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

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 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