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Original Investigation
July 2016

Effect of Adding Liraglutide vs Placebo to a High-Dose lnsulin Regimen in Patients With Type 2 DiabetesA Randomized Clinical Trial

Author Affiliations
  • 1Division of Endocrinology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas
  • 2Texas Diabetes and Endocrinology, Austin
  • 3Division of Biostatistics, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas
  • 4Division of Mineral Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas
JAMA Intern Med. 2016;176(7):939-947. doi:10.1001/jamainternmed.2016.1540
Abstract

Importance  An increasing number of patients with type 2 diabetes are treated with high doses of insulin. Such treatment is associated with weight gain, hypoglycemia, and high treatment burden.

Objective  To assess the effectiveness and safety of adding a glucagon-like peptide 1 receptor agonist to the treatment regimen of patients with type 2 diabetes requiring therapy with high-dose insulin.

Design, Setting, and Participants  This clinical trial was a double-blind, placebo-controlled, randomized (1:1) study with 6 months of follow-up, conducted from August 13, 2012, to February 9, 2015, at ambulatory clinics at the University of Texas Southwestern Medical Center and Parkland Hospital. Participants were 71 patients with uncontrolled type 2 diabetes (glycated hemoglobin level, 7.5%-11.0%) using more than 1.5 U/kg/d of insulin.

Interventions  Subcutaneous injection of liraglutide (1.8 mg/d) or matching placebo for 6 months.

Main Outcomes and Measures  The primary outcome was the change in glycated hemoglobin level. Secondary outcomes were changes in weight, hypoglycemia rate, insulin dosage, and quality-of-life measures.

Results  Among 71 patients, 45 (63%) were female. The mean (SD) age of patients was 54.2 (7.4) years, with a mean (SD) type 2 diabetes duration of 17.9 (8.4) years and a mean (SD) total daily dose of insulin of 247.0 (95.1) U. Ninety-three percent (66 of 71) of participants completed all scheduled visits. The glycated hemoglobin level improved from a mean (SD) of 9.0% (1.2%) to 7.9% (1.1%) in the liraglutide group (P < .001) and remained unchanged (8.9%) in the placebo group, with an estimated treatment difference of 0.9% (95% CI, −1.5 to −0.4) (P = .002). Weight decreased from a mean (SD) of 114.6 (21.4) kg to 113.6 (20.8) kg in the liraglutide group vs a mean (SD) increase from 116.1 (26.6) kg to 117.2 (27.2) kg in the placebo group, with a treatment difference of −2.3 kg (95% CI, −4.3 to −0.4 kg) (P = .02). The total daily dose of insulin decreased 11.5% (95% CI, −21.8% to −1.1%) in the liraglutide group (P = .20). The hypoglycemia rate was higher in the first month after initiation of liraglutide compared with placebo (2.30 vs 0.91 events per person-month, P = .01), while the overall hypoglycemia rate over the entire follow-up was similar between groups (P = .11). Glycemia control perception, satisfaction with insulin treatment, and willingness to continue insulin use improved more in the liraglutide group.

Conclusions and Relevance  Liraglutide added to high-dose insulin therapy improved glycemic control, decreased body weight, and enhanced treatment satisfaction in this difficult-to-treat patient population with high-dose insulin requirements. Further studies are warranted to confirm these findings and evaluate the long-term risk and benefit of this treatment option.

Trial Registration  clinicaltrials.gov Identifier: NCT01505673

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