Is Liraglutide Effective for Patients with Type 1 Diabetes?

What if there is an adjunct option in managing type 1 diabetes beyond insulin analogs in the form of GLP-1 RAs like liraglutide?

Patients with type 1 diabetes are at significant risk for microvascular and cardiovascular complications, especially those with poor glycemic control. Insulin analogs are the mainstay of the pharmacologic management of type 1 diabetes; however, they carry risks of hypoglycemia and weight gain. Thus, there is always the need for a safe and productive medication beyond insulin in managing type 1 diabetes. In previous studies, the ADJUNCT ONE and ADJUNCT TWO trials confirmed that liraglutide, a glucagon-like-peptide-1 receptor agonist (GLP-1 RA), showed efficacy in improving glycemic control, reducing both the need for exogenous insulin and body weight when used in adjunct to insulin. 

The ADJUNCT ONE and ADJUNCT TWO trials were multicentered, multination, randomized placebo-controlled, double-blind, parallel-group, phase 3 trials, with more than 2,000 participants with a past medical history of type 1 diabetes enrolled in the two trials to investigate whether liraglutide added to treat-to-target insulin improves glycemic control, and reduces insulin requirements and body weight. In the previous trials, the primary endpoint was the change from baseline in HbA_1c, and the secondary endpoint was the change from baseline in body weight to end-of-treatment. In addition, the safety endpoints included the occurrence of various categories of hypoglycemic episodes and hyperglycemia episodes with ketosis. 

The study in this discussion is a post hoc analysis of the ADJUNCT ONE and ADJUNCT TWO trials to evaluate the efficacy and safety of 26 weeks’ liraglutide treatment in patients with type 1 diabetes by the participants’ subgroups. The subgroups are defined by the level of glycemic control (HbA_1c < or ≥ 8.5%), the type of insulin regiment used (basal-bolus or continuous subcutaneous insulin infusion), and presence of overweight/obesity (BMI < or ≥ 27 kg/m²). The author used a mixed model for repeated measurements for estimations of continuous endpoints and a negative binomial regression model for rate estimates for treatment-emergent hypoglycemic and hyperglycemic episodes.

In both trials at week 26, reductions in HbA_1c, body weight, and daily insulin dose did not differ significantly (p > 0.05) by baseline HbA_1c or BMI. Besides, the risk of clinically significant hypoglycemia or hyperglycemia with ketosis did not differ significantly (p > 0.05) by baseline subgroups. There were statistically significant differences in placebo-adjusted reductions in HbA_1c (-0.30 %-point (-3.3 mmol/mol); 95% CI: -0.22 to -0.01 %-points; p = 0.0380 with liraglutide 1.8 mg), body weight (-5.0 kg; p < 0.0001 with liraglutide 1.8 mg), and insulin dose (-12%; 95% CI: -12% to 0%; p = 0.470 with liraglutide 1.8 mg) at week 26.

The author concluded that regardless of baseline level of glycemic control, overweight/obesity, and pre-existing insulin regimen, liraglutide “appears equally efficacious and safe in populations that were generally representative of individuals with type 1 diabetes.” Besides, even though the incidences of hyperglycemia with ketosis were reported higher in the liraglutide group, the risk of diabetes ketoacidosis remained very low in both trials. In addition, weight gain is a side effect of insulin analogs and a presentation of type 1 diabetes. Moreover, obesity further complicates an increased risk of insulin resistance, cardiovascular disease, and insulin secretion requirements. Therefore, an agent such as GLP-1 RA is desired to reduce body weight and prevent its associated complications in managing type 1 diabetes. Besides, the second-generation GLP-1 analogs such as semaglutide are potentially more potent and effective and warrant confirmatory studies. One limitation to this study is that the statistical analysis was based on a hypothetical-like analysis strategy due to the nature of this study. Therefore, the results of this study should be validated in future studies.

Practice Pearls:

• The risk of hypoglycemia or hyperglycemia with ketosis and decreases in HbA_1c did not differ between subgroups.
• Management with insulin and adjunct liraglutide can significantly reduce the body weight from baseline.
• Overall, liraglutide or GLP-1 RAs may be adjuncts to insulin in managing type 1 diabetes.

Dejgaard, Thomas Fremming et al. “Efficacy and Safety of Liraglutide in Type 1 Diabetes by Baseline Characteristics in the ADJUNCT ONE and ADJUNCT TWO Randomized Clinical Trials.”

Mathieu, Chantal et al. “Efficacy and Safety of Liraglutide Added to Insulin Treatment in Type 1 Diabetes: The ADJUNCT ONE treat-to-target Randomized Trial.“

Ahrén, Bo et al. “Efficacy and Safety of Liraglutide Added to Capped Insulin Treatment in Subjects With Type 1 Diabetes.“

Ding Nguyen, PharmD Candidate, University of South Florida Taneja College of Pharmacy