Which oral antidiabetic drug to combine with metformin to minimize the risk of hypoglycemia when initiating basal insulin?: A randomized controlled trial of a DPP4 inhibitor versus insulin secretagogues

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Highlights

  • To explore which dual therapy should be maintained when initiating basal insulin in T2DM patients.

  • A dual metformin/DPP4 inhibitor therapy allows achieving a similar efficacy vs. metformin/insulin secretagogues.

  • However it limits the frequency of hypoglycemic episodes.

Abstract

We conducted a pilot study to evaluate two therapeutic strategies at the time of insulin initiation in type 2 diabetic patients insufficiently controlled with metformin + insulin-secretagogues (IS, sulfonylureas or glinides). Patients were randomized to remain under the same dual therapy or to receive metformin + DPP4 inhibitors while starting insulin. Similar glycemic control was achieved in both groups. However less hypoglycemia was observed with DPP4 inhibitors despite higher doses of insulin.

Introduction

Insulin initiation to improve glycemic control in patients with type 2 diabetes (T2DM) under oral antidiabetic drugs (OADs) marks a critical time-point in the natural history of the disease [1]. While it is well-established that metformin should be maintained after basal insulin (BI) initiation [2], [3], it is less clear for other OADs. For example ADA/EASD guidelines do not recommend stopping DPP4 inhibitors (DPP4i) at insulin start [4] and sulfonylureas (SU) are generally continued until more complex insulin regimens with prandial insulin are needed [4]. In clinical practice most patients (95%) actually continue on OADs therapy when BI is initiated, even if the number of OAD taken is often reduced initially or during follow-up [1], [5]. In an international survey conducted in T2DM patients treated with insulin plus OADs for less than 6 months, 33%, 30% and 6.6% of the patients received respectively one, two or three OADs on top of insulin [1]. Among the usual difficulties with insulin initiation, fear of hypoglycemia remains the main barrier, along with a reluctance to start injections and to gain weight [2]. A pooled analysis reported no better efficacy but significantly more hypoglycemia when SU were combined with metformin versus metformin alone at insulin start [6]. While the benefit of adding a DPP4i to ongoing insulin as a second step has been extensively reported, few clinical data are available at insulin initiation in direct comparison of a dual metformin/DPP4i versus metformin/IS combination.

We thus designed a randomized, prospective, pilot study to investigate the key question of which oral agent to use, besides metformin, at initiation of BI therapy in T2DM patients.

Section snippets

Methods

The ADDONIS study was a randomized, controlled, open-label, 24-week pilot study (NCT01871558).

We included patients with T2DM insufficiently controlled (HbA1c between 7.0 and 9.0% (53 and 74.9 mmol/mol) despite a dual oral therapy with metformin and IS (i.e. SU or glinides), for at least 3 months and for whom the decision to start BI had been made. They were randomized in a 1:1 ratio to: BI + metformin + IS at unchanged doses (IS group) or to BI + metformin + the DPP4i vildagliptin 50 mg twice daily

Results

48 patients were recruited from 19 centers throughout France between 2013 and 2014; 42 patients were randomized and 19 patients in each group were included in the intent-to-treat population (at least one dose of the randomized treatment received with at least one efficacy assessment).

Patients were predominantly male (57%), with a mean age of 64 years, a mean BMI of 30.2 kg/m2 and a mean diabetes duration of 12 years. One-third of the patients had at least one diabetes complication (mainly

Discussion and conclusion

This randomized pilot study suggests that a dual metformin/vildagliptin therapy is a good option when initiating BI to limit the frequency of hypoglycemic episodes while achieving good efficacy. This better short-term efficacy with less confirmed hypoglycemia compared with SU/glinides may be partly due to a better titration of insulin and was associated with a better control of post-prandial glycemia. In this context DPP4i may be of special value to decrease glycemic excursions that are not

Authors’ contributions

Study concept and design: JFG, BC, SD.

Acquisition of data: SD, BF.

Analysis and interpretation of data: JFG, PM, OVM, PV, BF, SD, BC.

Drafting of the manuscript: JFG, SD, BF.

Critical revision of the manuscript for important intellectual content: JFG, PM, OVM, PV, BF, SD, SQ, BC.

Administrative, technical, or material support: BF.

Study supervision: JFG, PM, OVM, PV, BF, SD, BC.

JFG is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for

Competing interests

JFG has received research support from Novo Nordisk, Eli Lilly and speaker and consulting fees from AstraZeneca, Novartis, Novo Nordisk, Bristol-Myers Squibb, Eli Lilly, Sanofi and Servier.

PM has received research support and speaker and consulting fees from Astra Zeneca, Novartis, Sanofi, Novo Nordisk, MSD and Pierre Fabre.

OVM has received fees for consultancy, speaking, travel or accommodation from AstraZeneca, Boehringer-Ingelheim, Janssen, Lilly, Merck, Novartis, Novo-Nordisk, Sanofi and

Acknowledgments

The authors would like to thank all the patients and investigators at participating sites, and Felicity Neilson for her valuable suggestions to improve this article.

This work was funded by Novartis Pharmaceuticals, France.

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