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.

Keywords: :

• Antihyperglycemic therapy
• Combination therapy
• Dipeptidyl peptidase-4 inhibitor
• Hypoglycemia
• Incretin
• Oral therapy
• Type 2 diabetes mellitus

Transparency

Declaration of funding

Bristol-Myers Squibb and AstraZeneca funded medical writing support for the preparation of this manuscript, and agents of the sponsors reviewed the manuscript. All authors contributed to and approved this manuscript.

Declaration of financial/other relationships

A.H.B. has disclosed that he has received honoraria for lectures and advisory work as well as research funding from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi-Aventis, and Takeda. B.C. has disclosed that he has received fees for consultancy, speaking, travel, or accommodation from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Roche, Sanofi-Aventis, and Takeda. R.G.M. has disclosed that he has received sponsorship to attend international diabetes conferences and speaker fees from Bristol-Myers Squibb, AstraZeneca, and Boehringer Ingelheim. S.K. has disclosed that he has received honoraria for lectures for Novartis.

CMRO peer reviewer 1 has disclosed that he has received honoraria for consulting and lectures from GlaxoSmithKline, Takeda, Novo Nordisk, Sanofi-Aventis, Eli Lilly, Daiichi Sankyo, Pamlabs, AstraZeneca, Abbott, Bristol-Myers Squibb, and Boehringer Ingelheim. CMRO peer reviewer 2 has disclosed that he has been a consultant to AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, and Teva.

Acknowledgments

Medical writing support for the preparation of this manuscript was provided by Nicole Strangman PhD, Janet E. Matsuura PhD, and Meg Church MS, from Complete Healthcare Communications Inc., with funding from Bristol-Myers Squibb and AstraZeneca.