Could GLP-1 inhibitors be a useful adjunct therapy in type I diabetes?
Recent literature has looked at the possibility of using non-insulin adjunct therapies to optimize glycemic control in patients with type I diabetes (T1D). Previous small studies have shown the addition of liraglutide to insulin in patients with type I diabetes reduced daily doses of insulin and body weight.1,2 The present study was an international, double-blind, placebo-controlled non-inferiority trial designed to observe the effects of liraglutide added to treat-to-target insulin therapy on glycemic control, total insulin requirements, and body weight in patients with T1D.
The trial enrolled patients between the ages of 18 – 75 years, with a body mass index ≥ 20 kg/m2, diagnosed with T1D for at least 1 year with a glycosylated hemoglobin (HbA1c) between 7 – 10%, on basal-bolus or continuous subcutaneous insulin infusion for at least 6 months, and on a stable insulin regimen for at least 3 months prior to screening. Notable exclusion criteria for the study were treatment with a medication that interfered with glycemic control, diagnosis of acute or chronic pancreatitis in the past, presence of severe neuropathy, and eGFR less than 30mL/min/1.73m2. The primary endpoint was the effect of liraglutide on HbA1C, reduction in daily insulin dosing, and change in body weight when compared with placebo. Adverse effects including hypoglycemia and hyperglycemia were also gathered. Patients were randomly assigned to one of 4 treatment groups in a 3:1 fashion; liraglutide 0.6, 1.2, or 1.8mg or placebo (0.1, 0.2, or 0.3mL dose) via a subcutaneous injection once daily.
After screening and exclusion, 1,983 participants were enrolled. All treatment arms were similar in age, gender, baseline A1C, and time since T1DM diagnosis. Compared with placebo, HbA1c was significantly reduced in the liraglutide 1.8 and 1.2 mg arms (estimated treatment difference (ETD): -0.2 95%CI -0.32 to -0.07, P=0.0019 and ETD: -0.15 95%CI -0.27 to -0.03, P=0.0164 respectively). A higher proportion of patients in the liraglutide 1.8mg and 1.2mg groups achieved HbA1C <7% when compared to placebo (estimated odds ratio (EOR) 1.97 95%CI 1.24-3.11, P=0.0038 for 1.8mg and EOR 2.03 95%CI 1.29-3.21, p=0.0022 for 1.2mg). Total daily insulin dose was lower in the liraglutide 1.8mg (5% decrease) and 1.2mg (2% decrease) treatment groups, driven primarily by a reduction in prandial insulin requirements. All three liraglutide groups showed significant decreases in body weight compared to placebo with a reduction of 4.0, 2.7, and 1.3 kg for patients in the liraglutide 1.8mg, 1.2mg, and 0.6mg groups, respectively. Patients treated with insulin alone had a 0.9kg increase in body weight over the study period.
Analysis of the safety endpoints found a dose-dependent increase in adverse effects in the liraglutide-treated groups. Discontinuation rates were 14.7% for liraglutide 1.8mg, 12.6% for liraglutide 1.2mg, 4.9% for liraglutide 0.6mg, and 3.4% for placebo. More patients in the liraglutide treated arms experienced symptomatic hypoglycemia. The rate of symptomatic hypoglycemia for patients receiving liraglutide were 16.5 events/patient year of exposure (PYE), 16.1 events/PYE, and 15.7 events/PYE for the 1.8mg, 1.2mg, and 0.6mg doses respectively. The difference in symptomatic hypoglycemia rates were significantly more in all three liraglutide doses compared to placebo. Additionally, patients being treated with liraglutide 1.8mg had statistically significantly higher rates of hyperglycemia with ketosis when compared to placebo (ERR 2.22 95%CI 1.13-4.34, P=0.0205).
Strengths of this study included the randomized controlled, double blind design, the inclusion of a wide baseline A1C range, and the study did not exclude patients with hypoglycemia unawareness, history of severe hypoglycemic events, or history of ketoacidosis, reflecting the clinical spectrum of diabetes. However, this study was limited by possible loss of blinding due to necessity of decreased insulin doses, adverse effects such as nausea, and was funded by the manufacture of Victoza (NovoNordisk). The authors concluded addition of liraglutide to insulin therapy did decrease HbA1C, daily insulin dose, and body weight. However, it remains yet to be seen if these beneficial effects would persist in a longer study. While statistically significant, the decrease in HbA1c at week 52 was minimal, and the required units of insulin per Kg of body weight returned to baseline in all treatment groups at 52 weeks. The benefit of weight loss came at the price of an increase in adverse events, including symptomatic hypoglycemia and hyperglycemia with ketosis. These adverse effects will limit the use of this agent in patients with type 1 diabetes.
- Addition of liraglutide 1.8mg or 1.2mg significantly decreased HbA1C, total insulin dose, and body weight when added to insulin in patients with type I diabetes.
- Addition of liraglutide increases the rates of adverse effects, including symptomatic hypoglycemia and hyperglycemia with ketosis.
- Patients treated with liraglutide 1.8mg or 1.2mg plus insulin therapy were more likely to reach a goal HbA1C of <7%.
Mathieu C, Zinman B, Hemmingsson JU, Woo V, Colman P, Christiansen E, et al. Efficacy and safety of liraglutide added to insulin treatment in type 1 diabetes: the ADJUNCT ONE treat-to-target randomized trial. Diabetes Care 2016 [Epub ahead of print].
Dejgaard TF, Frandsen CS, Hansen TS, Almdal T, Urhammer S, Pedersen-Bjergaard U, et al. Efficacy and safety of liraglutide for overweight adult patients with type 1 diabetes and insufficient glycaemic control (Lira-1): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2016;4:211-32.
Frandsen CS, Dejgaard TF, Holst JJ, Andersen HU, Birger Thorsteinsson, and Madsbad S. Twelve-week treatment with liraglutide as add-on to insulin in normal-weight patients with poorly controlled type 1 diabetes: a randomized, placebo-controlled, double-blind parallel study. Diabetes Care 2015;38:2250-57
Researched and prepared by Christian Gill, Pharm.D. Candidate, Class of 2017. Reviewed by Michelle Caetano, Pharm.D., BCPS, BCACP, CDOE, CVDOE.