Barnabas Gellen1,2,3, Nathalie Thorin-Trescases4, Philippe Sosner5,6,7, Elise Gand8, Pierre-Jean Saulnier5,9,10, Stéphanie Ragot5, Mathilde Fraty8, Stéphanie Laugier10,11, Grégory Ducrocq12,13,14, David Montaigne15,16,17,18,19, Pierre Llaty5, Vincent Rigalleau20, Philippe Zaoui21,22, Jean-Michel Halimi23, Ronan Roussel12,13, Eric Thorin4, Samy Hadjadj5,9,10,11,24. 1. ELSAN, Polyclinique de Poitiers, 1 Rue de la Providence, F-8600, Poitiers, France. barnabas.gellen.cardio@gmail.com. 2. Department of Cardiology, CHU Henri Mondor, Créteil, France. barnabas.gellen.cardio@gmail.com. 3. Faculté de Médecine et Pharmacie, Université de Poitiers, Poitiers, France. barnabas.gellen.cardio@gmail.com. 4. Department of Surgery, Faculty of Medicine, Université de Montréal, Montreal Heart Institute, Montreal, QC, Canada. 5. CHU de Poitiers Centre d'Investigation Clinique, Poitiers, France. 6. Université de Poitiers, Laboratoire MOVE (EA 6314), Poitiers, France. 7. Centre Médico-Sportif Mon Stade, Paris, France. 8. CHU de Poitiers, Pôle Dune, Poitiers, France. 9. Inserm, CIC 1402, Poitiers, France. 10. UFR Médecine Pharmacie, Université de Poitiers, Poitiers, France. 11. Endocrinologie-Diabétologie, CHU de Poitiers, Poitiers, France. 12. Département Hospitalo-Universitaire FIRE, APHP, Hôpital Bichat, Paris, France. 13. Faculté de Médecine, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. 14. Inserm U-1148, Paris, France. 15. CHU Lille, Service d'Explorations Fonctionnelles Cardiovasculaires, Hôpital Cardiologique, Lille, France. 16. Faculté de Médecine, Université de Lille, Lille, France. 17. Inserm U1011, Lille, France. 18. EGID, Lille, France. 19. Institut Pasteur de Lille, Lille, France. 20. CHU Bordeaux, Haut-Lévêque Hospital, Nutrition-Diabetology Department, Pessac, France. 21. CHU de Grenoble, Service Néphrologie, Dialyse et Transplantation, Grenoble, France. 22. Faculté de Médecine, Université Joseph Fournier, Grenoble, France. 23. CHU de Tours, Service Néphrologie, Dialyse et Transplantation, Tours, France. 24. Inserm U1082, Poitiers, France.
Abstract
AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS/ INTERPRETATION: 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.
AIMS/HYPOTHESIS: 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. METHODS: A prospective, monocentric cohort of consecutive type 2 diabetespatients (the SURDIAGENE cohort; total of 1353 type 2 diabetespatients; 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. RESULTS: 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). CONCLUSIONS/ INTERPRETATION: 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 diabetespatients, and may prove to be a valuable therapeutic target.
Entities:
Keywords:
ANGPTL2; Angiopoietin-like 2; Biomarker; Death; MACE; Type 2 diabetes
Authors: Karen A Hicks; James E Tcheng; Biykem Bozkurt; Bernard R Chaitman; Donald E Cutlip; Andrew Farb; Gregg C Fonarow; Jeffrey P Jacobs; Michael R Jaff; Judith H Lichtman; Marian C Limacher; Kenneth W Mahaffey; Roxana Mehran; Steven E Nissen; Eric E Smith; Shari L Targum Journal: J Am Coll Cardiol Date: 2014-12-29 Impact factor: 24.094
Authors: Bernt Johan von Scholten; Henrik Reinhard; Tine Willum Hansen; Morten Lindhardt; Claus Leth Petersen; Niels Wiinberg; Peter Riis Hansen; Hans-Henrik Parving; Peter Karl Jacobsen; Peter Rossing Journal: Cardiovasc Diabetol Date: 2015-05-21 Impact factor: 9.951