title: Dipeptidyl peptidase-4 inhibitors in triple oral therapy regimens in patients with type 2 diabetes mellitus.
abstract: OBJECTIVE
  There is no clear consensus regarding treatment of patients with type 2 diabetes mellitus (T2DM) that is inadequately controlled using dual combination therapy. Recommended agents for triple combination therapy should have complementary mechanisms of action with minimal risk of added side effects such as weight gain and hypoglycemia. We discuss considerations in selecting triple oral therapy regimens in patients with T2DM, and review clinical trial data regarding triple oral therapy using dipeptidyl peptidase-4 (DPP-4) inhibitors.
  
  
  METHODS
  A search of the PubMed database was conducted to identify clinical trials of triple oral therapy incorporating a DPP-4 inhibitor (November 2013 to January 2015), using the following search terms: 'type 2 diabetes' AND 'alogliptin OR linagliptin OR saxagliptin OR sitagliptin OR vildagliptin' AND 'metformin'. Trials had to include adult patients with T2DM who received triple oral therapy with a DPP-4 inhibitor for ≥18 weeks. The bibliographies of retrieved articles were also searched to identify any other relevant trials.
  
  
  RESULTS
  A total of 17 clinical trials evaluating metformin and a DPP-4 inhibitor combined with a sulfonylurea (SU), thiazolidinedione (TZD), or sodium-glucose cotransporter 2 (SGLT2) inhibitor were identified and included in this review. Consistently, the addition of a DPP-4 inhibitor to metformin and SU, TZD, or SGLT2 inhibitor therapy improved glycemic measures, and these combinations were generally well tolerated. An increased incidence of hypoglycemia was reported for combinations that included an SU.
  
  
  CONCLUSIONS
  Triple oral therapy that includes a DPP-4 inhibitor is a valid option for patients with T2DM not adequately controlled with dual combination therapy, and offers an alternative to insulin therapy. Triple oral therapy with a DPP-4 inhibitor, metformin, and a TZD or SGLT2 inhibitor should be considered when avoidance of hypoglycemia is a primary goal.
authors.affiliation: a a Heart of England NHS Foundation Trust and University of Birmingham, Birmingham, UK , Nantes , France.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Barnett
authors.affiliation: b b Centre Hospitalier, Universitaire de Nantes , Nantes , France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Charbonnel
authors.affiliation: c c Illawarra Diabetes Service, South East Sydney & Illawarra Area Health Service , Wollongong , Australia.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Moses
authors.affiliation: d d Bharti Hospital and Bharti Research Institute of Diabetes and Endocrinology , Kamal , India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kalra
mesh_terms: D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007328:Insulin / Q000627:therapeutic use; D013453:Sulfonylurea Compounds / Q000008:administration & dosage
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D013453:Sulfonylurea Compounds
keywords: Antihyperglycemic therapy; Combination therapy; Dipeptidyl peptidase-4 inhibitor; Hypoglycemia; Incretin; Oral therapy; Type 2 diabetes mellitus