title: Cardiovascular risks associated with second-line oral antidiabetic agents added to metformin in patients with Type 2 diabetes: a nationwide cohort study.
abstract: OBJECTIVE
  To compare the cardiovascular risks associated with second-line oral antidiabetic agents added to initial metformin therapy in a large nationwide observational study.
  
  
  METHODS
  We conducted a nationwide retrospective cohort study using the Taiwan National Health Insurance database. A total of 36 118 users of different add-on oral antidiabetic agents (sulphonylureas, glinides, pioglitazone, α-glucosidase inhibitors and dipeptidyl peptidase-4 inhibitors) after initial metformin therapy were included in the analysis. The reference group was sulphonylureas added to metformin, the most commonly used combination regimen. The main outcomes of interest were hospitalizations for any cardiovascular event including acute myocardial infarction, congestive heart failure and ischaemic stroke. In the main analysis, all patients were followed within their initiation groups until the study end, disregarding any changes in treatment status over time.
  
  
  RESULTS
  In intention-to-treat analyses, there was no difference in the risk of any cardiovascular event among the add-on combination treatment groups, but significantly lower risks of acute myocardial infarction were found for the glinides plus metformin treatment group (crude hazard ratio 0.52, adjusted hazard ratio 0.39; 95% CI 0.20-0.75) and for the α-glucosidase inhibitors plus metformin treatment group (crude hazard ratio 0.63, adjusted hazard ratio 0.54; 95% CI 0.31-0.95). No difference in risk of congestive heart failure or ischaemic stroke risk was found among the combination treatment groups. In secondary as-treated analyses, similar but less significant associations were found as compared with the primary intention-to-treat analyses for all treatment groups.
  
  
  CONCLUSIONS
  There were no differences in overall cardiovascular risks among several add-on second-line oral antidiabetic agents; however, glinide plus metformin and α-glucosidase inhibitors plus metformin combination therapies might be associated with lower risks of acute myocardial infarction.
authors.affiliation: Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Department of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital HsinChu branch, HsinChu, Taiwan.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Department of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Institute of Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: L-M
authors.initials: LM
authors.lastname: Chuang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Department of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Cardiovascular Center, National Taiwan University Hospital Yun-Lin Branch, Dou-Liou City, Yun-Lin County, Taiwan.
authors.forename: J-W
authors.initials: JW
authors.lastname: Lin
authors.affiliation: Institute of Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: S-T
authors.initials: ST
authors.lastname: Chen
authors.affiliation: Institute of Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: M-S
authors.initials: MS
authors.lastname: Lai
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Department of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Institute of Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Chang
mesh_terms: D000284:Administration, Oral; D002318:Cardiovascular Diseases / Q000150:complications / Q000453:epidemiology / Q000517:prevention & control*; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D003925:Diabetic Angiopathies / Q000453:epidemiology / Q000517:prevention & control*; D058065:Diabetic Cardiomyopathies / Q000453:epidemiology / Q000517:prevention & control*; D004359:Drug Therapy, Combination; D057286:Electronic Health Records; D005260:Female; D005500:Follow-Up Studies; D065089:Glycoside Hydrolase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000627:therapeutic use*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000150:complications / Q000453:epidemiology / Q000517:prevention & control; D009313:National Health Programs; D012189:Retrospective Studies; D012306:Risk; D013624:Taiwan / Q000453:epidemiology
chemical_list: D065089:Glycoside Hydrolase Inhibitors; D007004:Hypoglycemic Agents; D008687:Metformin