title: Differential cardiovascular outcomes after dipeptidyl peptidase-4 inhibitor, sulfonylurea, and pioglitazone therapy, all in combination with metformin, for type 2 diabetes: a population-based cohort study.
abstract: OBJECTIVE
  Data on the comparative effectiveness of oral antidiabetics on cardiovascular outcomes in a clinical practice setting are limited. This study sought to determine whether a differential risk of cardiovascular disease (CVD) exists for the combination of a dipeptidyl peptidase-4 (DPP-4) inhibitor plus metformin versus a sulfonylurea derivative plus metformin or pioglitazone plus metformin.
  
  
  METHODS
  We conducted a cohort study of 349,476 patients who received treatment with a DPP-4 inhibitor, sulfonylurea, or pioglitazone plus metformin for type 2 diabetes using the Korean national health insurance claims database. The incidence of total CVD and individual outcomes of myocardial infarction (MI), heart failure (HF), and ischemic stroke (IS) were assessed using the hazard ratios (HRs) estimated from a Cox proportional-hazards model weighted for a propensity score.
  
  
  RESULTS
  During follow-up, 3,881 patients developed a CVD, including 428 MIs, 212 HFs, and 1,487 ISs. The adjusted HR with 95% confidence interval (CI) for a sulfonylurea derivative plus metformin compared with a DPP-4 inhibitor plus metformin was 1.20 (1.09-1.32) for total CVD; 1.14 (1.04-1.91) for MI; 1.07 (0.71-1.62) for HF; and 1.51 (1.28-1.79) for IS. The HRs with 95% CI for total CVD, MI, HF, and IS for pioglitazone plus metformin were 0.89 (0.81-0.99), 1.05 (0.76-1.46), 4.81 (3.53-6.56), and 0.81 (0.67-0.99), respectively.
  
  
  CONCLUSIONS
  Compared with a DPP-4 inhibitor plus metformin, treatment with a sulfonylurea drug plus metformin was associated with increased risks of total CVD, MI, and IS, whereas the use of pioglitazone plus metformin was associated with decreased total CVD and IS risks.
authors.affiliation: Office of Drug Safety Information II, Korea Institute of Drug Safety & Risk Management, Seoul, Republic of Korea; Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jong-Mi
authors.initials: JM
authors.lastname: Seong
authors.affiliation: Division of Clinical Epidemiology, Medical Research Collaborating Center, Seoul National University College of Medicine/Seoul National University Hospital, Seoul, Republic of Korea; Medical Research Center, Seoul National University, Seoul, Republic of Korea.
authors.forename: Nam-Kyong
authors.initials: NK
authors.lastname: Choi
authors.affiliation: Office of Drug Utilization Review, Korea Institute of Drug Safety & Risk Management, Seoul, Republic of Korea.
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Shin
authors.affiliation: Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, Seoul, Republic of Korea.
authors.forename: Yoosoo
authors.initials: Y
authors.lastname: Chang
authors.affiliation: Office of Drug Safety Information I, Korea Institute of Drug Safety & Risk Management, Seoul, Republic of Korea.
authors.forename: Ye-Jee
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Division of Clinical Epidemiology, Medical Research Collaborating Center, Seoul National University College of Medicine/Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Joongyub
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Family Medicine, Seoul National University Bundang Hospital, Seoul, Republic of Korea.
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Office of Drug Safety Information II, Korea Institute of Drug Safety & Risk Management, Seoul, Republic of Korea; Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Office of Drug Utilization Review, Korea Institute of Drug Safety & Risk Management, Seoul, Republic of Korea; Office of Drug Safety Information I, Korea Institute of Drug Safety & Risk Management, Seoul, Republic of Korea.
authors.forename: Byung-Joo
authors.initials: BJ
authors.lastname: Park
mesh_terms: D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000453:epidemiology*; D002319:Cardiovascular System / Q000187:drug effects*; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D004359:Drug Therapy, Combination / Q000009:adverse effects*; D005260:Female; D006333:Heart Failure / Q000453:epidemiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015994:Incidence; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology; D000077205:Pioglitazone; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D020521:Stroke / Q000453:epidemiology; D013453:Sulfonylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D008687:Metformin; D000077205:Pioglitazone