Serum Proenkephalin A Levels and Mortality After Long-Term Follow-Up in Patients with Type 2 Diabetes Mellitus (ZODIAC-32)

PLoS One. 2015 Jul 28;10(7):e0133065. doi: 10.1371/journal.pone.0133065. eCollection 2015.


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.

Objectives: 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.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers / blood
  • Cardiovascular Diseases / blood*
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / mortality*
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / mortality*
  • Enkephalins / blood*
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Middle Aged
  • Myocardial Infarction / etiology
  • Myocardial Infarction / mortality
  • Netherlands
  • Prospective Studies
  • Protein Precursors / blood*


  • Biomarkers
  • Enkephalins
  • Protein Precursors
  • proenkephalin

Grants and funding

BRAHMS GmbH / Thermo Fisher Scientific provided the PENK-A assay. AS worked at BRAHMS and participated in revising the manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.