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Original Investigation |

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

Anna Vanderheiden, MD1; Lindsay Harrison, MD1,2; Jeremy Warshauer, MD1; Xilong Li, PhD, MBA3; Beverley Adams-Huet, MSc3,4; Ildiko Lingvay, MD, MPH, MSCS1,3
[+] 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.
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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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Figure 1.
Consolidated Standards of Reporting Trials Diagram

DPPIV indicates dipeptidyl peptidase IV inhibitor; GFR, glomerular filtration rate; HbA1c, glycated hemoglobin.

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Figure 2.
Primary and Main Secondary Study Outcomes

Hypoglycemia is a capillary glucose level of less than 70 mg/dL (to convert glucose level to millimoles per liter, multiply by 0.0555). Quality of life was assessed on a scale of 1-5 using a modified Diabetes Quality of Life Clinical Trial Questionnaire.11 A negative number represents improvement from baseline. HbA1c indicates glycated hemoglobin; IRR, incident rate ratio; L-P, ratio of liraglutide to placebo; R, randomization; TDD, total daily dose.

aP < .01.

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