 ± 6.9**
5.1 ± 6.2
Duration of DM (yrs)
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Age (yrs)
(n=2022)
6.5 ± 6.2
9.1 ± 8.4 **
8.3 ± 7.4**
160 ± 57
163 ± 70
158 ± 57
8.8 ± 2.0
9.1 ± 2.4
9.1 ± 2.1
197 ± 39
204 ± 45
202 ± 41
HDL cholesterol (mg/dL)
43 ± 9.5
44 ± 10
44 ± 10
LDL cholesterol (mg/dL)
120 ± 33
127.1 ± 37*
125.1 ± 36 *
Triglycerides (mg/dL)^
153
152
144*
eGFR (mL/min/1.732)
77 ± 13
70 ± 14**
74 ± 13 **
Hypertension (n [%])
1100 [54.4]
118 [61.8]
161 [57.5]
188 [9.3]
29 [15.2]
46 [16.4]
341 [17.4]
23 [12.4]
32 [11.6]
Diet
19 [0.8]
1 [0.5]
5 [1.8]
OHA
1503 [65.3]
95 [51.3]**
155 [55.4]**
43 [1.9]
5 [2.6]
5 [1.8]
737 [32.0]
87 [45.5]**
115 [41.1]**
692 [34.2] 2
25.3 ± 3.8
Systolic BP (mmHg)
131 ± 16
Diastolic BP (mmHg)
83 ± 8
Pulse Pressure (mm Hg)
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Body mass index (kg/m )
HbA1c (%)
CAD (n [%])
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Total cholesterol (mg/dL)
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Fasting plasma glucose (mg/dL)
Ever smoked (n [%] ≠
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Female (n [%])
Management
Insulin OHA + Insulin
*P=<0.05; **P=<0.005 compared to patients without PAD ;^ Geometric mean;
≠
All
smokers were men PAD: Peripheral arterial disease; eGFR: Estimated Glomerular Filtration rate; CAD : Coronary Artery Disease ; OHA- Oral Hypoglycemic Agents
ACCEPTED MANUSCRIPT Table 2: Cox-Regression analysis for incident and progression of peripheral arterial disease Univariate Analysis Hazard Ratio
p-value
1.96 (1.55-2.48)
Duration of DM (per year)
4.38 (2.67-7.2)
Pulse Pressure (mm Hg)
1.03 (1.02-1.03)
HbA1c (%) LDL cholesterol (mg/dL)
(95% CI)
1.03 (1.01-1.05)
0.001
<0.001
1.86 (1.33-2.59)
<0.001
<0.001
1.03 (1.01-1.05)
0.010
<0.001
1.01 (0.99-1.02)
0.17
1.08 (1.02-1.15)
0.014
1.05 (0.98-1.13)
0.158
1.00 (1.00-1.01)
0.018
1.00 (1.00-1.01)
0.281
Low eGFR (mL/min/1.732)
0.98 (0.97-9.99)
<0.001
1.00 (0.99-1.01)
0.903
Smoking (yes)
0.65 (0.45-0.94
0.022
1.10 (0.99-1.02)
0.625
1.01 (1.00-1.03)
0.028
1.00 (0.70-1.75)
0.671
1.05 (1.03-1.07)
<0.001
1.04 (1.01-1.06)
0.002
0.80 (0.55-1.16)
0.24
1.08 (0.71-1.65)
0.718
Duration of DM (per year)
1.05 (1.03-1.08)
<0.001
1.01 (0.98-1.04)
0.422
Pulse Pressure (mm Hg)
1.03 (1.02-1.04)
<0.001
1.01 (1.00-1.02)
0.19
HbA1c Average (%)
1.12 (1.00-1.23)
0.047
1.16 (1.02-1.32)
0.022
LDL cholesterol (mg/dL)
1.00 (1.00-1.01)
0.132
1.00 (1.00-1.01)
0.231
Low eGFR (mL/min/1.732)
0.98 (0.97-9.99)
0.001
0.99 (0.98-1.01)
0.387
Smoking (yes)
0.80 (0.51-1.26)
0.336
HDL cholesterol (mg/dL)
1.00 (0.98-1.02)
0.866
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Female gender
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Age (per year)
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PAD Progression
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HDL cholesterol (mg/dL)
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Female gender
<0.001
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1.05 (1.04-1.06)
p-value
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Incident PAD Age (per year)
Hazard Ratio
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(95% CI)
Final Multivariate Model*
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Variable
* Included all variables with p<0.20 in univariate analysis. Pulse pressure and LDL and HDL cholesterol selected for being more significant than other measures of BP and lipid profile. Baseline ABI was forced into the model to adjust for regression to the mean.
ACCEPTED MANUSCRIPT LEGEND TO FIGURE:
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Figure 1: Gender-wise incidence of peripheral arterial disease in the study population
S1056-8727(14)00128-7 doi: 10.1016/j.jdiacomp.2014.04.013 JDC 6264
To appear in:
Journal of Diabetes and Its Complications
Received date: Revised date: Accepted date:
10 September 2013 24 April 2014 24 April 2014
Please cite this article as: Eshcol, J., Jebarani, S., Anjana, R.M., Mohan, V. & Pradeepa, R., Prevalence, incidence and progression of peripheral arterial disease in Asian Indian type 2 diabetic patients, Journal of Diabetes and Its Complications (2014), doi: 10.1016/j.jdiacomp.2014.04.013
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Prevalence, incidence and progression of peripheral arterial disease in Asian Indian type 2 diabetic patients
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Jayasheel Eshcol 1 Ranjit Mohan Anjana 2 Viswanathan Mohan 2
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Rajendra Pradeepa 2
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Saravanan Jebarani 2
University of Iowa Hospitals and Clinics, Iowa City, IA, USA
2
Madras Diabetes Research Foundation & Dr. Mohan’s Diabetes Specialities Centre, WHO Collaborating Centre for Non-communicable Diseases Prevention and Control & IDF Centre of Education, Chennai, India
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1
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Key words: Peripheral arterial disease, diabetes, prevalence, incidence, India, South Asians
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Running title: Incidence of peripheral arterial disease in type 2 diabetes
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Word count: 3206 Abstract: 208 No. of Tables: 2 No. of Figures: 1
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ADDRESS FOR CORRESPONDENCE Dr. V. MOHAN, M.D., FRCP (Lond, Edin, Glasg & Ire), Ph.D., D.Sc., FNASc., DIRECTOR & CHIEF OF DIABETES RESEARCH MADRAS DIABETES RESEARCH FOUNDATION & Dr. Mohan’s DIABETES SPECIALITIES CENTRE WHO Collaborating Centre for Noncommunicable Diseases Prevention & Control, 4, CONRAN SMITH ROAD, GOPALAPURAM, CHENNAI - 600 086, INDIA TEL NO: (9144) 4396 8888 FAX NO: (9144) 2835 0935 Email: [email protected] Website:www.drmohansdiabetes.com
ACCEPTED MANUSCRIPT ABSTRACT
Objective: To assess the prevalence, incidence, etiology and factors related to
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progression of peripheral arterial disease [PAD] in Asian Indian type 2 diabetic patients.
Methods: Patients with type 2 diabetes (T2DM), with multiple doppler studies done
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between 2001-2011 at a tertiary diabetes center in south India, were included. Baseline clinical and biochemical characteristics and Ankle Brachial Index [ABI] measurements
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were abstracted from the electronic medical records.
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Results: 2512 T2DM patients were followed for an average of 7 years. 7.6% of the study population had PAD in 2001 [women-11.8%, men- 5.1%] with an adjusted odds ratio (OR) of 3.09 [Confidence Interval (CI):1.9- 4.9] for women. Prevalent PAD was
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associated with increased mortality [Hazards ratio (HR) 3.3, CI:1.4-7.7]. 280 new patients of PAD were identified- crude incidence, 17/1000 patient years with higher rates
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in females [HR 1.94, CI:1.4-2.7]. Age and duration of diabetes were the other predictors of incident PAD. Progression of PAD was seen in 16.5% of patients, with age (p=0.002)
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and HbA1c (p= 0.022) being the predictors.
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Conclusions: Women had a higher prevalence of PAD. Older age, female gender and duration of diabetes were related to an increased incidence of PAD. An elevated HbA1c being associated with progression of PAD stresses the need for strict control of diabetes.
ACCEPTED MANUSCRIPT INTRODUCTION
Peripheral arterial disease (PAD) is a disease in which, atherosclerotic (AS)
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stenosis of arteries in organs other than the heart and the brain and most commonly,
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arteries in the lower extremities are involved. Since AS is a generalized disease, PAD is associated with increased mortality due to coronary artery disease (Weitz et al., 1996).
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PAD can be diagnosed noninvasively by measuring the ankle brachial index [ABI]. Diabetes is a well known risk factor for PAD and the American Diabetes Association
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[ADA] recommends screening for PAD in all patients with diabetes >50 years of age and in diabetic patients younger than age 50 with at least one other risk factor for coronary
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artery disease (American Diabetes Association.,2004).
According to the recent national Indian Council of Medical Research - India
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Diabetes [ICMR-INDIAB] study currently, in India, there are 62.4 million people with type 2 diabetes mellitus [T2DM] (Anjana et al., 2011). Furthermore, the burden of micro and
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macrovascular complications is immense since T2DM occurs at a younger age compared to an occidental population of Europe (Pradeepa et al., 2010). Overall the
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prevalence of PAD is lower in Asian Indians, but this is mainly due to the younger age at onset of T2DM. As the population ages, the prevalence of PAD will dramatically
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increase. Moreover as India’s population is currently 1.2 billion this means that already there are ~4 million people with PAD assuming the prevalence of PAD to be 6.3% (Premalatha et al., 2000). Indeed it is now known that the economic burden of PAD is equivalent to that of CVD (Mahoney et al., 2010). It is therefore crucial to understand the risk factors for PAD in the Indian diabetic population. Several studies have published information on the prevalence of PAD in the diabetic population. However, only a few studies have reported data on incident PAD or progression of PAD, and there are none from India. Hence the present study was taken up, to assess the prevalence, incidence and progression of, and factors associated with, PAD in Asian Indian T2DM patients attending a large diabetic centre in south India.
ACCEPTED MANUSCRIPT METHODS
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Study population
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Patients with T2DM, with multiple doppler studies (2001-2011) at the Dr Mohan's Diabetes Specialties Centre, a tertiary diabetes care center in Chennai city in south
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India, were included in the study. The centre has state-of-the-art facilities for diabetes and its complications at fifteen clinics in different geographical areas in southern India.
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All the clinics are linked through electronic medical records, from which baseline clinical and biochemical characteristics and Ankle Brachial Index [ABI] measurements were
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abstracted.
A total of 7,586 T2DM patients aged 20 years and above were registered in
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2001, of whom 6893 patients had ABI measurements (response rate 90.9%). Of these, 2512 patients [36.4%] had at least one follow up ABI measurement between the years
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2001 and 2011. They were termed ‘responders’ and were included in the study. The rest, i.e., 4,381 of the 6,893 were considered as ‘non-responders’. The mean number of
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ABI measurements was 3.6 ± 1.8 during the follow up period and the mean time between first and last ABI was 7.0 ± 2.8 years. There were no significant differences in and the 4,381 non-responders
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the baseline values between the 2512 responders
[responders vs non-responders: age (years) 51 10 vs 52 12, p = 0.174; fasting plasma glucose (mg/dl): 160 58 vs 163 58, p = 0.074; duration of diabetes (years) 7.8 6.7 vs 8.0 6.7, p = 0.246; systolic blood pressure (mm Hg): 131 16 vs 132 17, p = 0.128; diastolic blood pressure (mm Hg): 82 7 vs 82 8, p = 0.584)]. The exclusion criteria included patients aged <20 years, patients who had been examined earlier at the hospital, type 1 diabetes and other types of diabetes, those with any open wounds, casts, or dressings that interfered with testing or those who were not willing to undergo the Doppler test.
ACCEPTED MANUSCRIPT Approval of the Institutional Ethics Committee of Madras Diabetes Research Foundation was obtained prior to study commencement and written informed consent
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was obtained from all participants.
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Clinical and biochemical studies
Measurements of weight, height, and waist circumference were obtained using
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standardized techniques. The BMI was calculated using the following formula: weight [kg)/ height (m2)]. Blood pressure was recorded in the sitting position in the right arm
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with a mercury sphygmomanometer [Diamond Deluxe Industrial Electronics and Products, Pune, India]. The pulse pressure (pressure difference between the systolic
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and diastolic pressures) was also obtained.
A fasting blood sample was taken for estimation of fasting plasma glucose,
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serum cholesterol, serum triglycerides, high density lipoprotein [HDL] cholesterol and creatinine using a Hitachi-912 Autoanalyser [Hitachi, Mannheim, Germany]. The intra-
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and inter assay coefficient of variation for the biochemical assays ranged between 3.1% and 7.6%. Low-density lipoprotein [LDL] cholesterol was calculated using the
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Friedewald formula. Glycated hemoglobin [HbA1c] was estimated by high pressure liquid chromatography using the Variant machine [Bio-Rad, Hercules, CA, USA] certified
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by National Glycohemoglobin Standardization Program (NGSP). The intra- and interassay coefficients of variation of HbA1c nearest to 6.0% were 1.65% and 2.75% respectively for the Variant II machine which was used between 2001 and 2006 and 0.59% and 1.15% for the Variant II Turbo machine, which was used from 2007 to 2011.
Doppler studies
Blood pressure recordings were made of brachial, dorsalis pedis and posterior tibial arteries in the supine position by trained technicians by doppler probe using the KodyVaslab machine [Kody Labs, Chennai, India]. For each leg the highest pressure of the dorsalis pedis and posterior tibial arteries was used as the numerator while the higher of the brachial pressures was used as the denominator (Premalatha et al., 2000).
ACCEPTED MANUSCRIPT The lower ABI of the two legs was as defined as the ABI of the patient. The interobserver variation of the ABI measurements of two independent technicians and the intra-observer variation of the two readings measured by one technician were assessed
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by the kappa statistics [ ] in a subset of 100 patients. The unweighted
for inter-
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observer agreement was 0.756 indicating good concordance. While the unweighted
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for agreement for intra-observer variation was 0.880 indicating very good agreement.
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Electrocardiogram [ECG]
A resting 12-lead ECG was also carried out. Minnesota coding was used to
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grade the ECGs by a single trained grader who was masked to the clinical status of the patient.
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Definitions
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PAD was defined based on the American College of Cardiology/American Heart Association [ACC/AHA] 2005 guidelines (Hirsch et al., 2006) as an ABI ≤ 0.90 while an
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ABI > 1.30 was graded as unclassifiable. Progression of PAD was defined as a decrease in ABI>0.15 or a change in category of severity (Hirsch et al., 2006). For
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quantitative change the patients were grouped in 3 categories, less than −0.15, −0.15 to +0.15, and more than +0.15. The change in ABI was calculated using the first and last measurements of ABI.
Coronary artery disease [CAD] was diagnosed based on a past history of documented myocardial infarction and/or drug treatment for CAD (aspirin or nitrates) and/or electrocardiographic changes suggestive of ST segment depression and/or Qwave changes and/or T-wave changes using appropriate Minnesota codes (Rose et al., 1982).
Age was defined as the age at the time of the first examination i.e. in 2001.
ACCEPTED MANUSCRIPT Hypertension was diagnosed based on past medical history, drug treatment for hypertension, and/or if the patient had systolic blood pressure [SBP] of 140 mmHg or greater and/or diastolic blood pressure [DBP] of 90 mmHg (National High Blood
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Pressure Education Program, 2003) .
Estimated Glomerular Filtration Rate [eGFR] was estimated using the Modification of
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Diet in Renal Disease [MDRD] study equation [mL/min/1.73 m2] (Levey et al.,1999 ). The formula used for calculating the GFR was: GFR = 186 × (serum creatinine)−1.154 ×
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Age−0.203 × (0.742 if female) × (1.210 if African-American [not applicable to our population])
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Smoking: Individuals were classified as ‘never smoked’ and ‘ever smoked’.
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Statistical Analysis
All statistical analyses were performed with SAS version 9.1 [SAS Institute, Cary, North
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Carolina]. Patients with initial or final ABI values greater than >1.3 were not analyzed for incidence or progression. Baseline characteristics of the population of patients with and
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without PAD were compared by logistic regression analysis. Cox proportional hazard models were used to determine the hazard ratio for mortality, incident PAD and
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progression. For incident PAD, time was measured from the initial ABI in 2001 to the date of ABI ≤0.9 for incident cases. For mortality, time was measured from the initial ABI to the date of death and date of last visit for censored cases. To build the Cox model, we first did a univariate analysis of each variable .Categorical variables were analyzed with Kaplan-Meir curves to ensure proportionality and the variable was included in the multivariate model if the log rank test had a p-value <0.20. Cox proportional hazard model was done separately for each continuous variable and variables were included in the final model if the Chi-squared test had a p-value <0.20. The final Cox proportional hazard model for incident PAD and progression also included the first ABI to adjust for regression to the mean.
ACCEPTED MANUSCRIPT RESULTS
The study population consisting of 2512 type 2 diabetic patients [952 females
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and 1560 males] who were followed for a mean of 7.0 ± 2.8 years. Nineteen patients [3
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females] with a baseline or final ABI value >1.3 were excluded from the study. Thus, a
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total of 2493 patients were included in the study.
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Prevalence of PAD
Table 1 presents the clinical and biochemical characteristics of patients without
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PAD and those with PAD at baseline and those who developed PAD on follow up. The population with PAD at baseline were older, had a longer duration of hypertension and diabetes, higher blood pressure and pulse pressure, higher LDL cholesterol and lower
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eGFR compared to those without PAD. CAD was present in 9.3% among those without PAD, 15.2% among those with PAD at baseline and 16.4% among those who
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developed PAD during the follow up.
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The baseline prevalence of PAD was 7.6% [11.8% in women and 5.1% in men, p<0.001]. The prevalence of PAD among female patients ranged from 5.2% in patients
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under 40 years to 10.2% in those in the age group of 40-60 years and 20.2% in patients older than 60 years [trend 2 :17.99, p<0.001]. The corresponding prevalence among men were 1.7%, 3.9% and 11.1% [trend 2:27.61, p<0.001]. Thus the baseline prevalence of PAD was higher among female patients at all the age groups studied.
On multivariate analysis of prevalent PAD, female gender came out as the strongest predictor of PAD with an OR 3.09 [CI 1.96-4.89]. Other variables significantly associated with prevalent PAD were age [OR: 1.06 (CI1.04-1.09), p<0.001], duration of diabetes [OR: 1.03 (CI 1.00-1.06), p=0.04] and LDL cholesterol [OR: 1.01(CI 1.0021.013), p=0.01]. During the follow-up period, 43 patients died of whom 13 were females. Prevalent PAD was associated with higher mortality with an adjusted hazard ratio [HR] of 3.3 [CI 1.4-7.7]
ACCEPTED MANUSCRIPT Incidence of PAD
During the period of follow-up, 280 patients developed PAD, resulting in a crude
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PAD incidence rate of 17.2 per 1000 patient years. 15.3% of women compared to 8.7%
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of men developed PAD [p<0.001] [Figure 1]. On univariate analysis [Table 2], the group that developed PAD was older, had longer duration of diabetes, higher blood
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pressure, HbA1c and LDL cholesterol and the e-GFR was lower, compared to patients
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who remained free of PAD.
On multivariate analysis, the most powerful predictor of incident PAD was female
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gender with a hazard ratio of 1.94 [CI 1.4-2.7]. The only other predictors that remained significant were age [HR: 1.03 (CI 1.01- 1.05), p=0.001] and duration of diabetes [HR:
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1.03 (CI 1.01- 1.05), p=0.008].
In addition, the incidence of PAD increased with increasing age, with a crude
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incidence rate of 11.0 per 1000 patient years in the age group < 40 years, 20.3 for ages
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40-60 and 44.7 for the age group >60 years.
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Progression of PAD
There was a significant change in ABI [defined as ± 0.15] in 413 [16.5%] of patients. Of these 137 [5.5%] had a decrease and 276 [11%] had an increase in ABI. A change in ABI, was significantly associated with higher A1C compared to patients who had a stable ABI (HbA1c <7%: 14.9%; 7-8.9%: 15.7%; ≥9%: 19.1%, Trend p=0.044). Age and HbA1c were also predictors of progression in the multivariate analysis [Table 2]. There was no difference in progression between males and females. Low eGFR, pulse pressure and duration of diabetes were associated with progression on univariate, but not multivariate, analysis.
The relationship between treatment [exercise rehabilitation, anti-platelet therapy, lipid-lowering drugs] and progression of PAD was studied. Of the 191 subjects who had
ACCEPTED MANUSCRIPT PAD at baseline, PAD progression was observed in 80 subjects [41.9%]. Of the 80 subjects, 1.3% [n=1] were on exercise rehabilitation therapy, 47.5% [n=38] were on antiplatelet therapy, 36.2% [n=29] were on lipid-lowering medication and 15.0% [n=12] were
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on combination therapy of anti-platelet and lipid-lowering therapy [trend 2:6.58,
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p=0.010].”
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DISCUSSION
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This is the first study highlighting some of the factors associated with the progression of PAD in Asian Indians with T2DM. Thus, it may be possible to mitigate
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some of the complications responsible for the already huge burden of diabetes in this ethnic group (Gujral et al., 2013). The overall prevalence of PAD at baseline [2001] was similar to an earlier population based study done in our city (Premalatha et al., 2000) as
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well as data from diabetic patients in the 1999–2004 National Health and Nutrition Examination Surveys [NHANES] (Gregg et al., 2007). Earlier studies have shown a
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lower prevalence of PAD in Asian Indians compared to other ethnic groups (Premalatha & Mohan.,1995; Premaltha et al., 2000) which may be because of the lower age of the
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study participants in Indians compared to other ethnic group. It is well known that age is an important risk factor for PAD. The average age in this study was 51.5 years, which is
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much lower than most western studies of PAD in T2DM where the age is in the range of 55 -74 years (Alzamora et al., 2010).
One of the striking findings in our study is the higher prevalence and incidence of PAD in women. PAD is generally believed to equally affect men and women, although the data is primarily from the Caucasian populations (Hirsch et al., 2012). There are however some studies that show increased prevalence in women. A prospective population based study in Singapore showed that females had higher risk for PAD across three ethnic groups, with the highest in the Indian sub-group [adjusted OR 3.71] (Subramaniam et al., 2011). The Peripheral Arterial Disease in Interventional Patients Study which found 23.3% of women had ABI <0.9 compared to 11.6% of men (Moussa et al., 2009). There may indeed be ethinic differences as suggested by a recent meta-
ACCEPTED MANUSCRIPT analysis comparing PAD in different ethnic groups in America. While women in the fifth decade had a higher rates of PAD than men in all ethnic groups, among Asian American, and American Indians, prevalence of PAD was higher in women at all age
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groups (Allison et al., 2007).
There may be a physiologic basis for the difference in PAD prevalence between
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men and women and it could be related to differences in the risk factors for PAD. According to Nasir et al (2007), the gender differences in PAD may be related to
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differences in the biology between vascular beds. These authors reported that women tended to have higher thoracic aorta calcification in contrast to men who had higher
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coronary calcification. It is of interest that the prevalence rate of PAD in women was higher, despite the much lower smoking rate in women compared to men (0% vs. 12% respectively). Also, 20.2% of the female patients older than 60 years had PAD
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compared to 11.1% in men the same age group. One of the reasons for this could be that older women take poorer care of their diabetes than men. There is an obvious need
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for more studies to better understand the biology of differential susceptibility to PAD
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between women and men.
Several studies have reported both decreases as well increases in ABI. A cut-off
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value of 0.15 representing a significant change, has been used in multiple studies (Nicoloff et al., 2002) and has been found to be associated with an increase in all cause as well as CVD mortality (Criqui et al., 2008). In this study, there was a significant change in ABI (± 0.15) in over 15% of patients (<0.15: 5.5%; >0.15: 11%). However, the rate of progression as denoted by a decline in ABI is lower than that reported in other ethnic groups (Aboyans et al., 2006). This could likely be a reflection of the younger age of our patients. However, with regards to the increase in ABI observed in our study it is unclear whether this reflects an improvement or it is due to medial arterial calcification consequent to ageing which causes stiffening of the vessel wall thereby resulting in higher ABI readings. While relatively little attention has been given to a rise in ABI values, it is now being recognized that a high ABI confers a similar risk for CVD, as a low ABI (Resnick et al., 2004).
ACCEPTED MANUSCRIPT The intra- or inter observer variability of ABI measurements in this study varied from good to very good. The ABI test has been shown to have excellent reproducibility with a variation in measurements between 9-21%. de Graaf et al ( 2001 ) found that
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there was no significant intra or inter observer differences at 1 day and 1 week, with a
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repeatability coefficient of 9-27% (suggesting a difference greater than 27% is not
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related to measurement variation) and intra-class coefficient of 0.87-0.98..
There are several limitations to our study. First, as this is a retrospective chart
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review, it is subject to missing data at baseline [HbA1c values (n=585), lipids (n=72) and blood pressure (n=96) ]. Second, the study was conducted at a single private diabetes center and hence it may not be generalizable to diabetic populations of all
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socioeconomic classes or to the population of India. Third, as it is a retrospective ‘real life’ study, the number and duration between ABIs measurements varied between
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patients. Fourth, including patients with at least 2 ABI measurements may be a potential source of bias. Fifth, using only one ABI as a diagnostic tool has its own limitation
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according to the American Diabetes Association [ADA] (2004) which includes calcified or poorly compressible vessels in the elderly. Next, although there are stringent internal
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quality control measures at our centre to ensure accuracy of the ABI significant intra and inter observer variations could have occurred during the long period of the study
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due to different technicians doing the doppler study. Finally, patients with initial or final ABI values greater than >1.3 were not analyzed for incidence or progression as the measurements are less reliable, although such patients have been shown to have similar CVD risk as patients with PAD.
Conclusion Our study shows that women with T2DM had higher prevalence of PAD. Older age, female gender and duration of diabetes were related to an increased incidence of PAD. As an elevated HbA1c is associated with progression of PAD , this stresses the need for strict control of diabetes.
Conflict of interest: The authors declare that they have no conflicts of interest
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ACCEPTED MANUSCRIPT Table 1: Clinical and biochemical characteristics of the study population Characteristic
No PAD
PAD at Baseline
Developed PAD during follow-up (n = 280)
51.0 ± 9.9
57.5 ± 10*
54.7 ± 10*
112 [58.6]* 25.3 ± 5.5
25.3 ± 4.1
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(n=191)
145 [51.8]*
133 ± 16
135 ± 18**
81 ± 8*
82 ± 8
49 ± 13
52 ± 13**
53 ± 14 **
Duration of HTN (yrs)
4.8 ± 5.6
6.7 ± 6.9**
5.1 ± 6.2
Duration of DM (yrs)
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Age (yrs)
(n=2022)
6.5 ± 6.2
9.1 ± 8.4 **
8.3 ± 7.4**
160 ± 57
163 ± 70
158 ± 57
8.8 ± 2.0
9.1 ± 2.4
9.1 ± 2.1
197 ± 39
204 ± 45
202 ± 41
HDL cholesterol (mg/dL)
43 ± 9.5
44 ± 10
44 ± 10
LDL cholesterol (mg/dL)
120 ± 33
127.1 ± 37*
125.1 ± 36 *
Triglycerides (mg/dL)^
153
152
144*
eGFR (mL/min/1.732)
77 ± 13
70 ± 14**
74 ± 13 **
Hypertension (n [%])
1100 [54.4]
118 [61.8]
161 [57.5]
188 [9.3]
29 [15.2]
46 [16.4]
341 [17.4]
23 [12.4]
32 [11.6]
Diet
19 [0.8]
1 [0.5]
5 [1.8]
OHA
1503 [65.3]
95 [51.3]**
155 [55.4]**
43 [1.9]
5 [2.6]
5 [1.8]
737 [32.0]
87 [45.5]**
115 [41.1]**
692 [34.2] 2
25.3 ± 3.8
Systolic BP (mmHg)
131 ± 16
Diastolic BP (mmHg)
83 ± 8
Pulse Pressure (mm Hg)
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Body mass index (kg/m )
HbA1c (%)
CAD (n [%])
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Total cholesterol (mg/dL)
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Fasting plasma glucose (mg/dL)
Ever smoked (n [%] ≠
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Female (n [%])
Management
Insulin OHA + Insulin
*P=<0.05; **P=<0.005 compared to patients without PAD ;^ Geometric mean;
≠
All
smokers were men PAD: Peripheral arterial disease; eGFR: Estimated Glomerular Filtration rate; CAD : Coronary Artery Disease ; OHA- Oral Hypoglycemic Agents
ACCEPTED MANUSCRIPT Table 2: Cox-Regression analysis for incident and progression of peripheral arterial disease Univariate Analysis Hazard Ratio
p-value
1.96 (1.55-2.48)
Duration of DM (per year)
4.38 (2.67-7.2)
Pulse Pressure (mm Hg)
1.03 (1.02-1.03)
HbA1c (%) LDL cholesterol (mg/dL)
(95% CI)
1.03 (1.01-1.05)
0.001
<0.001
1.86 (1.33-2.59)
<0.001
<0.001
1.03 (1.01-1.05)
0.010
<0.001
1.01 (0.99-1.02)
0.17
1.08 (1.02-1.15)
0.014
1.05 (0.98-1.13)
0.158
1.00 (1.00-1.01)
0.018
1.00 (1.00-1.01)
0.281
Low eGFR (mL/min/1.732)
0.98 (0.97-9.99)
<0.001
1.00 (0.99-1.01)
0.903
Smoking (yes)
0.65 (0.45-0.94
0.022
1.10 (0.99-1.02)
0.625
1.01 (1.00-1.03)
0.028
1.00 (0.70-1.75)
0.671
1.05 (1.03-1.07)
<0.001
1.04 (1.01-1.06)
0.002
0.80 (0.55-1.16)
0.24
1.08 (0.71-1.65)
0.718
Duration of DM (per year)
1.05 (1.03-1.08)
<0.001
1.01 (0.98-1.04)
0.422
Pulse Pressure (mm Hg)
1.03 (1.02-1.04)
<0.001
1.01 (1.00-1.02)
0.19
HbA1c Average (%)
1.12 (1.00-1.23)
0.047
1.16 (1.02-1.32)
0.022
LDL cholesterol (mg/dL)
1.00 (1.00-1.01)
0.132
1.00 (1.00-1.01)
0.231
Low eGFR (mL/min/1.732)
0.98 (0.97-9.99)
0.001
0.99 (0.98-1.01)
0.387
Smoking (yes)
0.80 (0.51-1.26)
0.336
HDL cholesterol (mg/dL)
1.00 (0.98-1.02)
0.866
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Female gender
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Age (per year)
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PAD Progression
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HDL cholesterol (mg/dL)
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Female gender
<0.001
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1.05 (1.04-1.06)
p-value
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Incident PAD Age (per year)
Hazard Ratio
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(95% CI)
Final Multivariate Model*
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Variable
* Included all variables with p<0.20 in univariate analysis. Pulse pressure and LDL and HDL cholesterol selected for being more significant than other measures of BP and lipid profile. Baseline ABI was forced into the model to adjust for regression to the mean.
ACCEPTED MANUSCRIPT LEGEND TO FIGURE:
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Figure 1: Gender-wise incidence of peripheral arterial disease in the study population