Sequential Intensification of Metformin Treatment in Type 2 Diabetes With Liraglutide Followed by Randomized Addition of Basal Insulin Prompted by A1C Targets

J. Hans DeVries; Stephen C. Bain; Helena W. Rodbard; Jochen Seufert; David D’Alessio; Anne B. Thomsen; Marcin Zychma; Julio Rosenstock

doi:10.2337/dc11-1928

Sequential Intensification of Metformin Treatment in Type 2 Diabetes With Liraglutide Followed by Randomized Addition of Basal Insulin Prompted by A1C Targets

J. Hans DeVries, MD, PHD¹,
Stephen C. Bain, FRCP²,
Helena W. Rodbard, MD³,
Jochen Seufert, MD, PHD⁴,
David D’Alessio, MD⁵,
Anne B. Thomsen, MD, PHD⁶,
Marcin Zychma, MD, PHD⁶,
Julio Rosenstock, MD⁷ ⇓ and
on behalf of the Liraglutide-Detemir Study Group*

¹Department of Internal Medicine, Academic Medical Centre, Amsterdam, the Netherlands
²Institute of Life Sciences, Swansea University and Abertawe Bro Morgannwg University NHS Trust, Swansea, U.K.
³Endocrine and Metabolic Associates, Rockville, Maryland
⁴Division of Endocrinology and Diabetology, University Hospital of Freiburg, Freiburg, Germany
⁵Division of Endocrinology, Diabetes, and Metabolism, University of Cincinnati, Cincinnati VA Medical Center, Cincinnati, Ohio
⁶Medical & Science, GLP-1 & Obesity, Novo Nordisk A/S, Soeborg, Denmark
⁷Dallas Diabetes and Endocrine Center at Medical City, Dallas, Texas

Corresponding author: Julio Rosenstock, juliorosenstock{at}dallasdiabetes.com.

Abstract

OBJECTIVE We evaluated the addition of liraglutide to metformin in type 2 diabetes followed by intensification with basal insulin (detemir) if glycated hemoglobin (A1C) ≥7%.

RESEARCH DESIGN AND METHODS In 988 participants from North America and Europe uncontrolled on metformin ± sulfonylurea, sulfonylurea was discontinued and liraglutide 1.8 mg/day added for 12 weeks (run-in). Subsequently, those with A1C ≥7% were randomized 1:1 to 26 weeks’ open-label addition of insulin detemir to metformin + liraglutide (n = 162) or continuation without insulin detemir (n = 161). Patients achieving A1C <7% continued unchanged treatment (observational arm). The primary end point was A1C change between randomized groups.

RESULTS Of 821 participants completing the run-in, 61% (n = 498) achieved A1C <7% (mean change −1.3% from 7.7% at start), whereas 39% (n = 323) did not (−0.6% from 8.3% at start). During run-in, 167 of 988 (17%) withdrew; 46% of these due to gastrointestinal adverse events. At week 26, A1C decreased further, by 0.5% (from 7.6% at randomization) with insulin detemir (n = 162) versus 0.02% increase without insulin detemir (n = 157) to 7.1 and 7.5%, respectively (estimated treatment difference −0.52 [95% CI −0.68 to −0.36]; P < 0.0001). Forty-three percent of participants with insulin detemir versus 17% without reached A1C <7%. Mean weight decreased by 3.5 kg during run-in, then by 0.16 kg with insulin detemir or 0.95 kg without insulin detemir. In the randomized phase, no major hypoglycemia occurred and minor hypoglycemia rates were 0.286 and 0.029 events per participant-year with and without insulin detemir (9.2 vs. 1.3%).

CONCLUSIONS Supplementation of metformin with liraglutide and then insulin detemir was well tolerated in the majority of patients, with good glycemic control, sustained weight loss, and very low hypoglycemia rates.

Footnotes

↵*A complete list of the members of the Liraglutide-Detemir Study Group can be found in Supplementary Table 13.

Received October 4, 2011.
Accepted February 28, 2012.

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