title: ANGPTL2 is associated with an increased risk of cardiovascular events and death in diabetic patients.
abstract: A high serum angiopoietin-like 2 (ANGPTL2) concentration is an independent risk factor for developing diabetes and is associated with insulin resistance and atherosclerosis. In this work, we have examined the impact of serum ANGPTL2 on improving cardiovascular (CV) risk stratification in patients with type 2 diabetes.
  
  
  
  A prospective, monocentric cohort of consecutive type 2 diabetes patients (the SURDIAGENE cohort; total of 1353 type 2 diabetes patients; 58% men, mean ± SD age 64 ± 11 years) was followed for a median of 6.0 years for death as primary endpoint and major adverse CV events (MACE; i.e. CV death, myocardial infarction or stroke) as a secondary endpoint. Patients with end-stage renal disease, defined as a requirement for dialysis or a history of kidney transplantation, were excluded. Patients were grouped into quartiles according to ANGPTL2 concentrations at inclusion: <11.2 (Q1), 11.2-14.7 (Q2), 14.8-19.5 (Q3) or >19.5 (Q4) ng/ml.
  
  
  
  During follow up, 367 patients (representing 4.5% of the total person-years) died and 290 patients (representing 3.7% of the total person-years) presented with MACE. Both the survival and MACE-free survival rates were significantly different between ANGPTL2 quartiles (logrank 82.12, p < 0.0001 for death; and logrank 65.14, p < 0.0001 for MACE). Patients with ANGPTL2 concentrations higher than 19.5 ng/ml (Q4) had a significantly higher risk of death and MACE than those with ANGPTL2 levels of 19.5 ng/ml or less (Q1-3) (HR for death 2.44 [95% CI 1.98, 3.00], p < 0.0001; HR for MACE 2.43 [95% CI 1.92, 3.06], p < 0.0001) after adjustment for sex, age and established CV risk factors. Using ANGPTL2 concentrations, prediction of the risk of mortality, as assessed by integrated discrimination improvement (IDI), was significantly improved (IDI 0.006 ± 0.002, p = 0.0002).
  
  
  
  In patients with type 2 diabetes, serum ANGPTL2 concentrations were independently associated with death and MACE. Therefore, ANGPTL2 is a promising candidate biomarker for improving risk stratification in type 2 diabetes patients, and may prove to be a valuable therapeutic target.
authors: ELSAN, Polyclinique de Poitiers, 1 Rue de la Providence, F-8600, Poitiers, France. barnabas.gellen.cardio@gmail.com.|Department of Cardiology, CHU Henri Mondor, Créteil, France. barnabas.gellen.cardio@gmail.com.|Faculté de Médecine et Pharmacie, Université de Poitiers, Poitiers, France. barnabas.gellen.cardio@gmail.com.
authors: Barnabas
authors: 0000-0002-1128-2985
authors: B
authors: Gellen
authors: Department of Surgery, Faculty of Medicine, Université de Montréal, Montreal Heart Institute, Montreal, QC, Canada.
authors: Nathalie
authors: N
authors: Thorin-Trescases
authors: CHU de Poitiers Centre d'Investigation Clinique, Poitiers, France.|Université de Poitiers, Laboratoire MOVE (EA 6314), Poitiers, France.|Centre Médico-Sportif Mon Stade, Paris, France.
authors: Philippe
authors: P
authors: Sosner
authors: CHU de Poitiers, Pôle Dune, Poitiers, France.
authors: Elise
authors: E
authors: Gand
authors: CHU de Poitiers Centre d'Investigation Clinique, Poitiers, France.|Inserm, CIC 1402, Poitiers, France.|UFR Médecine Pharmacie, Université de Poitiers, Poitiers, France.
authors: Pierre-Jean
authors: PJ
authors: Saulnier
authors: CHU de Poitiers Centre d'Investigation Clinique, Poitiers, France.
authors: Stéphanie
authors: S
authors: Ragot
authors: CHU de Poitiers, Pôle Dune, Poitiers, France.
authors: Mathilde
authors: M
authors: Fraty
authors: UFR Médecine Pharmacie, Université de Poitiers, Poitiers, France.|Endocrinologie-Diabétologie, CHU de Poitiers, Poitiers, France.
authors: Stéphanie
authors: S
authors: Laugier
authors: Département Hospitalo-Universitaire FIRE, APHP, Hôpital Bichat, Paris, France.|Faculté de Médecine, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Inserm U-1148, Paris, France.
authors: Grégory
authors: G
authors: Ducrocq
authors: CHU Lille, Service d'Explorations Fonctionnelles Cardiovasculaires, Hôpital Cardiologique, Lille, France.|Faculté de Médecine, Université de Lille, Lille, France.|Inserm U1011, Lille, France.|EGID, Lille, France.|Institut Pasteur de Lille, Lille, France.
authors: David
authors: D
authors: Montaigne
authors: CHU de Poitiers Centre d'Investigation Clinique, Poitiers, France.
authors: Pierre
authors: P
authors: Llaty
authors: CHU Bordeaux, Haut-Lévêque Hospital, Nutrition-Diabetology Department, Pessac, France.
authors: Vincent
authors: V
authors: Rigalleau
authors: CHU de Grenoble, Service Néphrologie, Dialyse et Transplantation, Grenoble, France.|Faculté de Médecine, Université Joseph Fournier, Grenoble, France.
authors: Philippe
authors: P
authors: Zaoui
authors: CHU de Tours, Service Néphrologie, Dialyse et Transplantation, Tours, France.
authors: Jean-Michel
authors: JM
authors: Halimi
authors: Département Hospitalo-Universitaire FIRE, APHP, Hôpital Bichat, Paris, France.|Faculté de Médecine, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors: Ronan
authors: R
authors: Roussel
authors: Department of Surgery, Faculty of Medicine, Université de Montréal, Montreal Heart Institute, Montreal, QC, Canada.
authors: Eric
authors: E
authors: Thorin
authors: CHU de Poitiers Centre d'Investigation Clinique, Poitiers, France.|Inserm, CIC 1402, Poitiers, France.|UFR Médecine Pharmacie, Université de Poitiers, Poitiers, France.|Endocrinologie-Diabétologie, CHU de Poitiers, Poitiers, France.|Inserm U1082, Poitiers, France.
authors: Samy
authors: S
authors: Hadjadj
mesh_terms: D000368:Aged; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000453:epidemiology / Q000401:mortality; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000453:epidemiology / Q000401:mortality*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000453:epidemiology / Q000401:mortality; D011446:Prospective Studies; D012307:Risk Factors; D020521:Stroke / Q000097:blood / Q000453:epidemiology / Q000401:mortality
chemical_list: C485792:ANGPTL2 protein, human; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D015415:Biomarkers
keywords: ANGPTL2; Angiopoietin-like 2; Biomarker; Death; MACE; Type 2 diabetes