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Single and combined effects of peripheral artery disease and of type 2 diabetes mellitus on the risk of cardiovascular events: A prospective cohort study
Accepted Manuscript Single and combined effects of peripheral artery disease and of type 2 diabetes mellitus on the risk of cardiovascular events: A prospective cohort study Christoph H. Saely, Marc Schindewolf, Daniela Zanolin, Christine F. Heinzle, Alexander Vonbank, Guenter Silbernagel, Andreas Leiherer, Heinz Drexel, Iris Baumgartner PII:
S0021-9150(18)31404-7
DOI:
10.1016/j.atherosclerosis.2018.09.031
Reference:
ATH 15729
To appear in:
Atherosclerosis
Received Date: 10 March 2018 Revised Date:
13 July 2018
Accepted Date: 21 September 2018
Please cite this article as: Saely CH, Schindewolf M, Zanolin D, Heinzle CF, Vonbank A, Silbernagel G, Leiherer A, Drexel H, Baumgartner I, Single and combined effects of peripheral artery disease and of type 2 diabetes mellitus on the risk of cardiovascular events: A prospective cohort study, Atherosclerosis (2018), doi: https://doi.org/10.1016/j.atherosclerosis.2018.09.031. 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
Single and combined effects of peripheral artery disease and of type 2 diabetes mellitus on the risk of cardiovascular events: a
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prospective cohort study
Christoph H. Saely*, MD a,b,c,d, Marc Schindewolf *, MD d, Daniela Zanolin, PHD b,c, Christine F. Heinzle, PHD b, Alexander Vonbank, MD-PHD a,b,c, Guenter Silbernagel, MD d, Andreas
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Leiherer, PHD b,c, Heinz Drexel+, MD b,c,d,e, Iris Baumgartner+, MDd
Department of Medicine I, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
b
Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria
c
Private University of the Principality of Liechtenstein, Triesen, Liechtenstein
d
Division of Angiology, Swiss Cardiovascular Center, University Hospital Berne, Berne, Switzerland
e
Drexel University College of Medicine, Philadelphia, PA, USA
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a
*
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Equal contribution; +Equal contribution
Number of tables: 1
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Word count: 3301
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Number of figures: 2
Correspondence
Heinz Drexel, MD, Professor of Medicine, FESC, FAHA, FRCP Division of Clinical and Interventional Angiology
Swiss Cardiovascular Center, Inselspital, Berne University Hospital 3010 Berne, Switzerland Tel: +41 31 632 3034 Fax: +41 31 632 4793 Email: [email protected]
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ACCEPTED MANUSCRIPT Abstract
Background and aims: The individual and combined effects of type 2 diabetes (T2DM) and of peripheral artery disease (PAD) on future cardiovascular events are unknown and are
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addressed in the present investigation. Methods: Cardiovascular events were prospectively recorded in 1049 subjects, encompassing 4 groups: 558 with neither PAD nor diabetes, 153 with T2DM but without PAD, 192 with
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PAD but without T2DM and 146 with the combination of PAD and T2DM.
Results: Over a mean follow-up period of 7.2±2.6 years, the cardiovascular event rate was
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lowest in patients with neither PAD nor T2DM (16.7%). Compared to this group the event rate was not significantly increased in T2DM patients without PAD (22.2%, p=0.077) but higher in non-diabetic patients with PAD (52.6%; p <0.001) and further increased in patients with both PAD and T2DM (71.2%; p <0.001). Nondiabetic PAD patients were at a higher
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cardiovascular risk than T2DM patients without PAD (p <0.001). Compared to those with neither PAD nor T2DM, hazard ratios after multivariate adjustment were 1.26 [0.84-1.91]; p=0.267, 4.17 [2.97-5.85]; p <0.001, and 7.82 [5.49-11.12]; p <0.001 for those with T2DM
respectively.
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only, for those with PAD only and for those with the combination of PAD plus diabetes,
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Conclusions: PAD is a stronger risk factor for future cardiovascular events than T2DM, but T2DM in PAD patients accelerates atherothrombotic disease and strongly increases the incidence of cardiovascular events.
Key words: peripheral artery disease, type 2 diabetes, atherosclerosis, risk factors, cohort analysis, cardiovascular disease
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ACCEPTED MANUSCRIPT Introduction
Peripheral artery disease (PAD) and type 2 diabetes (T2DM) frequently coincide (1, 2). Indeed, PAD is one of the most common cardiovascular complications of diabetes (3-5). Both
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T2DM and PAD pose patients at a very high risk of cardiovascular events (6), and cardiovascular disease is the leading cause of death in patients with T2DM (7) as well as in those with PAD (8). Cardiovascular risk in patients with PAD (9-12) is even higher than in
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patients with coronary artery disease (CAD) (13).
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The presence of PAD increases the risk of cardiac death among patients with T2DM (14, 15). However, in as far T2DM increases cardiovascular risk in PAD patients is further increased when PAD is accompanied by T2DM is less clear (16-18). It is unknown how the cardiovascular risk of PAD patients without T2DM compares to the cardiovascular risk of
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T2DM patients without PAD, because the individual and combined effects of PAD and of T2DM on the cardiovascular event rate have not been investigated in a prospective cohort
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study so far.
The aim of this investigation was to prospectively assess the impact of T2DM and that of
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PAD, both combined and individual, on the risk of future cardiovascular events. We studied a large cohort, including 4 groups of patients: i) subjects who neither had diabetes nor PAD, ii) T2DM patients without PAD, iii) PAD patients without diabetes, and iv) patients with both, T2DM and PAD.
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ACCEPTED MANUSCRIPT Patients and Methods
Patients
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For the present investigation, we enrolled 1049 subjects of whom 338 had PAD and 711 did not have PAD. These patients were recruited at the Academic Teaching Hospital Feldkirch, Austria and at the Division of Angiology at the University Hospital Berne, Switzerland
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between September 2006 and January 2012.
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As PAD patients, we enrolled 338 symptomatic Caucasian patients with an ankle brachial index <0.9 or with previous revascularization of peripheral arteries who underwent routine duplex sonography and in whom PAD was sonographically verified. Patients with type 1
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diabetes or with Fontaine stage IV were excluded from recruitment.
For subjects without PAD we enrolled individuals from a cohort of 711 consecutive Caucasian patients referred for coronary angiography for clinical reasons, in whom
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significant CAD with lumen narrowing ≥50% was ruled out angiographically (19), and who neither at present nor in the past had any signs or symptoms of PAD (no
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intermittent limb claudication, no history of PAD or peripheral revascularization, no ABI <0.9). Patients with a history of myocardial infarction or acute coronary syndromes within three months prior to baseline angiography and patients with type 1 diabetes were excluded from recruitment.
At baseline, height and weight as well as waist and hip circumferences were recorded. Information on conventional cardiovascular risk factors (history of smoking, hypertension, established diabetes, and a family history of atherosclerotic disease) was obtained by a 4
ACCEPTED MANUSCRIPT standardized interview. Systolic as well as diastolic blood pressures were measured by the Riva-Rocci method under resting conditions in a sitting position at the day of hospital admission after a 1 hour rest. Hypertension was defined according to the 2013 ESC/ESH guidelines (20), and type 2 diabetes was diagnosed according to current ADA clinical practice
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recommendations (21).
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Prospective study design and endpoints
During follow-up, the incidence of cardiovascular events and of death was recorded. Time
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and cause of death was collected annually from a national registry (Statistik Austria, Vienna, Austria) as well as from hospital registries and telephone contacts, and non-fatal events were assessed using standardized interviews in 2-year intervals.
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As the primary study endpoint we used a composite consisting of coronary death (including fatal myocardial infarction, sudden cardiac death, mortality from congestive heart failure due to CAD), fatal ischemic stroke, non-fatal myocardial infarction, non-fatal ischemic stroke, and
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need for revascularization (coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), revascularization in the carotid or peripheral arterial beds) or amputation
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at the lower extremities. Coronary angioplasty, bypass surgery, revascularizations of the peripheral arteries or amputation at the lower extremities were only considered as end points if they were not scheduled due to the results of the baseline examinations and therefore could not be considered as “future” events. A follow-up rate of 98.3% was achieved.
The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki; it was approved by the Ethics Committees of the Universities of Innsbruck and Berne, and all participants gave written informed consent. 5
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Analytical procedures
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Venous blood samples in the PAD patients were drawn after an overnight fast of at least 12 hours. In the subjects without PAD venous blood samples were collected after an overnight fast of 12 hours before angiography was performed. Laboratory measurements were
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performed from fresh serum samples, as described previously (22, 23). Serum levels of triglycerides, total cholesterol, low density lipoprotein (LDL) cholesterol, high density
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lipoprotein (HDL) and cholesterol, C-reactive protein (CRP), and plasma glucose were determined on a Cobas Integra 800® (Roche, Basel, Switzerland). Haemoglobin A1c (HbA1c) was determined by high-performance liquid chromatography on a Menarini-Arkray KDK HA
Statistical analysis
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8140® (Arkray KDK, Kyoto, Japan).
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Differences in baseline characteristics were tested for statistical significance with the Chisquared and the Mann-Whitney U-tests for categorical and continuous variables, respectively.
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The Wilcoxon-Gehan statistic was used to compare differences in the cumulative incidence rates of cardiovascular events. Adjusted hazard ratios for the incidence of first cardiovascular events were derived from Cox proportional hazards models; for these calculations, continuous variables were z-transformed. Results are given as mean (standard deviation) if not denoted otherwise. All statistical analyses were performed with the software package SPSS 24.0 for Windows (SPSS, Chicago, IL, USA).
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ACCEPTED MANUSCRIPT Results
Baseline characteristics
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Among the 711 patients who did not have PAD, 558 did not have T2DM and 153 (21.5%) had T2DM. Among the 338 PAD patients, 192 did not have diabetes and 146 (43.2%) had both, PAD and T2DM. Thus, the prevalence of T2DM was higher in PAD patients than in
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subjects who did not have PAD (p <0.001).
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Table 1 summarizes baseline characteristics of our patients with PAD and of subjects who did not have PAD with respect to the presence of T2DM. Both, among PAD patients and among those who did not have PAD, HbA1c, BMI, waist circumference, triglycerides as well as the prevalence of hypertension was higher, and total cholesterol, LDL cholesterol, apolipoprotein
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A1 and HDL cholesterol were lower in patients with T2DM than in those who did not have diabetes; the prevalence of a smoking history was lower in PAD patients with T2DM than in
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PAD patients who did not have diabetes.
Next, we compared PAD alone with diabetes alone. In PAD patients who did not have T2DM
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when compared to T2DM patients who did not have PAD, age (p <0.001), apolipoprotein A1 (p <0.001) and apolipoprotein B (p=0.001) were significantly higher. Further, considering differences between T2DM patients with PAD to those who did not have PAD, those with PAD were older (p <0.001), had a longer diabetes duration (p=0.013), a higher prevalence of previously established versus newly diagnosed diabetes (p <0.001) and lower total cholesterol (p <0.001), LDL cholesterol (p <0.001), apolipoprotein B (p <0.001) and BMI (p <0.001).
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ACCEPTED MANUSCRIPT Incidence of cardiovascular events
During a mean (standard deviation) follow-up time of 7.2±2.6 years we recorded 332 cardiovascular endpoints, encompassing 53 coronary deaths, 40 non-fatal myocardial
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infarctions, 44 non-fatal ischemic strokes, 10 coronary artery bypass graftings, 22 percutaneous coronary interventions, 161 non-coronary revascularisations and 2 limb
year.
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Impact of PAD and of T2DM on cardiovascular events
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amputations. Thus, the overall incidence rate of endpoints was 31.6%, amounting to 4.4% per
Figure 1 shows event-free survival with regard to both PAD and T2DM. When compared to the cardiovascular event rate in subjects who neither had PAD nor T2DM (16.7%; 93 events),
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the event rate was not significantly different in T2DM subjects without PAD (22.2%; 34 events; p=0.077) but significantly higher in PAD patients who did not have diabetes (52.6%; 101 events; p <0.001) and highest in patients with both, PAD and T2DM (71.2%; 104 events;
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p <0.001). Concordantly, the event rate was higher in PAD patients with T2DM than in PAD patients without diabetes (p <0.001) or in T2DM patients without PAD (p <0.001). T2DM
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patients without PAD had a significantly lower event rate than PAD patients without diabetes (p <0.001).
When compared to those with neither PAD nor T2DM, hazard ratios (HRs) adjusted for age, gender, BMI, smoking, hypertension, LDL cholesterol, and HDL cholesterol were 1.26 [0.841.91]; p=0.267, 4.17 [2.97-5.85]; p <0.001, and 7.82 [5.49-11.12]; p <0.001 for those with T2DM only, for those with PAD only and for those with the combination of PAD plus diabetes, respectively (Figure 2). 8
ACCEPTED MANUSCRIPT PAD increased cardiovascular event risk in T2DM patients (HR 7.16 [4.44-11.53]; p <0.001), as well as in subjects without diabetes (HR 4.17 [2.97-5.85]; p <0.001). The impact of PAD on event risk in T2DM patients was not relevantly attenuated after additional adjustment for
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diabetes duration (HR 6.83 [4.14-11.26]; p <0.001).
Conversely, T2DM significantly increased cardiovascular risk only in patients with PAD
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(adjusted HR 1.95 [1.43-2.65]; p <0.001) but not in subjects without PAD (HR 1.16 [0.761.78]; p=0.494), and non-diabetic patients with PAD were at a significantly higher
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cardiovascular risk than T2DM patients without PAD (HR 3.22 [1.98–5.25]; p <0.001).
Overall, the incidence of cardiovascular events was significantly higher in the two groups of patients with PAD, i.e. in those with and those without T2DM combined, than in those who
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did not have PAD (60.7% vs. 17.9%; p <0.001) and also in the two groups of patients with T2DM, i.e. in those with and those without PAD combined, than among non-diabetic subjects (46.2% vs. 25.9%; p <0.001). The presence of PAD conferred a higher cardiovascular risk
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respectively).
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than the presence of T2DM (HR 4.83 [3.63–6.42]; p <0.001 and 1.64 [1.29–2.09]; p <0.001,
Gender specific results
Gender did not significantly affect the cardiovascular risk conferred by T2DM in patients with PAD (HR 1.83 [1.29-2.58] for men and 2.21 [1.12-4.36] for women, respectively; p-value for interaction = 0.341) and in those who did not have PAD (1.59 [0.93-2.73] for men and 0.74 [0.36-1.51] for women, respectively; p-value for interaction = 0.186). In accordance, there was no difference between men and women regarding the overall cardiovascular risks 9
ACCEPTED MANUSCRIPT conferred by PAD (HR 4.69 [3.33-6.60] and 5.18 [2.99-8.97], respectively; p-value for interaction = 0.500) and by T2DM (HR 1.76 [1.31-2.35] and 1.39 [0.89-2.19], respectively; p-
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value for interaction = 0.705).
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ACCEPTED MANUSCRIPT Discussion
From the results of this prospective cohort study we conclude that patients with T2DM have a much lower cardiovascular event risk compared to those with PAD alone, and it is PAD
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which drives cardiovascular event risk rather than diabetes. T2DM strongly increases the risk of future cardiovascular events in patients with PAD and patients with both, T2DM and PAD are at an extremely a very high cardiovascular risk. However, T2DM patients without PAD
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are at a significantly lower cardiovascular event risk than PAD patients without diabetes.
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The power of T2DM to predict future cardiovascular events in patients with established PAD has not been well defined. Higher mortality had been reported in PAD patients with T2DM than in nondiabetic PAD patients (16, 17), whereas in a large investigation addressing the effect of T2DM on cardiovascular events in patients with vascular disease at different
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locations, the impact of T2DM on vascular risk in patients with PAD remained inconclusive, and T2DM did not predict future vascular events in patients with symptomatic vascular disease in more than one location (18). The authors hypothesized that in an advanced disease
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state, the additional influence of diabetes on vascular risk processes was no longer relevant. In contrast, our investigation clearly demonstrates an increased cardiovascular event risk in PAD
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patients with versus those without T2DM.
Our data show that the baseline PAD state among patients with T2DM distinguishes subpopulations with very different risk. Indeed, the presence of T2DM conferred a strongly increased event risk among patients with PAD, while cardiovascular risk among patients with T2DM who did not have PAD was not significantly different from that of non-diabetic patients without PAD. Cardiovascular risk conferred by PAD was significantly higher than that conferred by T2DM during the 7.2 years of follow-up in this study; of course we cannot 11
ACCEPTED MANUSCRIPT exclude that the individual impact of T2DM on cardiovascular event risk would increase over longer time periods.
Diabetes previously has been considered as a CAD risk equivalent (24, 25). However,
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whereas some reports supported the observation that diabetes confers a cardiovascular risk as high as pre-existing CAD, most investigations found a higher risk with pre-existing CAD than with diabetes alone (26). Also, a meta-analysis demonstrated that T2DM per se is not a CAD
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risk equivalent (27). PAD is associated with an even stronger increase in the risk for
cardiovascular events than CAD, but no previous investigation directly compared the single
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and joint cardiovascular effects of PAD and T2DM. In line with the previous reports on a higher cardiovascular risk in CAD patients without diabetes than in diabetes patients without CAD (26, 27), we found that PAD patients who did not have diabetes were at a significantly
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higher cardiovascular risk than T2DM patients without PAD.
In our patients with T2DM, diabetes duration was significantly longer among those who had PAD than among those who did not have PAD at baseline, and the prevalence of previously
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established versus newly diagnosed diabetes in T2DM patients with PAD was higher than in T2DM patients who did not have PAD. It is pathophysiologically plausible that when diabetes
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duration is long, more diabetic individuals already have significant atherosclerotic disease than when diabetes duration is short (28). This also is in line with previous observations addressing the CAD risk equivalence of diabetes: when diabetes duration was short, the risk associated with diabetes was much lower than with longer diabetes duration, and only with longer diabetes duration diabetes became a CAD risk equivalent (26, 29). However, also after adjustment for diabetes duration the presence of PAD strongly increased cardiovascular risk in our T2DM patients. The presence of atherosclerotic disease is a paramount prognostic
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ACCEPTED MANUSCRIPT parameter, in particular in T2DM patients, and it provides prognostic information over and above diabetes duration.
Our finding of a relatively favourable prognosis of diabetic patients without PAD extends our
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previous observations that diabetic patients without significant CAD are at an only moderate risk of future cardiovascular events (13, 30), but by no means supports inconsequent risk factor control in these patients. It may be expected that many diabetic individuals eventually
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develop atherosclerotic disease such as PAD or significant CAD and then will face an
extraordinarily high vascular risk. Indeed, our study shows that when vascular disease
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becomes present, the coexistence of T2DM accelerates atherothrombotic disease and strongly increases the incidence of cardiovascular events. This might be prevented through rigorous risk factor control already in those T2DM patients who are not yet affected by PAD and
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therefore are at a more moderate risk of cardiovascular events (31).
Important strengths of our investigation are the sonographic verification of PAD and the meticulous acquisition of endpoint data. The present investigation applies a cumulative
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cardiovascular endpoint encompassing carefully assessed fatal and non-fatal events. Regarding the selection of study patients for this investigation, those with PAD had to have
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symptomatic disease with an ABI <0.9 or a previous lower extremity revascularization procedure as well as a sonographic verification of PAD. Special care was taken to select controls. This appears important because diabetic patients tend to have asymptomatic atherosclerotic disease, in particular CAD (32) that deteriorates their prognosis (26). The baseline characterization of atherosclerotic disease sharply distinguishes subgroups with different risk, regardless of whether diabetes is present. Sonographical visualization of PAD therefore in the present study helped to derive unambiguous risk estimates.
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ACCEPTED MANUSCRIPT A potential limitation is that while in our controls significant CAD was ruled out by angiography and no signs or symptoms of PAD were present, subclinical PAD was not formally excluded. However, the presence of clinically relevant PAD in our controls appears unlikely and, importantly, if present would only have diminished the real differences between
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PAD patients and controls and therefore by no means affects the validity of our data. However, the presence of clinically relevant PAD in our controls appears unlikely and, more importantly, if present would not have created spurious differences between PAD patients and
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controls. In the contrary it would only have diminished the real differences between PAD
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patients and controls.
In conclusion, our data show that T2DM strongly increases the risk of future cardiovascular events in patients with PAD, while T2DM patients without PAD are at a significantly lower cardiovascular event risk than non-diabetic PAD patients. PAD is a stronger risk factor for
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cardiovascular events than T2DM, but the coexistence of T2DM in PAD patients accelerates
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atherothrombotic disease and strongly increases the incidence of cardiovascular events.
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ACCEPTED MANUSCRIPT Conflicts of interest
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The authors declare that they have no conflicts of interests.
Financial support
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This work has been supported by the Jubiläumsfonds of the Austrian National Bank (project number 14159). This institution did not have any role in the design of the study and
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collection, analysis, and interpretation of data and in writing the manuscript.
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ACCEPTED MANUSCRIPT Author contributions
CHS: conception and design of the study, data evaluation and statistical analysis, drafting of the manuscript
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MS: data evaluation and statistical analysis, drafting of the manuscript DZ: data evaluation and statistical analysis, revision of the manuscript for intellectually important content
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CFH: data evaluation and statistical analysis, revision of the manuscript for intellectually important content
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AV: data evaluation and statistical analysis, revision of the manuscript for intellectually important content
GS: revision of the manuscript for intellectually important content AL: data evaluation and statistical analysis, revision of the manuscript for intellectually
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important content
HD: conception and design of the study, data evaluation and statistical analysis, drafting of the manuscript
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IB: conception and design of the study, drafting of the manuscript
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ACCEPTED MANUSCRIPT Acknowledgements
We thank the Jubiläumsfonds of the Austrian National Bank (Vienna, Austria), Dr. Karl Josef Hier and the Peter Goop Stiftung (Vaduz, Liechtenstein), the Fachhochschule Dornbirn
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(Dornbirn, Austria), and the Institute for Clinical Chemistry at the Academic Teaching Hospital Feldkirch (Feldkirch, Austria) for providing us with generous research grants.
The authors acknowledge Ms. Jacqueline Siebmann, Ms. Sandra Rohner, Ms. Rebecca
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Spescha, and Ms. Claudine Strametz for their important contributions to this study.
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insulin resistance, and cardiovascular risk in diabetic and nondiabetic patients. The Journal of
Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary
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heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. The New England Journal of Medicine 1998;339(4):229-34. Executive Summary of The Third Report of The National Cholesterol Education
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25.
Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285(19):2486-97. 26.
Saely CH, Drexel H. Is type 2 diabetes really a coronary heart disease risk equivalent?
27.
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Vascular Pharmacology 2013;59(1-2):11-8.
Bulugahapitiya U, Siyambalapitiya S, Sithole J, Idris I. Is diabetes a coronary risk
equivalent? Systematic review and meta-analysis. Diabetic Medicine 2009;26(2):142-8. Nicholls SJ, Tuzcu EM, Kalidindi S, Wolski K, Moon KW, Sipahi I, et al. Effect of
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28.
diabetes on progression of coronary atherosclerosis and arterial remodeling: a pooled analysis
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of 5 intravascular ultrasound trials. Journal of the American College of Cardiology 2008;52(4):255-62. 29.
Cho E, Rimm EB, Stampfer MJ, Willett WC, Hu FB. The impact of diabetes mellitus
and prior myocardial infarction on mortality from all causes and from coronary heart disease in men. Journal of the American College of Cardiology 2002;40(5):954-60. 30.
Saely CH, Aczel S, Marte T, Langer P, Drexel H. Cardiovascular complications in
Type 2 diabetes mellitus depend on the coronary angiographic state rather than on the diabetic state. Diabetologia 2004;47(1):145-6. 21
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Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman
DE, et al. 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2017;135(12):e726-e79. Iwasaki K, Matsumoto T, Aono H, Furukawa H, Samukawa M. Prevalence of
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32.
subclinical atherosclerosis in asymptomatic diabetic patients by 64-slice computed
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tomography. Coronary Artery Disease 2008;19(3):195-201.
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ACCEPTED MANUSCRIPT Tables
Table 1. Baseline characteristics with respect to the presence of peripheral artery disease and to the presence of type 2 diabetes PAD
T2DM+
n=558
n=153
62±11
63±27
0.214
Male gender (%)
52.0
51.6
0.941
Diabetes duration (years)
n.A.
Age (years)
0 [0-4]
p
n.A.
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3.5±6.9 n.A
46.6
55.0
73.9
49.5
Body mass index (kg/m²) Waist circumference (cm)
T2DM-
T2DM+
n=192
n=146
68±10
68±10
0.687
71.4
73.3
0.694
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T2DM-
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No PAD
p
5 [0-13]
n.A.
n.A. 7.7±8.2
n.A
20.3
n.A.
0.001
82.5
93.0
0.005
51.6
0.634
86.5
77.5
0.036
27.2±4.2
29.9±5.2
0.001
25.7±4.3
28.0±4.0
0.001
95±12
104±13
0.001
97±13
105±12
0.001
5.7±0.4
7.1±1.3
0.001
5.7±0,3
7.1±1.3
0.001
133±82
179±133
0.001
136±81
170±120
0.004
212±45
200±46
0.006
182±40
170±48
0.019
LDL cholesterol (mg/dl)
135±38
122±39
0.001
107±34
97±42
0.012
HDL cholesterol (mg/dl)
59±18
51±14
0.001
56±18
49±17
0.001
Apolipoprotein A1 (mg/dl)
159±31
148±27
0.001
161±36
152±37
0.061
Apolipoprotein B (mg/dl)
96±27
97±30
0.696
78±21
76±24
0.437
Systolic blood pressure (mm Hg)
135±19
140±21
0.018
140±22
144±25
0.170
Diastolic blood pressure (mm Hg)
81±10
83±12
0.263
80±11
80±14
0.998
Statins (%)
32.3
43.1
0.012
70.3
73.9
0.472
ACE inhibitors / AT II RBA (%)
33.5
51.6
<0.001
54.6
74.6
<0.001
Beta receptor blocking agents (%)
43.9
51.0
0.120
36.2
52.2
0.004
Aspirin or Clopidogrel (%)
63.3
68.9
0.205
90.6
86.3
0.213
Newly diagnosed diabetes (%) Hypertension (%)
HbA1c (%) Triglycerides (mg/dl)
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Total cholesterol (mg/dl)
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Smoking (%)
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ACCEPTED MANUSCRIPT LDL low density lipoprotein; HDL high density lipoprotein; ACE angiotensin converting enzyme; AT II RBA angiotensin II receptor blocking agents; to convert values for fasting plasma glucose to mmol/l multiply by 0.0555, to convert values for triglycerides to mmol/l multiply by 0.0113, and to convert values for total cholesterol, LDL cholesterol, or HDL
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cholesterol to mmol/l multiply by 0.0259. Data are shown as means ± standard deviations if not denoted otherwise. Diabetes duration is given as median together with the interquartile
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range.
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ACCEPTED MANUSCRIPT Figure legends
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Figure 1. Event-free survival in patients who neither had diabetes nor peripheral artery disease (solid line), in patients with type 2 diabetes who did not have peripheral artery disease (broken line), in patients with peripheral artery disease who did not have diabetes (dotted
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line), and in patients with both, type 2 diabetes and peripheral artery disease (semi-broken
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line).
Figure 2. Adjusted hazard ratios for the incidence of cardiovascular events in patients with type 2 diabetes who did not have peripheral artery disease (PAD-/T2DM+), in patients with
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peripheral artery disease who did not have diabetes (PAD+/T2DM-) and in patients with the combination of type 2 diabetes and peripheral artery disease (PAD+/T2DM+) when compared to subjects who neither had diabetes nor peripheral artery disease (PAD-/T2DM-).
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HDL cholesterol.
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Adjustments are made for age, gender, BMI, smoking, hypertension, LDL cholesterol, and
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Figure 2
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Figure 1
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ACCEPTED MANUSCRIPT Highlights
T2DM patients without PAD are at a lower risk than non-diabetic PAD patients.
•
PAD indicates a higher cardiovascular event risk than T2DM.
•
Risk is moderate in T2DM patients without PAD.
•
T2DM strongly increases the risk of cardiovascular events in patients with PAD.
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Patients with both, T2DM and PAD are at an extremely high cardiovascular risk.
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•
S0021-9150(18)31404-7
DOI:
10.1016/j.atherosclerosis.2018.09.031
Reference:
ATH 15729
To appear in:
Atherosclerosis
Received Date: 10 March 2018 Revised Date:
13 July 2018
Accepted Date: 21 September 2018
Please cite this article as: Saely CH, Schindewolf M, Zanolin D, Heinzle CF, Vonbank A, Silbernagel G, Leiherer A, Drexel H, Baumgartner I, Single and combined effects of peripheral artery disease and of type 2 diabetes mellitus on the risk of cardiovascular events: A prospective cohort study, Atherosclerosis (2018), doi: https://doi.org/10.1016/j.atherosclerosis.2018.09.031. 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
Single and combined effects of peripheral artery disease and of type 2 diabetes mellitus on the risk of cardiovascular events: a
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prospective cohort study
Christoph H. Saely*, MD a,b,c,d, Marc Schindewolf *, MD d, Daniela Zanolin, PHD b,c, Christine F. Heinzle, PHD b, Alexander Vonbank, MD-PHD a,b,c, Guenter Silbernagel, MD d, Andreas
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Leiherer, PHD b,c, Heinz Drexel+, MD b,c,d,e, Iris Baumgartner+, MDd
Department of Medicine I, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
b
Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria
c
Private University of the Principality of Liechtenstein, Triesen, Liechtenstein
d
Division of Angiology, Swiss Cardiovascular Center, University Hospital Berne, Berne, Switzerland
e
Drexel University College of Medicine, Philadelphia, PA, USA
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a
*
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Equal contribution; +Equal contribution
Number of tables: 1
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Word count: 3301
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Number of figures: 2
Correspondence
Heinz Drexel, MD, Professor of Medicine, FESC, FAHA, FRCP Division of Clinical and Interventional Angiology
Swiss Cardiovascular Center, Inselspital, Berne University Hospital 3010 Berne, Switzerland Tel: +41 31 632 3034 Fax: +41 31 632 4793 Email: [email protected]
1
ACCEPTED MANUSCRIPT Abstract
Background and aims: The individual and combined effects of type 2 diabetes (T2DM) and of peripheral artery disease (PAD) on future cardiovascular events are unknown and are
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addressed in the present investigation. Methods: Cardiovascular events were prospectively recorded in 1049 subjects, encompassing 4 groups: 558 with neither PAD nor diabetes, 153 with T2DM but without PAD, 192 with
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PAD but without T2DM and 146 with the combination of PAD and T2DM.
Results: Over a mean follow-up period of 7.2±2.6 years, the cardiovascular event rate was
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lowest in patients with neither PAD nor T2DM (16.7%). Compared to this group the event rate was not significantly increased in T2DM patients without PAD (22.2%, p=0.077) but higher in non-diabetic patients with PAD (52.6%; p <0.001) and further increased in patients with both PAD and T2DM (71.2%; p <0.001). Nondiabetic PAD patients were at a higher
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cardiovascular risk than T2DM patients without PAD (p <0.001). Compared to those with neither PAD nor T2DM, hazard ratios after multivariate adjustment were 1.26 [0.84-1.91]; p=0.267, 4.17 [2.97-5.85]; p <0.001, and 7.82 [5.49-11.12]; p <0.001 for those with T2DM
respectively.
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only, for those with PAD only and for those with the combination of PAD plus diabetes,
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Conclusions: PAD is a stronger risk factor for future cardiovascular events than T2DM, but T2DM in PAD patients accelerates atherothrombotic disease and strongly increases the incidence of cardiovascular events.
Key words: peripheral artery disease, type 2 diabetes, atherosclerosis, risk factors, cohort analysis, cardiovascular disease
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ACCEPTED MANUSCRIPT Introduction
Peripheral artery disease (PAD) and type 2 diabetes (T2DM) frequently coincide (1, 2). Indeed, PAD is one of the most common cardiovascular complications of diabetes (3-5). Both
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T2DM and PAD pose patients at a very high risk of cardiovascular events (6), and cardiovascular disease is the leading cause of death in patients with T2DM (7) as well as in those with PAD (8). Cardiovascular risk in patients with PAD (9-12) is even higher than in
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patients with coronary artery disease (CAD) (13).
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The presence of PAD increases the risk of cardiac death among patients with T2DM (14, 15). However, in as far T2DM increases cardiovascular risk in PAD patients is further increased when PAD is accompanied by T2DM is less clear (16-18). It is unknown how the cardiovascular risk of PAD patients without T2DM compares to the cardiovascular risk of
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T2DM patients without PAD, because the individual and combined effects of PAD and of T2DM on the cardiovascular event rate have not been investigated in a prospective cohort
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study so far.
The aim of this investigation was to prospectively assess the impact of T2DM and that of
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PAD, both combined and individual, on the risk of future cardiovascular events. We studied a large cohort, including 4 groups of patients: i) subjects who neither had diabetes nor PAD, ii) T2DM patients without PAD, iii) PAD patients without diabetes, and iv) patients with both, T2DM and PAD.
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ACCEPTED MANUSCRIPT Patients and Methods
Patients
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For the present investigation, we enrolled 1049 subjects of whom 338 had PAD and 711 did not have PAD. These patients were recruited at the Academic Teaching Hospital Feldkirch, Austria and at the Division of Angiology at the University Hospital Berne, Switzerland
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between September 2006 and January 2012.
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As PAD patients, we enrolled 338 symptomatic Caucasian patients with an ankle brachial index <0.9 or with previous revascularization of peripheral arteries who underwent routine duplex sonography and in whom PAD was sonographically verified. Patients with type 1
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diabetes or with Fontaine stage IV were excluded from recruitment.
For subjects without PAD we enrolled individuals from a cohort of 711 consecutive Caucasian patients referred for coronary angiography for clinical reasons, in whom
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significant CAD with lumen narrowing ≥50% was ruled out angiographically (19), and who neither at present nor in the past had any signs or symptoms of PAD (no
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intermittent limb claudication, no history of PAD or peripheral revascularization, no ABI <0.9). Patients with a history of myocardial infarction or acute coronary syndromes within three months prior to baseline angiography and patients with type 1 diabetes were excluded from recruitment.
At baseline, height and weight as well as waist and hip circumferences were recorded. Information on conventional cardiovascular risk factors (history of smoking, hypertension, established diabetes, and a family history of atherosclerotic disease) was obtained by a 4
ACCEPTED MANUSCRIPT standardized interview. Systolic as well as diastolic blood pressures were measured by the Riva-Rocci method under resting conditions in a sitting position at the day of hospital admission after a 1 hour rest. Hypertension was defined according to the 2013 ESC/ESH guidelines (20), and type 2 diabetes was diagnosed according to current ADA clinical practice
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recommendations (21).
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Prospective study design and endpoints
During follow-up, the incidence of cardiovascular events and of death was recorded. Time
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and cause of death was collected annually from a national registry (Statistik Austria, Vienna, Austria) as well as from hospital registries and telephone contacts, and non-fatal events were assessed using standardized interviews in 2-year intervals.
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As the primary study endpoint we used a composite consisting of coronary death (including fatal myocardial infarction, sudden cardiac death, mortality from congestive heart failure due to CAD), fatal ischemic stroke, non-fatal myocardial infarction, non-fatal ischemic stroke, and
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need for revascularization (coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), revascularization in the carotid or peripheral arterial beds) or amputation
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at the lower extremities. Coronary angioplasty, bypass surgery, revascularizations of the peripheral arteries or amputation at the lower extremities were only considered as end points if they were not scheduled due to the results of the baseline examinations and therefore could not be considered as “future” events. A follow-up rate of 98.3% was achieved.
The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki; it was approved by the Ethics Committees of the Universities of Innsbruck and Berne, and all participants gave written informed consent. 5
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Analytical procedures
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Venous blood samples in the PAD patients were drawn after an overnight fast of at least 12 hours. In the subjects without PAD venous blood samples were collected after an overnight fast of 12 hours before angiography was performed. Laboratory measurements were
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performed from fresh serum samples, as described previously (22, 23). Serum levels of triglycerides, total cholesterol, low density lipoprotein (LDL) cholesterol, high density
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lipoprotein (HDL) and cholesterol, C-reactive protein (CRP), and plasma glucose were determined on a Cobas Integra 800® (Roche, Basel, Switzerland). Haemoglobin A1c (HbA1c) was determined by high-performance liquid chromatography on a Menarini-Arkray KDK HA
Statistical analysis
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8140® (Arkray KDK, Kyoto, Japan).
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Differences in baseline characteristics were tested for statistical significance with the Chisquared and the Mann-Whitney U-tests for categorical and continuous variables, respectively.
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The Wilcoxon-Gehan statistic was used to compare differences in the cumulative incidence rates of cardiovascular events. Adjusted hazard ratios for the incidence of first cardiovascular events were derived from Cox proportional hazards models; for these calculations, continuous variables were z-transformed. Results are given as mean (standard deviation) if not denoted otherwise. All statistical analyses were performed with the software package SPSS 24.0 for Windows (SPSS, Chicago, IL, USA).
6
ACCEPTED MANUSCRIPT Results
Baseline characteristics
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Among the 711 patients who did not have PAD, 558 did not have T2DM and 153 (21.5%) had T2DM. Among the 338 PAD patients, 192 did not have diabetes and 146 (43.2%) had both, PAD and T2DM. Thus, the prevalence of T2DM was higher in PAD patients than in
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subjects who did not have PAD (p <0.001).
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Table 1 summarizes baseline characteristics of our patients with PAD and of subjects who did not have PAD with respect to the presence of T2DM. Both, among PAD patients and among those who did not have PAD, HbA1c, BMI, waist circumference, triglycerides as well as the prevalence of hypertension was higher, and total cholesterol, LDL cholesterol, apolipoprotein
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A1 and HDL cholesterol were lower in patients with T2DM than in those who did not have diabetes; the prevalence of a smoking history was lower in PAD patients with T2DM than in
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PAD patients who did not have diabetes.
Next, we compared PAD alone with diabetes alone. In PAD patients who did not have T2DM
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when compared to T2DM patients who did not have PAD, age (p <0.001), apolipoprotein A1 (p <0.001) and apolipoprotein B (p=0.001) were significantly higher. Further, considering differences between T2DM patients with PAD to those who did not have PAD, those with PAD were older (p <0.001), had a longer diabetes duration (p=0.013), a higher prevalence of previously established versus newly diagnosed diabetes (p <0.001) and lower total cholesterol (p <0.001), LDL cholesterol (p <0.001), apolipoprotein B (p <0.001) and BMI (p <0.001).
7
ACCEPTED MANUSCRIPT Incidence of cardiovascular events
During a mean (standard deviation) follow-up time of 7.2±2.6 years we recorded 332 cardiovascular endpoints, encompassing 53 coronary deaths, 40 non-fatal myocardial
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infarctions, 44 non-fatal ischemic strokes, 10 coronary artery bypass graftings, 22 percutaneous coronary interventions, 161 non-coronary revascularisations and 2 limb
year.
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Impact of PAD and of T2DM on cardiovascular events
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amputations. Thus, the overall incidence rate of endpoints was 31.6%, amounting to 4.4% per
Figure 1 shows event-free survival with regard to both PAD and T2DM. When compared to the cardiovascular event rate in subjects who neither had PAD nor T2DM (16.7%; 93 events),
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the event rate was not significantly different in T2DM subjects without PAD (22.2%; 34 events; p=0.077) but significantly higher in PAD patients who did not have diabetes (52.6%; 101 events; p <0.001) and highest in patients with both, PAD and T2DM (71.2%; 104 events;
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p <0.001). Concordantly, the event rate was higher in PAD patients with T2DM than in PAD patients without diabetes (p <0.001) or in T2DM patients without PAD (p <0.001). T2DM
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patients without PAD had a significantly lower event rate than PAD patients without diabetes (p <0.001).
When compared to those with neither PAD nor T2DM, hazard ratios (HRs) adjusted for age, gender, BMI, smoking, hypertension, LDL cholesterol, and HDL cholesterol were 1.26 [0.841.91]; p=0.267, 4.17 [2.97-5.85]; p <0.001, and 7.82 [5.49-11.12]; p <0.001 for those with T2DM only, for those with PAD only and for those with the combination of PAD plus diabetes, respectively (Figure 2). 8
ACCEPTED MANUSCRIPT PAD increased cardiovascular event risk in T2DM patients (HR 7.16 [4.44-11.53]; p <0.001), as well as in subjects without diabetes (HR 4.17 [2.97-5.85]; p <0.001). The impact of PAD on event risk in T2DM patients was not relevantly attenuated after additional adjustment for
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diabetes duration (HR 6.83 [4.14-11.26]; p <0.001).
Conversely, T2DM significantly increased cardiovascular risk only in patients with PAD
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(adjusted HR 1.95 [1.43-2.65]; p <0.001) but not in subjects without PAD (HR 1.16 [0.761.78]; p=0.494), and non-diabetic patients with PAD were at a significantly higher
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cardiovascular risk than T2DM patients without PAD (HR 3.22 [1.98–5.25]; p <0.001).
Overall, the incidence of cardiovascular events was significantly higher in the two groups of patients with PAD, i.e. in those with and those without T2DM combined, than in those who
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did not have PAD (60.7% vs. 17.9%; p <0.001) and also in the two groups of patients with T2DM, i.e. in those with and those without PAD combined, than among non-diabetic subjects (46.2% vs. 25.9%; p <0.001). The presence of PAD conferred a higher cardiovascular risk
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respectively).
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than the presence of T2DM (HR 4.83 [3.63–6.42]; p <0.001 and 1.64 [1.29–2.09]; p <0.001,
Gender specific results
Gender did not significantly affect the cardiovascular risk conferred by T2DM in patients with PAD (HR 1.83 [1.29-2.58] for men and 2.21 [1.12-4.36] for women, respectively; p-value for interaction = 0.341) and in those who did not have PAD (1.59 [0.93-2.73] for men and 0.74 [0.36-1.51] for women, respectively; p-value for interaction = 0.186). In accordance, there was no difference between men and women regarding the overall cardiovascular risks 9
ACCEPTED MANUSCRIPT conferred by PAD (HR 4.69 [3.33-6.60] and 5.18 [2.99-8.97], respectively; p-value for interaction = 0.500) and by T2DM (HR 1.76 [1.31-2.35] and 1.39 [0.89-2.19], respectively; p-
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value for interaction = 0.705).
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ACCEPTED MANUSCRIPT Discussion
From the results of this prospective cohort study we conclude that patients with T2DM have a much lower cardiovascular event risk compared to those with PAD alone, and it is PAD
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which drives cardiovascular event risk rather than diabetes. T2DM strongly increases the risk of future cardiovascular events in patients with PAD and patients with both, T2DM and PAD are at an extremely a very high cardiovascular risk. However, T2DM patients without PAD
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are at a significantly lower cardiovascular event risk than PAD patients without diabetes.
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The power of T2DM to predict future cardiovascular events in patients with established PAD has not been well defined. Higher mortality had been reported in PAD patients with T2DM than in nondiabetic PAD patients (16, 17), whereas in a large investigation addressing the effect of T2DM on cardiovascular events in patients with vascular disease at different
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locations, the impact of T2DM on vascular risk in patients with PAD remained inconclusive, and T2DM did not predict future vascular events in patients with symptomatic vascular disease in more than one location (18). The authors hypothesized that in an advanced disease
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state, the additional influence of diabetes on vascular risk processes was no longer relevant. In contrast, our investigation clearly demonstrates an increased cardiovascular event risk in PAD
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patients with versus those without T2DM.
Our data show that the baseline PAD state among patients with T2DM distinguishes subpopulations with very different risk. Indeed, the presence of T2DM conferred a strongly increased event risk among patients with PAD, while cardiovascular risk among patients with T2DM who did not have PAD was not significantly different from that of non-diabetic patients without PAD. Cardiovascular risk conferred by PAD was significantly higher than that conferred by T2DM during the 7.2 years of follow-up in this study; of course we cannot 11
ACCEPTED MANUSCRIPT exclude that the individual impact of T2DM on cardiovascular event risk would increase over longer time periods.
Diabetes previously has been considered as a CAD risk equivalent (24, 25). However,
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whereas some reports supported the observation that diabetes confers a cardiovascular risk as high as pre-existing CAD, most investigations found a higher risk with pre-existing CAD than with diabetes alone (26). Also, a meta-analysis demonstrated that T2DM per se is not a CAD
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risk equivalent (27). PAD is associated with an even stronger increase in the risk for
cardiovascular events than CAD, but no previous investigation directly compared the single
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and joint cardiovascular effects of PAD and T2DM. In line with the previous reports on a higher cardiovascular risk in CAD patients without diabetes than in diabetes patients without CAD (26, 27), we found that PAD patients who did not have diabetes were at a significantly
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higher cardiovascular risk than T2DM patients without PAD.
In our patients with T2DM, diabetes duration was significantly longer among those who had PAD than among those who did not have PAD at baseline, and the prevalence of previously
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established versus newly diagnosed diabetes in T2DM patients with PAD was higher than in T2DM patients who did not have PAD. It is pathophysiologically plausible that when diabetes
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duration is long, more diabetic individuals already have significant atherosclerotic disease than when diabetes duration is short (28). This also is in line with previous observations addressing the CAD risk equivalence of diabetes: when diabetes duration was short, the risk associated with diabetes was much lower than with longer diabetes duration, and only with longer diabetes duration diabetes became a CAD risk equivalent (26, 29). However, also after adjustment for diabetes duration the presence of PAD strongly increased cardiovascular risk in our T2DM patients. The presence of atherosclerotic disease is a paramount prognostic
12
ACCEPTED MANUSCRIPT parameter, in particular in T2DM patients, and it provides prognostic information over and above diabetes duration.
Our finding of a relatively favourable prognosis of diabetic patients without PAD extends our
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previous observations that diabetic patients without significant CAD are at an only moderate risk of future cardiovascular events (13, 30), but by no means supports inconsequent risk factor control in these patients. It may be expected that many diabetic individuals eventually
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develop atherosclerotic disease such as PAD or significant CAD and then will face an
extraordinarily high vascular risk. Indeed, our study shows that when vascular disease
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becomes present, the coexistence of T2DM accelerates atherothrombotic disease and strongly increases the incidence of cardiovascular events. This might be prevented through rigorous risk factor control already in those T2DM patients who are not yet affected by PAD and
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therefore are at a more moderate risk of cardiovascular events (31).
Important strengths of our investigation are the sonographic verification of PAD and the meticulous acquisition of endpoint data. The present investigation applies a cumulative
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cardiovascular endpoint encompassing carefully assessed fatal and non-fatal events. Regarding the selection of study patients for this investigation, those with PAD had to have
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symptomatic disease with an ABI <0.9 or a previous lower extremity revascularization procedure as well as a sonographic verification of PAD. Special care was taken to select controls. This appears important because diabetic patients tend to have asymptomatic atherosclerotic disease, in particular CAD (32) that deteriorates their prognosis (26). The baseline characterization of atherosclerotic disease sharply distinguishes subgroups with different risk, regardless of whether diabetes is present. Sonographical visualization of PAD therefore in the present study helped to derive unambiguous risk estimates.
13
ACCEPTED MANUSCRIPT A potential limitation is that while in our controls significant CAD was ruled out by angiography and no signs or symptoms of PAD were present, subclinical PAD was not formally excluded. However, the presence of clinically relevant PAD in our controls appears unlikely and, importantly, if present would only have diminished the real differences between
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PAD patients and controls and therefore by no means affects the validity of our data. However, the presence of clinically relevant PAD in our controls appears unlikely and, more importantly, if present would not have created spurious differences between PAD patients and
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controls. In the contrary it would only have diminished the real differences between PAD
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patients and controls.
In conclusion, our data show that T2DM strongly increases the risk of future cardiovascular events in patients with PAD, while T2DM patients without PAD are at a significantly lower cardiovascular event risk than non-diabetic PAD patients. PAD is a stronger risk factor for
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cardiovascular events than T2DM, but the coexistence of T2DM in PAD patients accelerates
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atherothrombotic disease and strongly increases the incidence of cardiovascular events.
14
ACCEPTED MANUSCRIPT Conflicts of interest
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The authors declare that they have no conflicts of interests.
Financial support
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This work has been supported by the Jubiläumsfonds of the Austrian National Bank (project number 14159). This institution did not have any role in the design of the study and
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collection, analysis, and interpretation of data and in writing the manuscript.
15
ACCEPTED MANUSCRIPT Author contributions
CHS: conception and design of the study, data evaluation and statistical analysis, drafting of the manuscript
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MS: data evaluation and statistical analysis, drafting of the manuscript DZ: data evaluation and statistical analysis, revision of the manuscript for intellectually important content
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CFH: data evaluation and statistical analysis, revision of the manuscript for intellectually important content
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AV: data evaluation and statistical analysis, revision of the manuscript for intellectually important content
GS: revision of the manuscript for intellectually important content AL: data evaluation and statistical analysis, revision of the manuscript for intellectually
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important content
HD: conception and design of the study, data evaluation and statistical analysis, drafting of the manuscript
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IB: conception and design of the study, drafting of the manuscript
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ACCEPTED MANUSCRIPT Acknowledgements
We thank the Jubiläumsfonds of the Austrian National Bank (Vienna, Austria), Dr. Karl Josef Hier and the Peter Goop Stiftung (Vaduz, Liechtenstein), the Fachhochschule Dornbirn
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(Dornbirn, Austria), and the Institute for Clinical Chemistry at the Academic Teaching Hospital Feldkirch (Feldkirch, Austria) for providing us with generous research grants.
The authors acknowledge Ms. Jacqueline Siebmann, Ms. Sandra Rohner, Ms. Rebecca
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Spescha, and Ms. Claudine Strametz for their important contributions to this study.
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DE, et al. 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2017;135(12):e726-e79. Iwasaki K, Matsumoto T, Aono H, Furukawa H, Samukawa M. Prevalence of
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tomography. Coronary Artery Disease 2008;19(3):195-201.
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ACCEPTED MANUSCRIPT Tables
Table 1. Baseline characteristics with respect to the presence of peripheral artery disease and to the presence of type 2 diabetes PAD
T2DM+
n=558
n=153
62±11
63±27
0.214
Male gender (%)
52.0
51.6
0.941
Diabetes duration (years)
n.A.
Age (years)
0 [0-4]
p
n.A.
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3.5±6.9 n.A
46.6
55.0
73.9
49.5
Body mass index (kg/m²) Waist circumference (cm)
T2DM-
T2DM+
n=192
n=146
68±10
68±10
0.687
71.4
73.3
0.694
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T2DM-
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No PAD
p
5 [0-13]
n.A.
n.A. 7.7±8.2
n.A
20.3
n.A.
0.001
82.5
93.0
0.005
51.6
0.634
86.5
77.5
0.036
27.2±4.2
29.9±5.2
0.001
25.7±4.3
28.0±4.0
0.001
95±12
104±13
0.001
97±13
105±12
0.001
5.7±0.4
7.1±1.3
0.001
5.7±0,3
7.1±1.3
0.001
133±82
179±133
0.001
136±81
170±120
0.004
212±45
200±46
0.006
182±40
170±48
0.019
LDL cholesterol (mg/dl)
135±38
122±39
0.001
107±34
97±42
0.012
HDL cholesterol (mg/dl)
59±18
51±14
0.001
56±18
49±17
0.001
Apolipoprotein A1 (mg/dl)
159±31
148±27
0.001
161±36
152±37
0.061
Apolipoprotein B (mg/dl)
96±27
97±30
0.696
78±21
76±24
0.437
Systolic blood pressure (mm Hg)
135±19
140±21
0.018
140±22
144±25
0.170
Diastolic blood pressure (mm Hg)
81±10
83±12
0.263
80±11
80±14
0.998
Statins (%)
32.3
43.1
0.012
70.3
73.9
0.472
ACE inhibitors / AT II RBA (%)
33.5
51.6
<0.001
54.6
74.6
<0.001
Beta receptor blocking agents (%)
43.9
51.0
0.120
36.2
52.2
0.004
Aspirin or Clopidogrel (%)
63.3
68.9
0.205
90.6
86.3
0.213
Newly diagnosed diabetes (%) Hypertension (%)
HbA1c (%) Triglycerides (mg/dl)
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Total cholesterol (mg/dl)
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Smoking (%)
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cholesterol to mmol/l multiply by 0.0259. Data are shown as means ± standard deviations if not denoted otherwise. Diabetes duration is given as median together with the interquartile
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ACCEPTED MANUSCRIPT Figure legends
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Figure 1. Event-free survival in patients who neither had diabetes nor peripheral artery disease (solid line), in patients with type 2 diabetes who did not have peripheral artery disease (broken line), in patients with peripheral artery disease who did not have diabetes (dotted
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line), and in patients with both, type 2 diabetes and peripheral artery disease (semi-broken
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line).
Figure 2. Adjusted hazard ratios for the incidence of cardiovascular events in patients with type 2 diabetes who did not have peripheral artery disease (PAD-/T2DM+), in patients with
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peripheral artery disease who did not have diabetes (PAD+/T2DM-) and in patients with the combination of type 2 diabetes and peripheral artery disease (PAD+/T2DM+) when compared to subjects who neither had diabetes nor peripheral artery disease (PAD-/T2DM-).
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HDL cholesterol.
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Adjustments are made for age, gender, BMI, smoking, hypertension, LDL cholesterol, and
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Figure 2
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Figure 1
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ACCEPTED MANUSCRIPT Highlights
T2DM patients without PAD are at a lower risk than non-diabetic PAD patients.
•
PAD indicates a higher cardiovascular event risk than T2DM.
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Risk is moderate in T2DM patients without PAD.
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T2DM strongly increases the risk of cardiovascular events in patients with PAD.
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Patients with both, T2DM and PAD are at an extremely high cardiovascular risk.
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•