title: Is the association of serum sodium with mortality in patients with type 2 diabetes explained by copeptin or NT-proBNP? (ZODIAC-46).
abstract: OBJECTIVE
  Hyponatremia has been associated with an increased mortality risk in the general population. Diabetes is a condition predisposing for elevated levels of arginine vasopressin (AVP) and heart failure, both common causes of hyponatremia. These factors, however, are also associated with an increased mortality risk. We aimed to investigate whether serum sodium is associated with cardiovascular and all-cause mortality in type 2 diabetes and whether these associations could be explained by copeptin, a surrogate for AVP, or NT-proBNP, a marker for heart failure.
  
  
  METHODS
  Patients with type 2 diabetes participating in the observational ZODIAC study were included. Cox regression analyses were used to investigate the association of serum sodium with mortality.
  
  
  RESULTS
  We included 1068 patients (age 67 ± 12 years, 45% male, serum sodium 142 ± 3 mmol/L). After 15 years of follow-up, 519 patients (49%) died, with 225 cardiovascular deaths (21%). In univariable analyses, serum sodium, copeptin, and NT-proBNP were all significantly associated with cardiovascular and all-cause mortality. These associations remained significant after combination of these markers in a multivariable model. Serum sodium and NT-proBNP remained significantly associated with mortality after further adjustment for potential confounders, whereas copeptin lost significance after adjustment for SCr and ACR.
  
  
  CONCLUSIONS
  Low serum sodium was associated with an increased risk of cardiovascular and all-cause mortality in type 2 diabetes. Moreover, these associations were not explained by copeptin and NT-proBNP. Whether low serum sodium itself leads to poor outcome or is a marker for (unidentified) co-morbidity severity or use of specific medications remains to be elucidated.
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands. Electronic address: i.j.riphagen@umcg.nl.
authors.forename: Ineke J
authors.initials: IJ
authors.lastname: Riphagen
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Diabetes Centre, Isala Clinics, Zwolle, The Netherlands.
authors.forename: Susan J J
authors.initials: SJ
authors.lastname: Logtenberg
authors.affiliation: Diabetes Centre, Isala Clinics, Zwolle, The Netherlands; Department of General Practice, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Klaas H
authors.initials: KH
authors.lastname: Groenier
authors.affiliation: Diabetes Centre, Isala Clinics, Zwolle, The Netherlands.
authors.forename: Kornelis J J
authors.initials: KJ
authors.lastname: van Hateren
authors.affiliation: Diabetes Centre, Isala Clinics, Zwolle, The Netherlands; Department of Medicine, Gelre Hospital, Apeldoorn, The Netherlands.
authors.forename: Gijs W D
authors.initials: GW
authors.lastname: Landman
authors.affiliation: BRAHMS GmbH, Thermo Fisher Scientific, Hennigsdorf, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Struck
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Kootstra-Ros
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Ido P
authors.initials: IP
authors.lastname: Kema
authors.affiliation: Diabetes Centre, Isala Clinics, Zwolle, The Netherlands; Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Henk J G
authors.initials: HJ
authors.lastname: Bilo
authors.affiliation: Diabetes Centre, Isala Clinics, Zwolle, The Netherlands; Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Langerhans Medical Research Group, Zwolle, The Netherlands.
authors.forename: Nanne
authors.initials: N
authors.lastname: Kleefstra
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands.
authors.forename: Stephan J L
authors.initials: SJ
authors.lastname: Bakker
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood* / Q000175:diagnosis / Q000401:mortality*; D002423:Cause of Death; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000175:diagnosis / Q000401:mortality*; D005260:Female; D006020:Glycopeptides / Q000097:blood*; D006801:Humans; D007010:Hyponatremia / Q000097:blood* / Q000175:diagnosis / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020097:Natriuretic Peptide, Brain / Q000097:blood*; D010446:Peptide Fragments / Q000097:blood*; D011379:Prognosis; D016016:Proportional Hazards Models; D012307:Risk Factors; D012964:Sodium / Q000097:blood*
chemical_list: D015415:Biomarkers; D006020:Glycopeptides; D010446:Peptide Fragments; C048197:copeptins; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D012964:Sodium
keywords: All-cause mortality; Cardiovascular mortality; Serum sodium; Type 2 diabetes