title: Serum Proenkephalin A Levels and Mortality After Long-Term Follow-Up in Patients with Type 2 Diabetes Mellitus (ZODIAC-32).
abstract: BACKGROUND
  Two previous studies concluded that proenkephalin A (PENK-A) had predictive capabilities for stroke severity, recurrent myocardial infarction, heart failure and mortality in patients with stroke and myocardial infarction.
  
  
  OBJECTIVE
  This study aimed to investigate the value of PENK-A as a biomarker for predicting mortality in patients with type 2 diabetes mellitus.
  
  
  METHODS
  Patients with type 2 diabetes mellitus were included from the prospective observational ZODIAC (Zwolle Outpatient Diabetes project Integrating Available Care) study. The present analysis incorporated two ZODIAC cohorts (1998 and 2001). Since blood was drawn for 1204 out of 1688 patients (71%), and information on relevant confounders was missing in 47 patients, the final sample comprised 1157 patients. Cox proportional hazard models were used for evaluating the relationship between PENK-A and (cardiovascular) mortality. Risk prediction capabilities were assessed with Harrell's C statistics and the integrated discrimination improvement (IDI).
  
  
  RESULTS
  After a follow-up period of 14 years, 525 (45%) out of 1157 patients had died, of which 224 (43%) were attributable to cardiovascular factors. Higher Log PENK-A levels were not independently associated with increased (cardiovascular) mortality. Patients with PENK-A values in the highest tertile had a 49% (95%CI 1%-121%) higher risk of cardiovascular mortality compared to patients in the reference category (lowest tertile). C-values were not different after removing PENK-A from the Cox models and there were no significant differences in IDI values.
  
  
  CONCLUSIONS
  The associations between PENK-A and mortality were strongly attenuated after accounting for all traditional risk factors. Furthermore, PENK-A did not seem to have additional value beyond conventional risk factors when predicting all-cause and cardiovascular mortality.
authors.affiliation: Diabetes Centre, Isala, Zwolle, the Netherlands.
authors.forename: Kornelis J J
authors.initials: KJ
authors.lastname: van Hateren
authors.affiliation: Diabetes Centre, Isala, Zwolle, the Netherlands; Department of Internal Medicine, Gelre hospital, Apeldoorn, the Netherlands.
authors.forename: Gijs W D
authors.initials: GW
authors.lastname: Landman
authors.affiliation: Diabetes Centre, Isala, Zwolle, the Netherlands.
authors.forename: Jarinke F H
authors.initials: JF
authors.lastname: Arnold
authors.affiliation: Diabetes Centre, Isala, Zwolle, the Netherlands; University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, the Netherlands.
authors.forename: Hanneke
authors.initials: H
authors.lastname: Joosten
authors.affiliation: Diabetes Centre, Isala, Zwolle, the Netherlands; University of Groningen, University Medical Center Groningen, Department of General Practice, Groningen, the Netherlands.
authors.forename: Klaas H
authors.initials: KH
authors.lastname: Groenier
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, the Netherlands.
authors.forename: Gerjan J
authors.initials: GJ
authors.lastname: Navis
authors.affiliation: Research Department, B.R.A.H.M.S GmbH (Thermo Fisher Scientific), Hennigsdorf/Berlin, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sparwasser
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, the Netherlands.
authors.forename: Stephan J L
authors.initials: SJ
authors.lastname: Bakker
authors.affiliation: Diabetes Centre, Isala, Zwolle, the Netherlands; University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, the Netherlands; Department of Internal Medicine, Isala, Zwolle, the Netherlands.
authors.forename: Henk J G
authors.initials: HJ
authors.lastname: Bilo
authors.affiliation: Diabetes Centre, Isala, Zwolle, the Netherlands; University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, the Netherlands; Langerhans Medical Research Group, Zwolle, the Netherlands.
authors.forename: Nanne
authors.initials: N
authors.lastname: Kleefstra
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood* / Q000209:etiology / Q000401:mortality*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications / Q000401:mortality*; D004745:Enkephalins / Q000097:blood*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology / Q000401:mortality; D009426:Netherlands; D011446:Prospective Studies; D011498:Protein Precursors / Q000097:blood*
chemical_list: D015415:Biomarkers; D004745:Enkephalins; D011498:Protein Precursors; C029992:proenkephalin