title: Metformin use and mortality in patients with advanced chronic kidney disease: national, retrospective, observational, cohort study.
abstract: BACKGROUND
  Metformin is recommended as a first-line treatment for patients with type 2 diabetes. However, use of this drug has been contraindicated in individuals with impaired kidney function because of the perceived risk of lactic acidosis. Evidence now supports cautious use of metformin in people with mild-to-moderate chronic kidney disease. However, studies examining the use of metformin in patients with advanced chronic kidney disease are lacking. We aimed to assess the safety of metformin in patients with type 2 diabetes and advanced (approximately stage 5) chronic kidney disease.
  
  
  METHODS
  We did a retrospective, observational, cohort study of patients with type 2 diabetes who were enrolled prospectively in Taiwan's national health insurance research database between Jan 1, 2000, and June 30, 2009, and had follow-up data until Dec 31, 2009. We included individuals with a serum creatinine concentration greater than 530 μmol/L, which is approximately equivalent to stage 5 chronic kidney disease. From a consecutive sample of 12 350 patients with type 2 diabetes and chronic kidney disease, 1005 used metformin and 11 345 were non-users. We matched users and non-users of metformin by propensity score in a 1:3 ratio. Our primary outcome was all-cause mortality.
  
  
  RESULTS
  813 metformin users were matched by propensity score to 2439 non-users. The two groups of patients did not differ significantly by 30 baseline clinical and socioeconomic variables. Median follow-up in the matched cohort was 2·1 years (range 0·3-9·8). All-cause mortality was reported in 434 (53%) of 813 metformin users and in 1012 (41%) of 2439 non-users. After multivariate adjustment, metformin use was an independent risk factor for mortality (adjusted hazard ratio 1·35, 95% CI 1·20-1·51; p<0·0001). The increased mortality risk was dose-dependent and was consistent across all subgroup analyses. However, metformin use compared with no use was associated with a higher but non-significant risk of metabolic acidosis (1·6 vs 1·3 events per 100 patient-years; adjusted hazard ratio 1·30, 95% CI 0·88-1·93; p=0·19).
  
  
  CONCLUSIONS
  Use of metformin in people with type 2 diabetes and a serum creatinine concentration greater than 530 μmol/L is associated with a significantly increased risk of all-cause mortality compared with non-users. Metformin use should not be encouraged in this patient group.
  
  
  BACKGROUND
  Taipei Tzu Chi Hospital, Taipei Veterans General Hospital, Foundation for Poison Control, National Health Research Institutes, Ministry of Science and Technology of Taiwan.
authors.affiliation: Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Szu-Chun
authors.initials: SC
authors.lastname: Hung
authors.affiliation: Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Yu-Kang
authors.initials: YK
authors.lastname: Chang
authors.affiliation: Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Jia-Sin
authors.initials: JS
authors.lastname: Liu
authors.affiliation: Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Ko-Lin
authors.initials: KL
authors.lastname: Kuo
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Taipei City Hospital Yang-Ming Branch, Taipei, Taiwan.
authors.forename: Yu-Hsin
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan; Department of Health Services Administration, China Medical University, Taichung, Taiwan. Electronic address: cch@nhri.org.tw.
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Hsu
authors.affiliation: Institutes of Physiology and Clinical Medicine, National Yang-Ming University, and Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: dctarng@vghtpe.gov.tw.
authors.forename: Der-Cherng
authors.initials: DC
authors.lastname: Tarng
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D003404:Creatinine / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000401:mortality*; D005500:Follow-Up Studies; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D008687:Metformin / Q000009:adverse effects*; D008875:Middle Aged; D051436:Renal Insufficiency, Chronic / Q000150:complications* / Q000401:mortality*; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin; D003404:Creatinine