title: Presentations of major peripheral arterial disease and risk of major outcomes in patients with type 2 diabetes: results from the ADVANCE-ON study.
abstract: 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.
  
  
  
  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.
  
  
  
  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].
  
  
  
  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).
authors: The George Institute for Global Health, University of Sydney, PO Box M201, Missenden road, Camperdown, Sydney, NSW, 2050, Australia. kmohammedi@georgeinstitute.org.au.
authors: Kamel
authors: K
authors: Mohammedi
authors: The George Institute for Global Health, University of Sydney, PO Box M201, Missenden road, Camperdown, Sydney, NSW, 2050, Australia.|The George Institute for Global Health, University of Oxford, Oxford, UK.|Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA.
authors: Mark
authors: M
authors: Woodward
authors: The George Institute for Global Health, University of Sydney, PO Box M201, Missenden road, Camperdown, Sydney, NSW, 2050, Australia.
authors: Yoichiro
authors: Y
authors: Hirakawa
authors: The George Institute for Global Health, University of Sydney, PO Box M201, Missenden road, Camperdown, Sydney, NSW, 2050, Australia.|Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Clayton, VIC, Australia.
authors: Sophia
authors: S
authors: Zoungas
authors: Boden Institute of Obesity, Nutrition, Exercise and Eating Disorders, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors: Stephen
authors: S
authors: Colagiuri
authors: Research Centre, Centre Hospitalier de l'Université de Montréal, Montreal, Canada.
authors: Pavel
authors: P
authors: Hamet
authors: The University of Melbourne and Royal Melbourne Hospital, Melbourne, VIC, Australia.
authors: Stephen
authors: S
authors: Harrap
authors: The International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College, London, UK.
authors: Neil
authors: N
authors: Poulter
authors: Oxford Centre for Diabetes, Endocrinology and Metabolism, National Institute for Health Research, Oxford Biomedical Research Centre, Harris Manchester College, University of Oxford, Oxford, UK.
authors: David R
authors: DR
authors: Matthews
authors: INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.|Department of Diabetology, Endocrinology and Nutrition, Assistance Publique-Hôpitaux de Paris, Bichat Hospital, DHU FIRE, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, UFR de Médecine, Paris, France.
authors: Michel
authors: M
authors: Marre
authors: The George Institute for Global Health, University of Sydney, PO Box M201, Missenden road, Camperdown, Sydney, NSW, 2050, Australia.
authors: John
authors: J
authors: Chalmers
mesh_terms: D000368:Aged; D000671:Amputation, Surgical; D017130:Angioplasty; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality; D003925:Diabetic Angiopathies / Q000175:diagnosis / Q000209:etiology* / Q000401:mortality / Q000628:therapy; D003930:Diabetic Retinopathy / Q000209:etiology; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007871:Leg Ulcer / Q000209:etiology; D023821:Limb Salvage; D035002:Lower Extremity / Q000098:blood supply*; D008297:Male; D008875:Middle Aged; D058729:Peripheral Arterial Disease / Q000175:diagnosis / Q000209:etiology* / Q000401:mortality / Q000628:therapy; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014656:Vascular Surgical Procedures
chemical_list: D007004:Hypoglycemic Agents
keywords: Cardiovascular diseases; Diabetic retinopathy; Lower-extremity amputation; Lower-extremity ulceration; Major macrovascular events; Mortality; Peripheral arterial disease; Type 2 diabetes