Effects on Clinical Outcomes on Adding Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylureas to Metformin Therapy in Patients With Type 2 Diabetes Mellitus

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Ou SM, et al. "Effects on Clinical Outcomes of Adding Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylureas to Metformin Therapy in Patients With Type 2 Diabetes Mellitus". Annals of Internal Medicine. 2015. 163(9):663-672.

Clinical Question

In patients with Type 2 diabetes taking metformin, does adding dipeptidyl-peptidase-4 inhibitor versus sulfonylureas effect clinical outcomes on all-cause mortality, major adverse cardiac events (MACEs), hospitalization for HF, and hypoglycemia?

Bottom Line

DPP-4-Inhibitors added to metformin reduced the risk for all-cause mortality and MACEs, are associated with lower risk for ischemic stroke, and are associated with lower risk for hypoglycemia compared to sulfonylureas. However, they did not alter risk for myocardial infarction and hospitalization for heart failure.

Major Points

  • Compared to Sulfonylureas, DPP4-Inhibitors users had:
    • Lower risks for all cause death, MACEs, ischemic stroke, and hypoglycemia than sulfonylureas
  • DPP4-Inhibitors’ and sulfonylureas’ risk for MI and hospitalization for HF were similar
  • Cancer risk for DPP-4-Inhibitor and sulfonylurea were no different
  • DPP4-Inhibitors when added to metformin appear to be safer than sulfonylureas in regards to risk of cardiovascular events


The American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) recommend metformin as the optimal first-line medication for type 2 diabetes mellitus. The choice for a second-line agent is unclear. Most patients progress on metformin, and require further assistance to optimize glycemic control. Second-line drug therapy should be chosen based on patient specific factors such as cost, comorbidities, and drug characteristics. Previous studies suggest sulfonylureas as second-line agents, but may increase risk of cardiovascular-related events


  • Population-based observational cohort study
  • Nationwide study using Taiwan’s National Health Insurance Research Database
  • N=10,089 propensity score-matched pairs of DPP-4-Inhibitor users and sulfonylurea users were examined
    • Metformin (+) DPP-4-Inhibitor (n=10,131)
    • Metformin (+) sulfonylurea (n=60,209)
  • Setting: outpatient
  • Enrollment: March 2009 to June 2012, February 2003 to October 2005
  • Mean follow-up: 3.3 years
  • Analysis: Propensity matching score
  • Primary outcomes: All-cause mortality, MACEs (composite of hospitalization for ischemic stroke, myocardial infarction, hospitalization for heart failure, and hospitalization for hypoglycemia)


Inclusion Criteria

  • Age > 20 years
  • Previously treated with metformin monotherapy
  • Metformin in addition to one of the medicines listed below:
    • DPP-4-Inhibitor (sitagliptin, vildagliptin, saxagliptin)
    • Sulfonylurea (acetohexamide, chlorpropamide, tolazamide, tolbutamide, gliclazide, glimepiride, glipizide, gliquidone, glibornuride, or glyburide)

Exclusion Criteria

  • Age < 20 years
  • Missing information on birth date or sex
  • Did not receive add-on therapy
  • Add-on therapy did not include metformin or included non-study medications

Baseline Characteristics

  • Before propensity score matching, patients using DPP-4-Inhibitors were:
    • Older
    • Longer diabetes durations
    • Higher creatinine clearance
    • Higher diabetes complication severity index (DCSI) scores
    • More baseline comorbidities than sulfonylureas
  • After propensity score matching, baseline characteristics did not differ significantly between groups


  • Metformin (+) DPP-4-Inhibitor
  • Metformin (+) sulfonylurea


Comparisons are metformin (+) DPP-4-Inhibitor versus metformin (+) sulfonylurea:

Primary Outcomes

  • All-cause mortality
    • (HR 0.63; 95% CI 0.55-0.72; p < 0.001; NNT 25 for 5 years)
  • MACEs
    • (HR 0.68; 95% CI 0.55-0.83; p <0.001; NNT 40 for 5 years)
  • Ischemic stroke
    • (HR 0.64; 95%CI 0.51-0.81; p <0.001; NNT 50 for 5 years)
  • Myocardial infarction
    • (HR 0.75; 95% CI 0.52-1.07; p = 0.109)
  • Hospitalization for heart failure
    • (HR 0.78; 95% CI 0.57-1.06; p = 0.108)
  • Hypoglycemia
    • (HR 0.43; 95% CI 0.33-0.56; p <0.001; NNH 40 for 5 years)
  • Secondary Outcomes
    • None

Subgroup Analysis

Subgroup analyses were performed for each primary outcome except hypoglycemic events (all-cause mortality, myocardial infarction, hospitalization for heart failure, ischemic stroke) and produced similar results to primary analyses and favored DPP-4 Inhibitors over sulfonylureas. Majority of the subgroup analysis for primary outcomes favored DDP-4 Inhibitors versus sulfonylureas.

Adverse Events

Adverse effects were not listed in the study, but hypoglycemia was analyzed in both study groups (HR 0.43; 95% CI 0.33-0.56; p <0.001; NNH 40 for 5 years). Descriptive analysis for add-on therapy during follow-up was reported, but the reason for switching, stopping, or starting therapy was not reported.


  • The study did not report adverse drug reactions other than hypoglycemia
  • One of the limitations is that the study is an population-based observational study. This type of study cannot control for external factors that may influence patient outcomes.
  • Population was based on patients in Taiwan and gathered from NHIRD, which raises concern for the external validity for other populations around the world.


  • No primary funding source
  • Disclosures
    • Dr. Wang reports grants from Ministry of Science and Technology, Taipei Veterans General Hospital, and National Yang-Ming University and personal fees from GlaxoSmithKline (Taiwan), Eli Lilly and Company (Taiwan), MSD Taiwan, Allergan, Eli Lilly and Company, and Daiichi Sankyo outside the submitted work.

Further Reading

1. Ou S, Shih C, Chao P, Chu H, Kuo S, Lee Y et al. Effects on Clinical Outcomes of Adding Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylureas to Metformin Therapy in Patients With Type 2 Diabetes Mellitus. Annals of Internal Medicine. 2015;163(9):663-671.

2. Consoli A, Gomis R, Halimi S, Home PD, Mehnert H, Strojek K, et al. Initiating oral glucose-lowering therapy with metformin in type 2 diabetic patients: an evidence-based strategy to reduce the burden of late-developing diabetes complications. Diabetes Metabo. 2004; 30:509-16. [PMID: 15671920]

3. Rojas LB, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013;5:6. [PMID: 23415113] doi:10.1186/1758-5996-5-6 4. 7. Approaches to Glycemic Treatment. Diabetes Care. 2014;38(Supplement_1):S42.