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

PLoS One. 2015 May 20;10(5):e0124287. doi: 10.1371/journal.pone.0124287. eCollection 2015.


Background/objectives: 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.

MeSH terms

  • Adult
  • Aged
  • Cardiovascular Diseases / epidemiology*
  • Cardiovascular System / drug effects*
  • Cohort Studies
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dipeptidyl-Peptidase IV Inhibitors / adverse effects
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use
  • Drug Therapy, Combination / adverse effects*
  • Female
  • Heart Failure / epidemiology
  • Humans
  • Hypoglycemic Agents / adverse effects*
  • Hypoglycemic Agents / therapeutic use
  • Incidence
  • Male
  • Metformin / adverse effects
  • Metformin / therapeutic use
  • Middle Aged
  • Myocardial Infarction / epidemiology
  • Pioglitazone
  • Proportional Hazards Models
  • Retrospective Studies
  • Stroke / epidemiology
  • Sulfonylurea Compounds / adverse effects
  • Sulfonylurea Compounds / therapeutic use
  • Thiazolidinediones / adverse effects
  • Thiazolidinediones / therapeutic use
  • Treatment Outcome
  • Young Adult


  • Dipeptidyl-Peptidase IV Inhibitors
  • Hypoglycemic Agents
  • Sulfonylurea Compounds
  • Thiazolidinediones
  • Metformin
  • Pioglitazone

Grant support

The authors have no support or funding to report.