title: Metformin and low levels of thyroid-stimulating hormone in patients with type 2 diabetes mellitus.
abstract: BACKGROUND
  Small cross-sectional studies have suggested that metformin, a first-line oral hypoglycemic agent, may lower thyroid-stimulating hormone (TSH) levels. Our objective was to determine whether the use of metformin monotherapy, when compared with sulfonylurea monotherapy, is associated with an increased risk of low TSH levels (<0.4 mIU/L) in patients with type 2 diabetes mellitus.
  
  
  METHODS
  Using the Clinical Practice Research Datalink, we identified patients who began receiving metformin or sulfonylurea monotherapy between Jan. 1, 1988, and Dec. 31, 2012. We assembled 2 subcohorts of patients with treated hypothyroidism or euthyroidism, and followed them until Mar. 31, 2013. We used Cox proportional hazards models to evaluate the association of low TSH levels with metformin monotherapy, compared with sulfonylurea monotherapy, in each subcohort.
  
  
  RESULTS
  A total of 5689 patients with treated hypothyroidism and 59,937 euthyroid patients were included in the subcohorts. Among patients with treated hypothyroidism, 495 events of low TSH levels were observed during follow-up (incidence rate 119.7/1000 person-years). In the euthyroid group, 322 events of low TSH levels were observed (incidence rate 4.5/1000 person-years). Compared with sulfonylurea monotherapy, metformin monotherapy was associated with a 55% increased risk of low TSH levels in patients with treated hypothyroidism (incidence rate 79.5/1000 person-years v. 125.2/1000 person-years, adjusted hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.09-2.20), with the highest risk in the 90-180 days after initiation (adjusted HR 2.30, 95% CI 1.00-5.29). No association was observed in euthyroid patients (adjusted HR 0.97, 95% CI 0.69-1.36).
  
  
  CONCLUSIONS
  In this longitudinal population-based study, metformin use was associated with an increased incidence of low TSH levels in patients with treated hypothyroidism, but not in euthyroid patients. The clinical consequences of this need further investigation.
authors.affiliation: Centre for Clinical Epidemiology (Fournier, Yin, Yu, Azoulay), Lady Davis Institute, Jewish General Hospital; Department of Epidemiology, Biostatistics and Occupational Health (Fournier), McGill University; Division of Endocrinology (Yu), Jewish General Hospital; Department of Oncology (Azoulay), McGill University, Montréal, Que.
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Fournier
authors.affiliation: Centre for Clinical Epidemiology (Fournier, Yin, Yu, Azoulay), Lady Davis Institute, Jewish General Hospital; Department of Epidemiology, Biostatistics and Occupational Health (Fournier), McGill University; Division of Endocrinology (Yu), Jewish General Hospital; Department of Oncology (Azoulay), McGill University, Montréal, Que.
authors.forename: Hui
authors.initials: H
authors.lastname: Yin
authors.affiliation: Centre for Clinical Epidemiology (Fournier, Yin, Yu, Azoulay), Lady Davis Institute, Jewish General Hospital; Department of Epidemiology, Biostatistics and Occupational Health (Fournier), McGill University; Division of Endocrinology (Yu), Jewish General Hospital; Department of Oncology (Azoulay), McGill University, Montréal, Que.
authors.forename: Oriana Hoi Yun
authors.initials: OH
authors.lastname: Yu
authors.affiliation: Centre for Clinical Epidemiology (Fournier, Yin, Yu, Azoulay), Lady Davis Institute, Jewish General Hospital; Department of Epidemiology, Biostatistics and Occupational Health (Fournier), McGill University; Division of Endocrinology (Yu), Jewish General Hospital; Department of Oncology (Azoulay), McGill University, Montréal, Que. laurent.azoulay@mcgill.ca.
authors.forename: Laurent
authors.initials: L
authors.lastname: Azoulay
mesh_terms: D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007037:Hypothyroidism / Q000097:blood* / Q000188:drug therapy; D008137:Longitudinal Studies; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D012307:Risk Factors; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D013972:Thyrotropin / Q000097:blood*; D016896:Treatment Outcome; D006113:United Kingdom
chemical_list: D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D013972:Thyrotropin; D008687:Metformin