Open Access

Presentations of major peripheral arterial disease and risk of major outcomes in patients with type 2 diabetes: results from the ADVANCE-ON study

  • Kamel Mohammedi1Email author,
  • Mark Woodward1, 2, 3,
  • Yoichiro Hirakawa1,
  • Sophia Zoungas1, 4,
  • Stephen Colagiuri5,
  • Pavel Hamet6,
  • Stephen Harrap7,
  • Neil Poulter8,
  • David R. Matthews9,
  • Michel Marre10, 11, 12,
  • John Chalmers1 and
  • on behalf of the ADVANCE Collaborative Group
Cardiovascular Diabetology201615:129

https://doi.org/10.1186/s12933-016-0446-x

Received: 9 July 2016

Accepted: 20 August 2016

Published: 2 September 2016

Abstract

Background

Peripheral arterial disease (PAD) is known to be associated with high cardiovascular risk, but the individual impact of PAD presentations on risk of macrovascular and microvascular events has not been reliably compared in patients with type 2 diabetes. We aimed to evaluate the impact of major PAD, and its different presentations, on the 10-year risk of death, major macrovascular events, and major clinical microvascular events in these patients.

Methods

Participants in the action in diabetes and vascular disease: PreterAx and DiamicroN modified-release controlled evaluation (ADVANCE) trial and the ADVANCE-ON post-trial study were followed for a median of 5.0 (in-trial), 5.4 (post-trial), and 9.9 (overall) years. Major PAD at baseline was subdivided into lower-extremity chronic ulceration or amputation secondary to vascular disease and history of peripheral revascularization by angioplasty or surgery.

Results

Among 11,140 participants, 516 (4.6 %) had major PAD at baseline: 300 (2.7 %) had lower-extremity ulceration or amputation alone, 190 (1.7 %) had peripheral revascularization alone, and 26 (0.2 %) had both presentations. All-cause mortality, major macrovascular events, and major clinical microvascular events occurred in 2265 (20.3 %), 2166 (19.4 %), and 807 (7.2 %) participants, respectively. Compared to those without PAD, patients with major PAD had increased rates of all-cause mortality (HR 1.35, 95 % CI 1.15–1.60, p = 0.0004), and major macrovascular events (1.47 [1.23–1.75], p < 0.0001), after multiple adjustments for region of origin, cardiovascular risk factors and treatments, peripheral neuropathy markers, and randomized treatments. We have also observed a trend toward an association of baseline PAD with risk of major clinical microvascular events [1.31 (0.96–1.78), p = 0.09]. These associations were comparable for patients with a lower-extremity ulceration or amputation and for those with a history of peripheral revascularization. Furthermore, the risk of retinal photocoagulation or blindness, but not renal events, increased in patients with lower-extremity ulceration or amputation [1.53 (1.01–2.30), p = 0.04].

Conclusions

Lower-extremity ulceration or amputation, and peripheral revascularization both increased the risks of death and cardiovascular events, but only lower-extremity ulceration or amputation increased the risk of severe retinopathy in patients with type 2 diabetes. Screening for major PAD and its management remain crucial for cardiovascular prevention in patients with type 2 diabetes (ClinicalTrials.gov number, NCT00949286).

Keywords

Type 2 diabetes Peripheral arterial disease Lower-extremity ulceration Lower-extremity amputation Mortality Cardiovascular diseases Major macrovascular events Diabetic retinopathy

Background

Peripheral arterial disease (PAD) is a public health problem across the world with a significant impact on healthcare and a high economic burden [15]. It is associated with an increased risk of cardiovascular disease [68], and is particularly common in patients with type 2 diabetes [912]. Previous studies have shown poor survival and cardiovascular outcomes in patients with both type 2 diabetes and PAD [1315]. However, the individual impact of different presentations of major PAD on survival and risk of major macrovascular and microvascular events in patients with type 2 diabetes has not been reliably evaluated in long-term prospective studies. The Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) trial followed patients with type 2 diabetes for a median of 5.0 years, and the ADVANCE-ON post-trial observational study followed them up for further 5.4 years, to a median overall period of 9.9 years [16, 17]. The current investigation aimed to examine the impact of major PAD at baseline on the risk of mortality and major macrovascular and microvascular outcomes in patients with type 2 diabetes across the full 9.9 years, and to compare the effects on these outcomes, of presentation with lower-extremity ulceration or amputation on one hand, as against presentation with previous peripheral revascularization on the other.

Methods

Population study

ADVANCE was an international randomized trial in 11,140 patients with type 2 diabetes with the objectives to test the effect of intensive glucose control and blood pressure treatment on the incidence of major microvascular and macrovacular events [16]. Participants with type 2 diabetes at high risk of cardiovascular events were randomly assigned to a gliclazide (modified release)–based intensive glucose-control regimen, aiming to achieve an HbA1c ≤6.5 %, or to standard glucose control, with targets and regimens based on local guidelines. Participants were also randomly assigned to a fixed-dose combination of perindopril (4 mg) and indapamide (1.25 mg) or matching placebo. Subsequently 8494 surviving participants were enrolled in the post-trial observational evaluation, ADVANCE-ON, study. Design, characteristics of participants, and the main results of both studies have been previously published [1619].

Definition of peripheral arterial disease

Major PAD at baseline was defined, as in the ADVANCE study, as lower-extremity chronic ulceration (at least 6 weeks) or amputation below the knee (of at least one toe), secondary to vascular disease, or history of peripheral revascularization procedure by angioplasty or surgery [16]. Two presentations of major PAD were compared: lower-extremity ulceration or amputation versus peripheral revascularization. Patients with both presentations (n = 26) were excluded in the comparison of the outcomes according to each PAD presentation.

Definition of outcomes

There were three primary outcomes: all-cause mortality, major macrovascular events (a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death), and major clinical microvascular events (a composite of end-stage renal disease (ESRD), defined as requirement for renal-replacement therapy; death induced by renal disease; requirement for retinal photocoagulation; or diabetes-related blindness in either eye). The secondary outcomes were cardiovascular death, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, ESRD or renal death, and requirement for retinal photocoagulation or blindness. Outcomes were adjudicated by an independent End Point Adjudication Committee in the ADVANCE trial, through to the end of randomized treatment, and were reported by investigators without adjudication in the ADVANCE-ON study, in accord with its pre-specified protocol [17]. Information about the occurrence of study outcomes and of all serious adverse events was reported at the time of occurrence between visits. When study outcomes or serious adverse events occured, the responsible investigator of each centre ensured that the event was reported immediately by completing a serious adverse events form. The data and safety monitoring committee regularly reviewed all such events for each centre.

Statistical analyses

Categorical variables were presented as the number of patients with the corresponding percentage. Continuous variables were expressed as mean (SD) or median (interquartile range) for those with skewed distribution. Characteristics of participants according to major PAD status (absence vs. presence) and presentation (lower-extremity ulceration or amputation vs. peripheral revascularization) were compared at baseline using Chi squared, ANOVA, or Wilcoxon tests. Cumulative incidence curves were used to plot survival (outcome-free) rates during follow-up. Survival curves were compared using the log-rank test. Cox proportional hazards survival regression models were fitted to examine the effect of baseline history of major PAD and its presentations on time-related survival (outcome-free) rates. Hazard ratios (HR), with associated 95 % confidence intervals (CI), were estimated according to major PAD status at baseline. Basic (model 1: region of origin, sex, age, body mass index, systolic blood pressure, history of ever smoking and study allocations), and full (model 2: model 1 plus duration of diabetes, HbA1c, waist circumference, heart rate, diastolic blood pressure, disturbance of 10-g monofilament sensation, absence of ankle and knee reflexes, estimated glomerular filtration rate (eGFR) [and its square for macrovascular analyses], total-, and HDL-cholesterol, triglycerides, use of antihypertensive, lipid lowering and antiplatelet drugs, and history of current alcohol drinking) adjustments were performed. Participants with a history of macrovascular disease (defined as the presence at baseline, of myocardial infarction, stroke, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, hospital admission for unstable angina or transient ischaemic attack) were excluded in sensitivity analyses. p < 0.05 was considered as significant. Statistical analyses were performed using SAS software, version 9.3 (SAS Institute, http://www.sas.com).

Results

Clinical characteristics at baseline

Among 11,140 patients randomized at baseline, 516 (4.6 %) had a history of major PAD. Clinical characteristics of participants at baseline are shown in Additional file 1: Table S1. Participants with major PAD at baseline, compared to those without PAD, were older, and more frequently men and from established market economies. They had higher body mass index, waist circumference, and urinary albumin–creatinine ratio, and lower diastolic blood pressure, eGFR, and serum total and HDL-cholesterol. They were also more likely to use lipid lowering and antiplatelet drugs, and to have a history of ever smoking or current alcohol drinking. Patients with major PAD had also more frequent disturbance of 10-g monofilament sensation and absence of ankle and knee reflexes.

Incidence of outcomes during follow-up according to the history of major PAD at baseline

The median (interquartile interval) duration of overall follow-up was 9.9 (5.6–10.9) years. All-cause mortality, major macrovascular events, cardiovascular death, and major clinical microvascular events occurred in 2265 (20.3 %), 2166 (19.4 %), 988 (8.9 %), and 807 (7.2 %) participants, respectively. The cumulative incidence of all-cause mortality, major macrovascular events, cardiovascular death, and fatal or non-fatal myocardial infarction were higher in participants with history of major PAD at baseline compared to those without PAD (p < 0.0001 for all): Fig. 1; Table 1. Significant associations of PAD with the risk of all-cause mortality (HR 1.35, 95 % CI 1.15–1.60, p = 0.0004), major macrovascular events (HR 1.47, 95 % CI 1.23–1.75, p < 0.0001), cardiovascular death (HR 1.75, 95 % CI 1.39–2.21, p < 0.0001), and myocardial infarction (HR 1.58, 95 % CI 1.19–2.09, p = 0.001) persisted after adjustment for all potential confounding variables. A trend toward an association of major PAD with requirement of retinal photocoagulation or blindness persisted in the fully adjusted model (HR 1.39, 95 % CI 0.99–1.95, p = 0.05). However, we did not observe association of major PAD at baseline with the risk of ESRD or renal death (Table 1).
Fig. 1

Cumulative incidence of all-cause mortality, major macrovascular events, cardiovascular death, and fatal or nonfatal myocardial infarction according to the absence (solid line) or the presence of major PAD (dashed line) at baseline (p < 0.0001 for all)

Table 1

Hazard ratios for outcomes during follow-up by history of major PAD at baseline

 

Baseline history of major PAD

Hazard ratios (major PAD vs. not)

No (n = 10,624)

Yes (n = 516)

Model 1

Model 2

HR

95 % CI

p

HR

95 % CI

p

All-cause mortality, n (%)

2101 (19.8)

164 (31.8)

1.57

1.33–1.84

<0.0001

1.35

1.15–1.60

0.0004

Major macrovascular events, n (%)

2025 (19.1)

141 (27.3)

1.59

1.34–1.88

<0.0001

1.47

1.23–1.75

<0.0001

Cardiovascular death, n (%)

904 (8.5)

84 (16.3)

1.99

1.59–2.49

<0.0001

1.75

1.39–2.21

<0.0001

Myocardial infarction, n (%)

665 (6.3)

57 (11.0)

1.76

1.34–2.31

<0.0001

1.58

1.19–2.09

0.001

Stroke, n (%)

924 (8.7)

44 (8.5)

1.24

0.92–1.68

0.16

1.19

0.87–1.62

0.28

Major clinical microvascular events, n (%)

763 (7.2)

44 (8.5)

1.43

1.05–1.94

0.02

1.31

0.96–1.78

0.09

Retinal photocoagulation or blindness, n (%)

632 (5.9)

37 (7.2)

1.48

1.06–2.07

0.02

1.39

0.99–1.95

0.05

End-stage renal disease or renal death, n (%)

160 (1.5)

8 (1.6)

1.15

0.56–2.34

0.71

0.96

0.46–1.97

0.90

Model 1: adjusted for region of origin, sex, age, body mass index, systolic blood pressure, history of ever smoking, and study allocations. Model 2: adjusted as in model 1 plus duration of diabetes, HbA1c, waist circumference, heart rate, diastolic blood pressure, disturbance of 10-g monofilament sensation, absence of ankle and knee reflexes, estimated glomerular filtration rate (and its square for macrovascular analyses), total-, and HDL-cholesterol, triglycerides, use of antihypertensive, lipid lowering and antiplatelet drugs, and history of current alcohol drinking. p < 0.05 was significant

Incidence of outcomes during follow-up according to different presentations of major PAD at baseline

Lower-extremity ulceration or amputation, and history of peripheral revascularization, not concurrently occurring, were established at baseline in 300 (2.7 %) and 190 (1.7 %) participants, respectively (p < 0.0001). Only 26 (0.2 %) patients had both presentations of major PAD at baseline. Compared to those with lower-extremity ulceration or amputation, participants with history of peripheral revascularization, were more frequently men and from established market economies (Table 2). They had a shorter duration of diabetes, lower eGFR and serum total cholesterol, were more likely to use lipid lowering and antiplatelet drugs, and to have a history of ever smoking or current alcohol drinking. The cumulative incidence of all-cause mortality, major macrovascular events, cardiovascular death, and fatal and non-fatal myocardial infarction increased comparably in subjects with different presentations of major PAD, compared to those without PAD (Fig. 2; Table 3). Associations of both presentations with all-cause mortality, major macrovascular events, cardiovascular death, and myocardial infarction were confirmed in the fully adjusted model 2. Furthermore, lower-extremity ulceration or amputation was significantly associated with a higher risk of blindness or of requirement for retinal photocoagulation (HR 1.53, 95 % CI 1.01–2.30, p = 0.04). A non-significant trend toward an association of lower-extremity ulceration or amputation was also observed with the risk of major clinical microvascular events (HR 1.44, 95 % CI 0.98–2.11, p = 0.06). However, no association of lower-extremity ulceration or amputation was observed with the risk of ESRD or renal death. The risks for outcomes according to each presentation of major PAD were comparable for mortality and major macrovascular outcomes, but not for retinal complications.
Table 2

Clinical characteristics of participants according to different presentations of major PAD at baseline

 

Lower-extremity ulceration or amputation (n = 300)

Peripheral revascularization (n = 190)

p

Male sex, n (%)

177 (59.0)

140 (73.7)

0.0009

Region of origin: Asia, n (%)

81 (27.0)

12 (6.3)

<0.0001

Region of origin: established market economies, n (%)

158 (52.7)

135 (71.0)

Region of origin: Eastern Europe, n (%)

61 (20.3)

43 (22.6)

Age (years): mean (SD)

66.2 (6.7)

66.6 (6.9)

0.55

Duration of diabetes (years): median (Q1, Q3)

8.0 (4.0, 12.0)

6.0 (3.0, 11.0)

0.007

Waist circumference (cm): mean (SD)

101 (14)

102 (14)

0.72

Body mass index (kg/m2): mean (SD)

29.0 (5.9)

28.5 (4.4)

0.32

Heart rate (bpm): mean (SD)

74.5 (11.1)

72.4 (13.2)

0.06

Systolic blood pressure (mmHg): mean (SD)

145 (22)

144 (22)

0.76

Diastolic blood pressure (mmHg): mean (SD)

80 (11)

78 (10)

0.13

Use of antihypertensive treatment, n (%)

210 (70.0)

143 (75.3)

0.21

Disturbance of 10-g monofilament sensation, n (%)

59 (19.7)

30 (15.8)

0.28

Absence of ankle reflex, n (%)

102 (34.0)

51 (26.8)

0.10

Absence of knee reflex, n (%)

54 (18.0)

19 (10.0)

0.02

HbA1c (%): median (Q1, Q3)

7.3 (6.5, 8.7)

7.0 (6.4, 7.9)

0.18

HbA1c (mmol/mol): median (Q1, Q3)

56 (47, 72)

53 (46, 63)

eGFR (ml/min/1.73 m2)

74 (18)

70 (18)

0.01

Urinary albumin to creatinine ratio (µg/mg): median (Q1, Q3)

19 (9, 64)

14 (6, 55)

0.06

Serum total cholesterol (mmol/l): mean (SD)

5.2 (1.1)

4.8 (1.0)

0.0004

Serum HDL cholesterol (mmol/l): mean (SD)

1.2 (0.3)

1.2 (0.3)

0.37

Serum triglycerides (mmol/l): median (Q1, Q3)

1.7 (1.2, 2.5)

1.8 (1.2, 2.3)

0.56

Use of lipid lowering drugs, n (%)

103 (34.3)

126 (66.3)

<0.0001

Use of antiplatelet drugs, n (%)

139 (46.3)

143 (75.3)

<0.0001

History of current smoking, n (%)

47 (15.7)

30 (15.8)

0.97

History of ever smoking, n (%)

153 (51.0)

133 (70.0)

<0.0001

History of current drinking, n (%)

86 (28.7)

89 (46.8)

<0.0001

Comparison of qualitative and quantitative parameters were performed using Chi square and ANOVA tests, respectively. Wilcoxon test was used for variables with skewed distribution (duration of diabetes, HbA1c, urinary albumin-creatinine ratio and triglycerides). p < 0.05 was significant

Asia: Philippines, China, Malaysia, India; Established market economies: Australia, Canada, France, Germany, Ireland, Italy, Netherlands, New Zealand, United Kingdom; Eastern Europe: the Czech Republic, Estonia, Hungary, Lithuania, Poland, Russia, Slovakia. eGFR, estimated Glomerular Filtration Rate computed by the Chronic Kidney Disease Epidemiology Collaboration equation

History of current drinking was defined as consumption of alcohol at least once a week for most weeks of the previous year

Fig. 2

Cumulative incidence of all-cause mortality, major macrovascular events, cardiovascular death, and fatal or nonfatal myocardial infarction according to the absence (solid line) or the presence of lower-extremity ulceration or amputation (dashed line) and peripheral revascularization (dotted line) at baseline (p < 0.0001 for all)

Table 3

Hazard ratios for outcomes during follow-up according to different presentations of major PAD at baseline

 

Absence of PAD

Lower-extremity ulceration or amputation

Peripheral revascularization

Lower-extremity ulceration or amputation

(vs. absent PAD)

Peripheral revascularization

(vs. absent PAD)

HR (95 % CI)

p

HR (95 % CI)

p

All-cause mortality, n (%)

2101 (19.8)

92 (30.7)

63 (33.2)

1.39 (1.12-1.72)

0.003

1.31 (1.01–1.70)

0.04

Major macrovascular events, n (%)

2025 (19.1)

78 (26.0)

56 (29.5)

1.39 (1.11–1.75)

0.005

1.64 (1.25–2.16)

0.0004

Cardiovascular death, n (%)

904 (8.5)

50 (16.7)

29 (15.3)

1.91 (1.43–2.54)

<0.0001

1.52 (1.04–2.23)

0.03

Myocardial infarction, n (%)

665 (6.3)

29 (9.7)

25 (13.2)

1.50 (1.03–2.19)

0.03

1.73 (1.14–2.62)

0.01

Stroke, n (%)

924 (8.7)

24 (8.0)

18 (9.5)

1.02 (0.67–1.55)

0.92

1.54 (0.96–2.48)

0.07

Major clinical microvascular events, n (%)

763 (7.2)

28 (9.3)

11 (5.8)

1.44 (0.98–2.11)

0.06

0.88 (0.48–1.61)

0.68

Retinal photocoagulation or blindness, n (%)

632 (5.9)

24 (8.0)

9 (4.7)

1.53 (1.01–2.30)

0.04

0.94 (0.48–1.83)

0.85

End-stage renal disease or renal death, n (%)

160 (1.5)

4 (1.3)

3 (1.6)

0.84 (0.31–2.30)

0.74

0.94 (0.29–3.02)

0.92

Adjusted as in model 2: region of origin, sex, age, duration of diabetes, body mass index, waist circumference, heart rate, systolic and diastolic blood pressure, disturbance of 10-g monofilament sensation, absence of ankle and knee reflexes, HbA1C, estimated glomerular filtration rate (and its square for macrovascular analyses), total-, and HDL-cholesterol, triglycerides, history of ever smoking and current alcohol drinking, use of antihypertensive, lipid lowering and antiplatelet drugs, and study allocations. p < 0.05 was significant

Sensitivity analyses

Major PAD was established in 283 (3.7 %) patients among 7679 participants free from history of macrovascular disease at baseline. In this subset of participants, the association of major PAD with the risk of all-cause mortality, major macrovascular events and cardiovascular death remained significant (Additional file 1: Table S2). Lower-extremity ulceration or amputation, and the history of peripheral revascularization also remained significantly associated with increased risk for all-cause mortality (HR 1.60, 95 % CI 1.22–2.10, p = 0.0007, and HR 1.57, 95 % CI 1.06–2.34, p = 0.02, respectively) and major macrovascular events (HR 1.63, 95 % CI 1.20–2.21, p = 0.002, and HR 1.80, 95 % CI 1.14–2.86, p = 0.01, respectively).

Discussion

We have investigated the risk of vascular outcomes with major PAD, and its different presentations, in patients with type 2 diabetes followed for 10 years in the ADVANCE and ADVANCE-ON studies. Major PAD at baseline was associated with increased risk of all-cause mortality, major macrovascular events, cardiovascular death, and myocardial infarction. Lower-extremity ulceration or amputation, and the history of peripheral revascularization displayed similar risks of death and major cardiovascular events. However, lower-extremity ulceration or amputation, but not peripheral revascularization, was also associated with increased risk of retinal photocoagulation or blindness.

History of PAD and risk of macrovascular events

In line with our findings, poor survival and macrovascular outcomes associated with PAD were reported in other prospective studies of patients with type 2 diabetes, even in those who have not been treated with hypoglycaemic drugs [1315, 20]. In the PROspective pioglitAzone clinical trial in macrovascular events (PROactive) trial, baseline PAD was associated with high risk of all-cause mortality, and macrovascular complications in 5238 patients with type 2 diabetes during a mean follow-up of 2.9 years [14]. In the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, low ankle-brachial index or non-compressible artery were associated with increased risks of death and major cardiovascular events in 2368 patients with type 2 diabetes followed for an average of 4.3 years [15]. Our larger study demonstrates that the association of major PAD with death and major macrovascular events persisted during 10 years of follow-up, even after adjustment for major risk factors. Furthermore, these associations persisted in patients free for any history of macrovascular disease at baseline.

Presentations of PAD and risk of macrovascular events

As distal PAD is known to be associated with a high rate of ulceration and amputation, and is rarely accessible for revascularization [9, 21], it is tempting to speculate that our patients with history of lower-extremity ulceration or amputation, were more likely to have a distal than a proximal origin for their PAD. The determination of PAD localizations differs among studies, but angiography and Doppler ultrasound are still considered as the key imaging methods [21, 22]. A recent study has reported a semi-quantitative ultrasonographic score to evaluate the association of PAD severity and localizations with cardiovascular risk factors and adverse events [23]. This showed that the magnitude of the association of PAD with diabetes was greater with distal than proximal localizations. Major PAD presentations had different clinical characteristics in our study. Lower-extremity ulceration or amputation was more common than peripheral revascularization, and associated with a longer duration of diabetes. Furthermore, lower-extremity ulceration, amputation, and peripheral revascularization occurred concurrently in only 26 patients, suggesting that these presentations of major PAD have different origins. Comparison of survival, macrovascular and microvascular outcomes according to different presentations of major PAD have not been extensively performed in people with diabetes. Despite decrease in its prevalence and incidence during last decades in some regions in the world [24, 25], lower-extremity amputation will still exert an important health burden. Lower-extremity amputation and ulceration were associated with increased risk of major macrovascular events, and of cardiovascular and non-cardiovascular death in patients with diabetes [2629]. The risk of major cardiovascular events was also high in patients with PAD undergoing peripheral revascularization in a general population cohort including 39 % of participants with diabetes [30]. The pathophysiological links by which PAD might predispose to poor vascular outcomes have not yet been fully elucidated in patients with diabetes. The increased formation of advanced glycation end-products (AGE) and its receptors (RAGE) may be a potential pathway linking PAD and other major vascular outcomes. A recent study has shown association of high plasma levels of AGE-RAGE components with increased risk for amputation, PAD, or death in patients with type 2 diabetes [31].

Presentations of PAD and risk of microvascular events

Importantly, our findings highlight for the first time, the association of lower-extremity ulceration or amputation with the risk of severe eye complications during 10-years follow-up. This is comparable to a recent cross-sectional study, which showed a higher prevalence of PAD in patients with proliferative diabetic retinopathy rather than those with non-proliferative retinopathy [32]. We have also reported recently, association of history of diabetic retinopathy with requirement for laser photocoagulation at baseline with excess risk of major PAD during follow-up in ADVANCE study [33]. Our present findings are unlikely to be explained by a possible effect of peripheral diabetic neuropathy, since associations we have observed persisted despite adjustment for disturbance of 10-g monofilament sensation and absence of ankle and knee reflexes. Furthermore, the distribution of the key neuropathic markers was comparable between the different presentations of major PAD. However, we did not observe an association of either presentation of major PAD with the risk of major renal outcomes. Remarkably, only 3 patients with major PAD at baseline developed ESRD during 10 years of follow-up. Based on their high rate of mortality, patients with both PAD and chronic kidney disease (CKD) may have died before experiencing more advanced renal outcomes [34, 35]. A recent study showed that the 4-year mortality rate of patients with PAD and CKD stages 4, and 5 was 72 and 78 %, respectively [36].

Strengths and limitations

As compared to previous studies in people with type 2 diabetes, we have observed a lower prevalence of PAD, which may partially be explained by the differences in PAD definitions used [13, 14]. The main limitation of our investigation is that we have studied patients with symptomatic and severe PAD, and may have underestimated outcomes associated with asymptomatic PAD. However, our work has several strengths including the investigation of a large contemporary cohort of patients with type 2 diabetes at high cardiovascular risk, with a comprehensive clinical history of major PAD at baseline, and pre-specified major endpoints during the study period.

Conclusions

Our study underlines worse survival and cardiovascular outcomes in patients with type 2 diabetes and major PAD during 10 years of follow-up. Lower-extremity ulceration or amputation, and peripheral revascularization had similar effects on the risk of these outcomes. Furthermore, lower-extremity ulceration or amputation was associated with higher incidence of severe eye disease. Prompt screening and more intensive management of both presentations of major PAD may help to improve prognosis, particularly cardiovascular outcomes in patients with long-standing type 2 diabetes.

Abbreviations

ADVANCE: 

action in diabetes and vascular disease—preterax and diamicron modified-release controlled evaluation trial

AGE: 

advanced glycation end-products

ANOVA: 

analysis of variance

BARI 2D: 

bypass angioplasty revascularization investigation 2 diabetes trial

CI: 

confidence interval

CKD: 

chronic kidney disease

CKD-EPI: 

chronic kidney disease–epidemiology collaboration equation

eGFR: 

estimated glomerular filtration rate

ESRD: 

end stage renal disease

HR: 

hazard ratio

PAD: 

peripheral arterial disease

PROactive: 

PROspective pioglitAzone clinical trial in macrovascular events trial

RAGE: 

receptor of advanced glycation end-products

SD: 

standard deviation

Declarations

Authors’ contributions

KM wrote the manuscript with assistance from MW and JC; KM, MW and JC designed the study; YH contributed to statistical analyses and reviewed the manuscript; SZ, SC, PH, SH, NP, DRM and MM contributed to the discussion and reviewed the manuscript. JC and KM are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

Competing interests

Dr. Kamel Mohammedi reports personal fees from Novo-Nordisk, outside the submitted work; Prof. Marc Woodward reports personal fees from Amgen, outside the submitted work; Prof. Pavel Hamet reports grants from Servier, during the conduct of the study; other from Servier, outside the submitted work; Prof. Stephen Harrap reports grants from National Health and Medical Research Council of Australia, grants from The George Institute for Global Health, during the conduct of the study; other from Servier, outside the submitted work; Prof. Neil Poulter reports grants from The George Institute, grants from British Heart Foundation/Diabetes UK/The George Institute, during the conduct of the study; grants from The George Institute, grants from BHF/DUK/The George Institute, outside the submitted work; Prof. Michel Marre reports grants and personal fees from Novo Nordisk, grants and personal fees from Sanofi, grants and personal fees from Eli Lilly, personal fees from Servier, grants and personal fees from Merck Sharp and Dohme, personal fees from Abbott, grants and personal fees from Novartis, personal fees from Astra Zeneca, outside the submitted work; and Prof. John Chalmers reports grants from National Health and Medical Research Council of Australia, grants and personal fees from Servier, outside the submitted work. No other potential conflict of interest relevant to this article was reported.

Availability of data and material

The datasets analyzed during the current study are not publicly available due to consideration of intellectual property, due to many ongoing active collaborations worldwide, and to continuing analyses by the study investigators, but may be available from the principal investigator on reasonable request.

Ethics approval and consent to participate

The Institutional Ethics Committee of each participating centre approved the ADVANCE and ADVANCE-ON protocols, and all participants provided written informed consent.

Funding

Dr. Kamel Mohammedi was supported by grants from the Société Francophone du Diabète (SFD) and the Association Diabète Risque Vasculaire (ADRV).

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
The George Institute for Global Health, University of Sydney
(2)
The George Institute for Global Health, University of Oxford
(3)
Department of Epidemiology, Johns Hopkins University
(4)
Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University
(5)
Boden Institute of Obesity, Nutrition, Exercise and Eating Disorders, Sydney Medical School, University of Sydney
(6)
Research Centre, Centre Hospitalier de l’Université de Montréal
(7)
The University of Melbourne and Royal Melbourne Hospital
(8)
The International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College
(9)
Oxford Centre for Diabetes, Endocrinology and Metabolism, National Institute for Health Research, Oxford Biomedical Research Centre, Harris Manchester College, University of Oxford
(10)
INSERM, UMRS 1138, Centre de Recherche des Cordeliers
(11)
Department of Diabetology, Endocrinology and Nutrition, Assistance Publique-Hôpitaux de Paris, Bichat Hospital, DHU FIRE
(12)
Université Paris Diderot, Sorbonne Paris Cité, UFR de Médecine

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Copyright

© The Author(s) 2016

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