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


METHODS
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.


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


METHODS
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
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.


BACKGROUND
clinicaltrials.gov Identifier: NCT01505673.
Division of Endocrinology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas.
Anna
A
Vanderheiden
Division of Endocrinology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas2Texas Diabetes and Endocrinology, Austin.
Lindsay
L
Harrison
Division of Endocrinology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas.
Jeremy
J
Warshauer
Division of Biostatistics, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas.
Xilong
X
Li
Division of Biostatistics, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas4Division of Mineral Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas.
Beverley
B
Adams-Huet
Division of Endocrinology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas3Division of Biostatistics, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas.
Ildiko
I
Lingvay
D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced / Q000175:diagnosis / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects; D007279:Injections, Subcutaneous; D007328:Insulin / Q000008:administration & dosage / Q000009:adverse effects; D000069450:Liraglutide / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D015430:Weight Gain / Q000187:drug effects; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D000069450:Liraglutide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists