Combination therapy with metformin plus sulphonylureas versus metformin plus DPP-4 inhibitors: association with major adverse cardiovascular events and all-cause mortality

Diabetes Obes Metab. 2014 Oct;16(10):977-83. doi: 10.1111/dom.12306. Epub 2014 May 22.


Aims: To compare the risk of major adverse cardiovascular events (MACE) and mortality for combination therapies with metformin and either sulphonylurea (SU) or dipeptidyl peptidase-4 inhibitor (DPP-4i).

Methods: Data were from the UK Clinical Practice Research Datalink (CPRD). Patients with type 2 diabetes were selected if initiated with combination therapies comprising metformin plus SU or DPP-4i 2007-2012. The co-primary endpoints were all-cause mortality and MACE (myocardial infarction or stroke). Times to endpoints were compared using Cox proportional hazards models. Additional analyses were performed on subsets matched directly on key characteristics and by propensity score.

Results: A total of 33 983 patients were prescribed SU and 7864 DPP-4i, and 5447 patients in each cohort could be matched directly and 6901 by propensity score. In the main analysis, there were 716 MACE events and 1217 deaths. Crude event rates for MACE were 11.3 events per 1000 person-years (pkpy) for SU, versus 5.3 pkpy for DPP-4i. For all-cause mortality, rates were 16.9 versus 7.3 pkpy, respectively. Following adjustment, there was a significant increase in the adjusted hazard ratio (aHR) for all-cause mortality in those exposed to SU across all analytical models: aHR = 1.357 (95% CI 1.076-1.710) for all subjects, 1.850 (1.245-2.749) directly matched and 1.497 (1.092-2.052) propensity-matched. For MACE, aHR was 1.710 (1.280-2.285) for all subjects, 1.323 (0.832-2.105) directly matched and 1.547 (1.076-2.225) propensity-matched.

Conclusions: There was a reduction in all-cause mortality for patients treated with metformin combined with DPP-4i versus metformin plus SU, and a similar trend for MACE.

Keywords: MACE; dipeptidyl peptidase-4 inhibitors; metformin; mortality; myocardial infarction; stroke; sulphonylurea.

Publication types

  • Comparative Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Glucose / drug effects
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / mortality
  • Dipeptidyl-Peptidase IV Inhibitors / administration & dosage*
  • Dipeptidyl-Peptidase IV Inhibitors / adverse effects
  • Drug Therapy, Combination
  • Female
  • Glycated Hemoglobin A / drug effects
  • Humans
  • Hypoglycemic Agents / administration & dosage*
  • Hypoglycemic Agents / adverse effects
  • Male
  • Metformin / administration & dosage*
  • Metformin / adverse effects
  • Middle Aged
  • Myocardial Infarction / chemically induced*
  • Myocardial Infarction / mortality
  • Myocardial Infarction / prevention & control
  • Proportional Hazards Models
  • Stroke / chemically induced*
  • Stroke / mortality
  • Stroke / prevention & control
  • Sulfonylurea Compounds / administration & dosage*
  • Sulfonylurea Compounds / adverse effects
  • United Kingdom / epidemiology


  • Blood Glucose
  • Dipeptidyl-Peptidase IV Inhibitors
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Sulfonylurea Compounds
  • hemoglobin A1c protein, human
  • Metformin