What do I need to know about liraglutide (Saxenda), the glucagon-like peptide 1 receptor agonist for weight management in children with obesity?

Glucagon-like peptide 1 (GLP-1) is a gut hormone, or incretin, which is secreted into circulation by intestinal L cells in response to nutritional intake (1). Although incretin-based therapies, such as GLP-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase 4 inhibitors (DPP-4i), are now well established as effective agents in the control of type 2 diabetes (T2D) and obesity in adults (2), their application in children is relatively novel. In early 2021, Health Canada approved a once daily subcutaneous injectable formulation of the GLP-1RA liraglutide (Saxenda) for use as a weight management therapy in adolescents with obesity (3). The same drug given at a lower dose of 1.8 mg daily (Victoza) was approved in 2020 for use as an add on therapy to metformin in children and adolescents with T2D (4).

MECHANISM OF ACTION

Once in circulation, GLP-1 acts by increasing insulin secretion and sensitivity, inhibiting glucagon secretion, slowing gastrointestinal motility, and inducing satiety through interaction with the central nervous system (5). Preloaded syringes of Saxenda deliver an adjustable dose of up to 3 mg of liraglutide (C₁₇₂H₂₆₅N₄₃O₅₁), a GLP-1 analogue with an amino acid substitution (arginine for lysine) and C-16 fatty acid addition. These alterations confer protection from its degrading exopeptidase counterpart, DPP-4, which typically limits the half-life of intrinsically produced GLP-1 to seconds or minutes in circulation (6). GLP-1RA are designed to mimic the effects of endogenous GLP-1 over a prolonged period, given their resistance to degradation.

EFFICACY

We recently reviewed the efficacy of GLP-1RA for the treatment of obesity in children and adolescents (7). This meta-analysis included 9 randomized controlled trials, 6 in which liraglutide was assessed and 3 in which the first-in-class GLP-1RA, exenatide, was assessed. The synthesis of data from 574 children and adolescents with obesity and a mean age of 14.15 (± 2.16) years found that GLP-1RAs were effective in modestly reducing body weight (mean difference [MD] −1.50 [−2.50, −0.50] kg, I² 64%), body mass index (BMI; MD −1.24 [−1.71, −0.77] kg/m², I² 0%), and BMI z-score (MD −0.14 [−0.23, −0.06] SD, I² 43%). However, concurrent lifestyle intervention substantially bolstered the efficacy of these medications in reducing body weight (MD −4.25 kg [−6.31, −2.20] kg, I² 0%), BMI (−1.60 [−2.32, −0.88] kg/m², I² 0%), and BMI z-score (−0.22 [−0.37, −0.07] SD, I² 43%). Since publication, trials continue to appear supporting the weight loss efficacy of these medications in adolescents with obesity (8).

INDICATIONS

Liraglutide is licensed in the subcutaneous injectable formulation, Saxenda, as an adjunct therapy to a lifestyle intervention (i.e., calorie restriction and physical activity) in the treatment of obesity in adolescents aged 12–18 years. Prospective patients are required to have an International Obesity Task Force BMI cut-point for obesity by gender which equates to an adult BMI ≥ 30 kg/m²—a table specifying BMI cut-offs by age is available in the product monograph (3).

CONTRAINDICATIONS

Liraglutide is contraindicated in individuals with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, given the putative increased risk of such malignancies in those treated with GLP-1RA stemming primarily from rodent research (9). Pregnancy and breastfeeding remain precautionary contraindications and individuals who are hypersensitive to liraglutide or included inactive ingredients are also advised against the therapy.

DOSING, ADMINISTRATION, AND COST

The dosing regimen for Saxenda (6 mg/mL) in children is initiated at 0.6 mg (i.e., 100 µL) once daily delivered subcutaneously via autoinjector and increases by 0.6 mg per week up to a maximum of 3 mg (i.e., 500 µL), as tolerated. The therapy can be taken at any time of day, independently of meals, and should be injected into the subcutaneous portion of the abdomen, thigh or upper arm. On review of Canadian pharmacies across several provinces, the average annual cost for full dose Saxenda use ranges from $2,500 to $3,500 and is not yet covered by provincial health plans. Private insurance plan coverage is variable. Thus, this therapy remains prohibitively expensive for many families.

SAFETY AND TOLERABILITY

Factors relating to the tolerability and the safety profile of GLP-1RAs were also assessed in the aforementioned meta-analysis (7). Liraglutide or exenatide use increased the risk of nausea (risk ratio 2.11 [1.44, 3.09]; I² 0%), but were not consistently associated with any other treatment-emergent adverse events. However, amongst the more robustly powered adult trials, several other gastrointestinal treatment-emergent adverse events were described, including diarrhea, constipation, vomiting, and dyspepsia (10). Given the increased rate of pancreatitis in adults treated with the therapy (0.1%–0.3%) and the aforementioned medullary thyroid cancer risk signal, monitoring of amylase and calcitonin is occasionally performed in the research setting. Amongst the 302 children and adolescents who received a GLP-1RA in the aforementioned meta-analysis, there was a single case of moderate severity acute pancreatitis uncovered via elevated amylase, without any increased levels of calcitonin. Clinically significant hypoglycemia (defined as blood glucose < 3 mmol/L) occurred in 1.6% of participants, although the fact that GLP-1RA stimulate insulin secretion only in the presence of glucose makes them particularly safe in this regard (1).

COUNSELLING AND CONSIDERATIONS

Liraglutide is most effective and exclusively licensed as an adjunct to lifestyle intervention. Therefore, the most appropriate setting under which to prescribe it is when the patient is under obesity specialist supervision and participating in an interdisciplinary weight management program which involves dietary and physical activity counselling, as well as mental health support.

As with any injectable formulation, appropriate training must be provided to patients and their caregivers. Additionally, counselling should be provided on effective administration and potential adverse events, including nausea. However, patients commonly tolerate the full 3 mg dose without significant compliance issues following the escalating dosing schedule.

Families should be educated that obesity is considered a chronic disease by many professional medical organizations and GLP-1RAs are not curative. Therefore, long-term treatment is required in order to sustain effects and weight regain is to be expected if the therapy is discontinued. Finally, patients must be told that they should discontinue liraglutide if they have not achieved a 5% minimum weight loss in the initial 12 weeks of therapy.

CONCLUSIONS

Liraglutide (Saxenda), given as a daily subcutaneous injection, has been recently licensed by Health Canada for use as an adjunctive weight management therapy in adolescents with obesity. Although there is limited data available on its efficacy, safety, and tolerability in paediatric populations, such therapies have become ubiquitous amongst adult populations with T2D and obesity. From the limited relevant data which are available, liraglutide appears to be effective in reducing body weight without appreciable adverse effects beyond increased nausea and rare cases of pancreatitis. Importantly, implementation of concurrent lifestyle intervention is a prerequisite to initiation of liraglutide which may require referral to a paediatric weight management clinic. Cost limits the widespread use of such adjunct therapies in the management of paediatric obesity in Canada at present.

Funding: JH receives unrestricted research funding from the Hospital for Sick Children and the University of Toronto with the Mead Johnson Chair in Child Nutrition.

Potential Conflicts Of Interest: JH has participated in advisory boards for Novo Nordisk. There are no other disclosures. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.