Pharmacological Management of Obesity in Children and Young People

Introduction

Obesity now affects one in five children in the UK. The impact on the quality of life and mental health is dramatic, with long-term complications including obstructive sleep apnoea, hypertension, impaired mobility, type 2 diabetes, fatty liver disease, and early onset of cardiovascular disease.

In 2021, NHS England funded 15 specialist centres to pilot complications of excess weight (CEW) clinics for children and young people, in line with the NHS Long Term Plan. University Hospital Southampton has been selected as one of the centres, with a leading regional role for accepting referrals across the South East region.

Given the above initiatives, and the rise in pharmacological options (licensed and unlicensed) for management of obesity, there is a need to develop clinical guidelines to support clinicians and the multidisciplinary team with rational selection of drugs and safe monitoring and follow up.

Scope and Purpose

This document is for all healthcare professionals, including doctors, dieticians, nurses and pharmacists, who support children and young people with management of obesity and complications of excess weight. This includes both specialist CEW teams and general paediatricians in secondary care settings.

The aim of this document is to provide a rational, evidence-based guideline that supports clinical teams with the rational use of pharmacological options for the management of obesity. This includes when to initiate treatment, prescribing guidance, monitoring, assessing outcomes, and when to discontinue therapy.

Definitions

Abbreviation

Pharmacological Management of Paediatric Obesity - Summary

General Considerations

Treatment initiation

Pharmacological treatment is often not immediately needed in the initial assessment, where the focus should remain on patient engagement and agreeing on dietary and lifestyle modifications. Therapy should ideally be started when the patient has successfully stabilised their weight trajectory with diet and exercise. This is particular important with GLP-1RA, which should only be started at a point where weight change is static or there is some weight loss. This helps reduce the incidence of GI adverse events and maximise benefit from treatment.

Age considerations:
Glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy is unlicensed in children younger than 12 years, while metformin can be used in children as young as 8 years old for management of insulin resistance.
For GLP-1RA, it is not recommended to start this for adolescents 17 years and older. This is currently because there is no access to therapy on transition to adults, and the paediatric service aims to offer therapy for at least two years (including dose uptitration and weaning) in order to see clinically-meaningful benefit.

Dual therapy:
Where a patient is eligible for dual therapy with metformin and a GLP-1RA, metformin should be started first, followed by the GLP-1RA at least 2-3 months later. This helps improve tolerance to treatment by minimising GI side effects, as well as help identify which drug has resulted in the side effects or reactions should these occur.

BMI thresholds:
When assessing criteria for treatment initiation, a slightly lower BMI threshold should be used for south Asian and Chinese ethnicities, given the higher risks of metabolic complications. In adults, the BMI threshold is lower by 2.5 kg/m2. Similarly, children with short stature, a weight that is 3 or more centile lines above their height centile should be treated similar to those having a BMI SDS over 2.

Assessing treatment outcomes

A clinically meaningful outcome is considered to be a reduction of BMI SDS of 0.2-0.25 over 6-12 months [Srivastava et al. 2019]. This is approximately equivalent to a 5% reduction in weight or BMI, and has been associated with cardiovascular and metabolic risk reduction.

The DIRECT trial showed that weight loss of ≥15kg in adults with type 2 diabetes achieved remission in 86% of patients [Lean et al. 2018]. This can be used as a therapeutic target for young people with dysglycaemia or at risk of developing type 2 diabetes. A more tailored target for children based on the Association of Children’s Diabetes Clinicians (ACDC) recommendations is 5% weight loss in the first 3-6 months and 10% weight loss in the first year.

Generally, pharmacological therapy should be discontinued if weight or BMI reduction is <5% (or BMI SDS reduction is <0.2) after 3-6 months on the maximum dose. However, a noticeable change in weight trajectory (slowing in weight gain or weight stabilisation) is a positive clinical outcome and would justify continuing therapy. For children and young people who have not achieved final height, the BMI trajectory would be a more reliable indicator. Note that these considerations do not apply to metformin, which, despite its modest effect on weight loss, would still produce positive benefits on insulin resistance and should continue for the long-term.

The below are adult BMI ranges and approximate equivalent in children:

*Lower end of range for older children; higher end of range for younger children.

Metformin

Mechanism of action

Metformin activates AMP-activated protein kinase (AMPK), a key regulator of energy metabolism. Through this action, it recruits glucose transporters to skeletal muscle cells, thus enhancing cellular glucose uptake and increasing insulin sensitivity. In the liver, it inhibits hepatic gluconeogenesis and stimulates fatty acid oxidation, the latter being beneficial in metabolic dysfunction-associated fatty liver disease (MAFLD).

Licensing and funding

Licensed for children ≥10 years with T2DM, and adults ≥18 years with T2DM or pre-diabetes. Given the wide experience with its use at a younger age, the BNF recommends use from age 8 years.

Metformin is funded by primary care (CCGs/ICSs).

Criteria for starting

Children ≥8 years with:

• Any BMI SDS and evidence of insulin resistance or dysglycaemia

• BMI SDS ≥2.5 with no evidence of insulin resistance or dysglycaemia only if:

  • a) They have confirmed MAFLD, or

  • b) They are on long-term treatment with drugs that cause insulin resistance (e.g., atypical antipsychotics, corticosteroids)

If an OGTT is planned within 2-3 months, consider delaying start until after OGTT to avoid affecting the test outcomes. Metformin is licensed for type 2 diabetes in children ≥10 years irrespective of weight and other comorbidities. 

Evidence Base

The benefits of metformin on weight are modest. Based on a 2021 meta-analysis, it was shown to reduce BMI SDS in children by up to 0.15 [Masarwa et al. 2021]. Its effect on insulin resistance and metabolic syndrome is more pronounced, where it lowered HOMA-IR by up to 3.5 [Masarwa et al. 2021] and reduced fasting insulin by up to 22 µU/mL [Brufani et al. 2013]. In obese adults, it reduced the progression to type 2 diabetes by 7-31% [Lentferink et al. 2018].

Metformin’s effect on fasting glucose, total cholesterol and triglycerides is less conclusive [Masarwa et al. 2021]. The TONIC trial showed that metformin did not provide benefit in reducing ALT in children with MAFLD [Lavine et al. 2011]. International guidance by the American Association for the Study of Liver Disease do not recommend it specifically for MAFLD [Chalasani et al. 2018, Pala et al. 2014, Younossi et al. 2014]. However, its effect on reducing insulin resistance and oxidative stress may still be of indirect benefit, and children with MAFLD tend to show the greatest reduction in BMI and insulin resistance when started on metformin [Masarwa et al. 2021].

Metformin has also shown considerable benefit in children on antipsychotic medications that cause weight gain, with a placebo-adjusted weight reduction of 4.1% (2.7kg) [Björkhem-Bergman et al. 2010, Anagnostou et al. 2016].

Although unlicensed in children, modified-release (MR) metformin tablets have been used for adolescent obesity at a dose of 2g daily, with good benefit [Wilson et al. 2010]. In adults with type 2 diabetes, head-to-head trial of MR metformin at 2g once daily compared to immediate-release metformin at 1g twice daily showed equivalent efficacy at HbA1c reduction, but with the advantage of once-daily dosing [Aggarwal et al. 2017].

Prescribing guidance

Metformin is taken orally. Modified-release tablets are preferred to promote adherence and minimise side effects, as long as the child can swallow tablets.

For children <10y, consider an extra titration step with a starting dose of 250mg once daily using the immediate-release formulation.
* Immediate-release metformin should be taken with or after a meal.

Adverse effects and cautions

• Gastrointestinal side effects in 30% of patients: nausea, diarrhoea, epigastric pain. Generally all disappear in the first few weeks of treatment.

• Vitamin B12 malabsorption (up to 10% of patients).

• Lactic acidosis is extremely rare, with a maximum incidence of 4 per 100,000 patient-years. Only known to occur in the context of other acute illnesses (e.g., sepsis, dehydration, AKI).

• Withhold during perioperative period or if due a procedure involving contrast media.

Counselling points and management

• Give with or after meals to reduce incidence of side effects.

• Advise to persevere with GI side effects. If still not tolerated, consider one of the following:

  • Uptitrate dose every 10-14 days instead of 7 days

  • Split the dose to be more frequent (BD or TDS)

  • Switch to modified-release tablets at the same total daily dose once daily. The dose may be split into BD if still not tolerated

  • If all else fails, reduce to the maximum tolerated dose.

• Advise to stop metformin if acutely unwell (‘sick day rules’): vomiting, diarrhoea, fevers; and only restart after 24-48 hours of eating and drinking normally.

• Withhold treatment during procedure involving contrast media, and in the perioperative period until able to eat and drink.

Metformin patient information leaflet is available on Staffnet.

Monitoring

• U&Es annually to observe renal function.

• Vitamin B12 annually.

• Renal impairment results in metformin accumulation and higher risk of lactic acidosis:

  • GFR <45 mL/min: max dose 1000mg daily

  • GFR <30 mL/min: stop metformin

Preparation and prescribing advice

Metformin should be prescribed generically.

Semaglutide (Wegovy®)

Mechanism of action

Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1RA), with a more prolonged action and higher potency than that of natural GLP-1. It acts on brain GLP-1 receptors to increase satiety and reduce central hunger signals. The resultant effect on weight loss is preferential for visceral fat mobilisation compared to subcutaneous fat. GLP-1RA also stimulate insulin secretion and lower glucagon secretion, resulting in lowering of post-prandial glucose. The effect is glucose-dependent and thus cannot cause hypoglycaemia.

Licensing and funding

Wegovy® is licensed for adults and children aged ≥12y with obesity, with a maximum dose of 2.4mg once weekly.

Obesity for adults is defined as a BMI ≥30kg/m2 or a BMI ≥27kg/m2 in the presence of at least one weight-related comorbidity. For adolescents, obesity is defined as a BMI ≥98th centile for age (BMI SDS ≥2). At CEW service, it is agreed to consider therapy at a BMI SDS of ≥2.5.

NICE recommends the use of Wegovy® for adults with obesity and at least 1 weight-related comorbidity if referred to a tier 3 obesity service and only for a maximum treatment duration of 2 years. The technology appraisal for children has been terminated, as not enough evidence had been submitted by the company, thus funding decisions are made by the local hospital or ICB.

The use of Wegovy® for obesity in children aged ≥10y has been approved by the UHS Drugs and Therapeutics Committee for the local population. Use is restricted to secondary care and is funded by individual hospitals. Information can be found here.

At the time of writing, there is still no local service or commissioning pathway for use of Wegovy® in adults. This should be a consideration in preparation for transition of paediatrics under endocrine or CEW services.

Ozempic® is a different brand of semaglutide licensed only for adults ≥18 years with T2DM, and allows dialling doses up to 1mg once weekly. The off-label use of Ozempic® for children aged ≥10 years with T2DM has been approved by the UHS District Prescribing Committee. Off-label use is restricted to secondary care and is funded by individual hospitals

Criteria for starting

Children ≥12 years (or exceptionally ≥10 years) with:

• BMI SDS ≥2.5 and 1 or more obesity-related comorbidities.

• BMI SDS >3 and confirmed POMC or LEPR deficiency.

Semaglutide (Ozempic® 1mg) is also approved locally for off-label management of children ≥10 years with type 2 diabetes irrespective of weight and other comorbidities.

Transition:
Currently there is no tier 3 adult obesity service at Southampton commissioned to prescribe GLP-1RA for weight management. Until this is developed, patients should be informed that treatment may need to be stopped on transition to adult services.

Evidence base

The STEP TEENS study, published in 2022, showed outcomes of semaglutide 2.4mg in the adolescent population from age 12 years [Weghuber et al. 2022]. Over a period of 68 weeks, semaglutide showed BMI reduction by 16.7%, equivalent to a BMI SDS reduction of 1.0. The evidence was similar in the adult STEP 1 study, which showed a weight reduction of 12.4% (12.7kg) over 1 year [Wilding et al. 2021]. Weight loss reaches a plateau after around 1 year, and patients gained some weight back when semaglutide was stopped [Rubino et al. 2021].

Ahead of Wegovy® launch, a study of the local cohort using semaglutide 1mg (Ozempic®) once weekly showed a BMI SDS reduction of 0.32 at 6 months and 0.52 at 12 months [van Boxel et al 2024]. Average weight loss over the first year was 9.7 kilograms.

The weight loss from semaglutide is associated with improvement in cardiometabolic risk factors [Rubino et al. 2021, Aroda et al. 2019]. The STEP 6 trial demonstrated benefits of semaglutide 2.4mg on reducing fasting plasma glucose, fasting insulin, lipid levels, triglycerides, and CRP, with an 11mmHg reduction in systolic blood pressure, all of which are largely a result of the weight loss attained [Kadowaki et al. 2022]. In a post-hoc analysis of the STEP 1 trial, semaglutide 2.4mg showed a relative risk reduction in developing type 2 diabetes by 61% compared to only 12.9% reduction with placebo [Wilkinson et al 2023]. This was proportional to the weight loss achieved. The results were sustained after 2 years.

Semaglutide produced significant ALT reduction, with 46% of adult patients with obesity and high baseline ALT showing normalised ALT after 1 year of treatment [Newsome et al. 2019]. It also resulted in the resolution of metabolic syndrome in around half of adult patients after 6 months of treatment [Newsome et al. 2019].

Results from a meta-analysis show there is no association between GLP-1RA and a risk of acute pancreatitis [Storgaard et al. 2017]. Cases of acute pancreatitis were reported in more recent studies, although it should be noted that in many cases these occurred in patients with a history of pancreatitis or gallstones [Wilding et al. 2021]. All cases were mild to moderate, and resolved without need for medical intervention. There is no risk of hypoglycaemia unless combined with insulin. There is a small risk of acute gallbladder disease, with a reported incidence of 4% from the paediatric trial [Weghuber et al. 2022], although it should be noted that gallbladder disease can also be a complication of obesity.

Psychiatric adverse events

A European pharmacovigilance analysis of patients on GLP-1 receptor agonists noted an increased rate of 1.2% of psychiatric adverse events in this patient group [Tobalqy and Elkout 2024]. The European Medicines Agency (EMA) provided a statement on the subject after review of the evidence, and concluded that ‘the available evidence does not support a causal association between GLP-1 receptor agonists and suicidal and self-injurious thoughts and actions’ [EMA 2024].

Moreover, a psychiatric assessment was undertaken as part of the STEP TEENS trial, using PHQ-9 (Patient Health Questionnaire-9) and C-SSRS (Columbia-Suicide Severity Rating Scale). Children in both groups (semaglutide vs placebo) scored similarly on the PHQ-9 score, while those on the semaglutide group scored lower on the C-SSRS scale. Only one patient in the semaglutide group showed evidence of suicidality (scored as ‘passive suicidality’ on C-SSRS) compared to 9 patients in the placebo group (of which 6 showed ‘active suicidality’ on C-SSRS) [Suppl to Weghuber et al.]

Risk of thyroid cancer

The Food and Drug Administration (FDA) has issued warnings of the risk of thyroid cancer with GLP-1RA. This warning, only made in the USA, is based on pre-clinical studies on rodents [NovoNordisk 2022, NovoNordisk 2024]. The same studies noted that rodents are particularly sensitive to this GLP-1 receptor-mediated mechanism, which may be less relevant to humans. These tumours were not seen in monkeys treated with GLP-1RA [NovoNordisk 2022].

One French case-controlled population-based study concluded that GLP-1RA are associated with an increased risk of thyroid cancer [Besin et al. 2023]. On the background of this study, the EMA reviewed all available evidence in light of this study. This included a meta-analysis of 45 trials (n=16,201) [Hu et al. 2022] and two cohort study (n=21,722 and n=145,410) [Bea et al. 2023, Pasternak et al. 2024], all of which showed no evidence of increased risk of thyroid cancer. Based on this, the EMA has concluded that available evidence does not support a link with thyroid cancer [EMA 2023], and consequently UK literature does not have the same warnings as American literature.

GLP-1 receptor agonist comparison

The STEP 8 trial compared semaglutide 2.4mg against liraglutide 3mg in obese adults, with a reported weight reduction of 15.8% vs 6.4%, respectively [Rubino et al. 2022]. Adverse effects leading to treatment discontinuation were lower with semaglutide vs liraglutide (3.2% vs 12.6%) [Rubino et al. 2022].

There are no comparative data for GLP-1RAs in paediatrics. From adult trials, it appears that semaglutide 1mg (Ozempic®) is equivalent to liraglutide 3mg in its weight-lowering effect, while semaglutide 2.4mg (Wegovy®) is superior to both.

Prescribing guidance

Wegovy® dosage

Wegovy® is injected subcutaneously once weekly. Timing is independent of meals.

Can be considered exceptionally for children from age 10 years (unlicensed).
*The day of injection can be changed if needed as long as the time between any two doses is at least 3 days.

Adverse effects and cautions

• GI side effects (nausea, diarrhoea, vomiting, dyspepsia) and fatigue. Generally will disappear in the first few weeks or months.

• Cholelithiasis and cholecystitis are less common.

• Acute pancreatitis is rare. There is no benefit in routine amylase monitoring as it can be transiently elevated by GLP-1RA without correlation with pancreatitis risk.

Counselling points & management

• Use of pen device, injection sites (abdomen or thigh preferred) and site rotation. Demonstration devices available from NovoNordisk.

• Persevere with GI side effects. If severe (including severe vomiting), consider dose reduction and slower uptitration.

• Reduce meal portions and snacking when starting treatment to reduce the severity of GI side effects.

• If persistent abdominal pain, withhold treatment and investigate for cholelithiasis/pancreatitis.

• If started in patients on insulin, they will likely need a basal insulin dose reduction of 20% over the first 2 months of treatment. Aim to review insulin requirements after 2-3 weeks of starting semaglutide.

• For patients showing dose ‘wear off’ before next injection, consider whether injecting mid-week would be beneficial in order to have maximum benefit over weekends.

• For girls of childbearing potential, they should be counselled that GLP-1RA should be avoided during pregnancy, and that GLP-1RA should be stopped at least 2 months before any future planned pregnancy. The following wording is suggested for discussions or patient leaflets:

  • The effects of semaglutide on an unborn baby are unknown. If your child is sexually active, we advise that they use suitable contraception to prevent pregnancy. For more information on contraception, speak to your child’s doctor or nurse. If you know or think that your child might be pregnant, please contact us for advice as soon as possible.

• Semaglutide (Wegovy®) patient information leaflet is available on Staffnet.

Patient support resources are available here.  These include a video on how to administer the injection and a booklet on dosing, side effects, and basic dietetic and activity advice.

Monitoring

• Baseline abdominal ultrasound and serum triglycerides to assess risk of gallstones or acute pancreatitis.

• Bioelectrical impedance analysis for younger and prepubertal patients.

• Nutrition screening bloods if rapid or high rate of weight loss, defined as: ≥20% of total weight since starting treatment, or ≥10% of total weight within 3 months, or continuing to lose weight where weight is within 2 centiles of height on growth chart.

• Nutrition bloods: full blood count, liver profile, bone profile, ferritin, folate, vitamin B12, selenium, magnesium, phosphate.

• U&Es annually.

• Renal impairment: discontinue if creatinine clearance <15mL/min.

Preparation and prescribing advice

• Semaglutide should always be prescribed by brand name. The drug is available as three brands, with different devices/routes, dose ranges, and licensing.

• Rybelsus® is an oral (tablet) formulation of semaglutide licensed for T2DM in adults. This is not licensed for use in paediatrics or for weight management.

• Needles are included in the medicine package.

• Sharps bin to be supplied by hospital or requested from GP.

Liraglutide (Saxenda®)

Mechanism of action

Liraglutide is a glucagon-like peptide-1 receptor agonist (GLP-1RA), with a more prolonged action and higher potency than that of natural GLP-1. It acts on brain GLP-1 receptors to increase satiety and reduce central hunger signals. The resultant effect on weight loss is preferential for visceral fat mobilisation compared to subcutaneous fat. GLP-1RA also stimulate insulin secretion and lower glucagon secretion, resulting in lowering of post-prandial glucose. The effect is glucose-dependent and thus cannot cause hypoglycaemia.

Licensing and funding

Saxenda® is licensed for adults and children aged ≥12y with obesity, with a maximum dose of 3mg once daily.

As for Wegovy®, NICE recommends the use of Saxenda® for adults with obesity, but the technology appraisal for children has been terminated as insufficient evidence was submitted by the company.

Funding and commissioning considerations for Saxenda® are identical to that for Wegovy® discussed in the previous section, and is funded by individual hospitals.  Information can be found here.

Victoza® is a different brand of liraglutide licensed for children ≥10 years and adults with T2DM, and allows dialling doses up to 1.8mg once daily. Not for use in weight management.

Criteria for starting

Children ≥12 years (or exceptionally ≥10 years) with

• BMI SDS ≥2.5 and 1 or more obesity-related comorbidities.

Note that liraglutide (as Victoza® 1.8mg) is licensed for type 2 diabetes in children ≥10 years irrespective of weight and other comorbidities.

Transition:
Currently there is no tier 3 adult obesity service at Southampton commissioned to prescribe GLP-1RA for weight management. Until this is developed, patients should be informed that treatment may need to be stopped on transition to adult services.

Evidence base

The use of liraglutide 3mg resulted in a weight loss of 5% (-4.5kg) and BMI reduction of 4.6% (BMI SDS -0.22) in adolescents [Kelly et al. 2020]. Patients gain back weight when treatment is discontinued [Pi-Sunyer et al. 2015], indicating the need for long-term treatment whenever possible.

Some of the benefits of liraglutide are more prominent in the adult population. A 3mg dose resulted in weight loss of 8% (5.6kg) in adults, with a concomitant reduction in inflammatory markers and a modest improvement in lipid profile [Pi-Sunyer et al. 2015]. The onset to T2DM was also delayed in the liraglutide group. More recently, it demonstrated ≥5% weight loss and increased satiety in genetic obesity, with a proposed role through the POMC pathway [Welling et al. 2021].

The LEAN study demonstrated that liraglutide 1.8mg resulted in resolution of non-alcoholic steatohepatitis (NASH) in 39% of obese adult patients vs 9% in placebo control, with a resultant reduced progression to fibrosis [Armstrong et al. 2016]. The higher dose (3mg) showed reduction in ALT by 34 units/L and HOMA-IR by 2.9 in Asian adults with obesity and MAFLD, despite not making any dietary or lifestyle interventions [Khoo et al. 2017]. It should be noted that the drug did not show improvement in lipid profile in children [Ryan et al. 2021], although the study was conducted using the lower (1.8mg) dosing.

Liraglutide increased the incidence of cholelithiasis and cholecystitis by 1.5% during treatment [Pi-Sunyer et al. 2015].

See the Wegovy® section for information on psychiatric adverse events, risk of thyroid cancer, and a comparison of GLP-1 efficacy.

Prescribing Guidance

Saxenda® dosing

Saxenda® is injected subcutaneously once daily. Timing is independent of meals.

*Can be considered exceptionally for children from age 10 years (unlicensed).

Adverse effects and cautions

• GI side effects (nausea, diarrhoea, vomiting, dyspepsia) and fatigue. All disappear in the first few weeks.

• Cholelithiasis and cholecystitis are less common.

• Acute pancreatitis is rare. There is no benefit in routine amylase monitoring as it can be transiently elevated by GLP-1RA without correlation with pancreatitis risk.

Counselling points and management

• Use of pen device, injection sites (abdomen or thigh preferred) and site rotation. Demonstration devices available from NovoNordisk.

• Persevere with GI side effects. If severe (including severe vomiting):

  • Omit one day of treatment, then restart at a lower dose (0.6-1.2mg lower than the last tolerated dose step). Slowly uptitrate every 2 weeks and keep on maximum tolerated dose.

• Reduce meal portions and snacking when starting treatment to reduce the severity of GI side effects.

• If persistent abdominal pain, withhold treatment and investigate for cholelithiasis/pancreatitis.

• If started in patients on insulin, they will likely need a basal insulin dose reduction of at least 10% over the first 2 months of treatment. Aim to review insulin requirements after 2-3 weeks of starting liraglutide.

• For girls of childbearing potential, they should be counselled that GLP-1RA should be avoided during pregnancy, and that GLP-1RA should be stopped at least 2 months before any future planned pregnancy. The following wording is suggested for discussions or patient leaflets:

  • The effects of liraglutide on an unborn baby are unknown. If your child is sexually active, we advise that they use suitable contraception to prevent pregnancy. For more information on contraception, speak to your child’s doctor or nurse. If you know or think that your child might be pregnant, please contact us for advice as soon as possible.

Liraglutide (Saxenda®) patient information leaflet is available on Staffnet.

Monitoring

• Baseline abdominal ultrasound and serum triglycerides to assess risk of gallstones or acute pancreatitis.

• Bioelectrical impedance analysis for younger and prepubertal patients.

• Nutrition screening bloods if rapid or high rate of weight loss, defined as: ≥20% of total weight since starting treatment, or ≥10% of total weight within 3 months, or continuing to lose weight where weight is within 2 centiles of height on growth chart.

• Nutrition bloods: full blood count, liver profile, bone profile, ferritin, folate, vitamin B12, selenium, magnesium, phosphate.

• U&Es annually.

• Renal impairment: discontinue if creatinine clearance <30mL/min.

Preparations and prescribing advice

• Liraglutide should always be prescribed by brand name. The drug is available as two brands, with different devices, dose ranges, and licensing.

• Needles to be prescribed separately (free supply available via NovoNordisk to hospital).

• Sharps bin to be supplied by hospital or requested from GP.

Implementation

The guideline will be made available on Staffnet. The authors are responsible for ensuring the effective dissemination of this guideline. Methods of dissemination may include:

• Presenting the guideline at multidisciplinary team meetings

• Email correspondence (e.g., to general paediatricians)

• Introducing the guidelines locally via Grand Round

• Introducing the guidelines regionally via quarterly CEW Development Day

Roles and Responsibilities

The guideline applies to all clinical staff employed or contracted by University Hospital Southampton (UHS) Foundation Trust who provide care to children within Southampton Children’s Hospital. Staff have a responsibility to ensure that they are aware of this guideline and its contents. They should clearly document their rationale if they have not complied with the recommendations detailed in this guideline. It is the responsibility of department managers, consultants, team leaders and education leaders to ensure staff are aware of this guideline.The guideline applies to all clinical staff employed or contracted by University Hospital Southampton (UHS) Foundation Trust who provide care to children within Southampton Children’s Hospital. Staff have a responsibility to ensure that they are aware of this guideline and its contents. They should clearly document their rationale if they have not complied with the recommendations detailed in this guideline. It is the responsibility of department managers, consultants, team leaders and education leaders to ensure staff are aware of this guideline.

Document Review

All Trust policies will be subject to a specific minimum review period of one year; we do not expect policies to be reviewed more frequently than annually unless changes in legislation occur or new evidence becomes available. The maximum review period for policies is every three years. The author of the policy will decide an appropriate frequency of review between these boundaries.

Where a policy becomes subject to a partial review due to legislative or national guidance, but the majority of the content remains unchanged, the whole document will still need to be taken through the agreed process as described in this policy with highlighted changes.

This clinical guideline will be reviewed in 12 months time, then every 3 years thereafter.

Process for monitoring compliance

The purpose of monitoring is to provide assurance that the agreed approach is being followed. This ensures that we get things right for patients, use resources well and protect our reputation. Our monitoring will therefore be proportionate, achievable and deal with specifics that can be assessed or measured.

Key aspects of this policy will be monitored:

Where monitoring identifies deficiencies, action plans will be developed to address them.

References

1. Aggarwal N, Singla A, Mathieu C, Montanya E, Pfeiffer A, Johnsson E, Zhao J, Iqbbal N, and Bailey C. Metformin extended-release versus immediate-release: an international, randomized, double-blind, head-to-head trial in pharmacotherapy-naïve patients with type 2 diabetes. Diabetes, Obesity & Metabolism 2018;20:463-467.

2. Anagnostou E, Aman M, Handen B, Sanders K, Shul A, Hollway A, et al. Metformin for treatment of overweight induced by atypical antipsychotic medication in young people with autism spectrum disorder: a randomized clinical trial. JAMA Psychiatry 2016;73(9):928-937.

3. Armstrong M, Gaunt P, Aithal G, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016;387(10019):679-690.

4. Aroda V, Ahmann A, Cariou B, Chow F, Davies M, Jódar E, et al. Comparative efficacy, safety, and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the treatment of type 2 diabetes: insights from the SUSTAIN 1-7 trials. Diabetes & Metabolism 2019;45:409-418.

5. Association of Children’s Diabetes Clinicians (ACDC). A practical approach to management of type 2 diabetes in children and young people (CYP) under 18 years. ACDC 2023 [Online]. 

6. Bea S, Son H, Bae J, Cho S, Shin J, and Cho Y. Risk of thyroid cancer associated with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: a population-based cohort study. Diabetes, Obesity and Metabolism 2023;26(1):108-117.

7. Bezin J, Gouverneur A, Pénichon M, Mathieu C, Garrel R, Hillaire-Buys D, Pariente A, and Faillie J. GLP-1 receptor agonists and the risk of thyroid cancer. Diabetes Care 2023;46(2):384-390.

8. Björkhem-Bergman L, Asplund A, and Lindh J. Metformin for weight reduction in non-diabetic patients on antipsychotic drugs: a systematic review and meta-analysis. Journal of Psychopharmacology 2010;25(3):299-305.

9. Brufani C, Crinò A, Fintini D, Patera P, Cappa M, and Manco M. Systematic review of metformin use in obese nondiabetic children and adolescents. Horm Res Paediatr 2013;80:78-85.

10. Chalasani N, Younossi Z, Lavine J, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Disease. Hepatology 2018;67(1):328-357.

11. Chanoine J, Hampl S, Jensen C, Boldrin M, and Hauptman J. Effect of orlistat on weight and body composition in obese adolescents: a randomized controlled trial. JAMA 2005;293(23):2873-2884.

12. European Medicines Agency (EMA). GLP-1 receptor agonists: available evidence not supporting link with thyroid cancer. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 23-26 October 2023 [Online]. 

13. European Medicines Agency (EMA). Meeting highlights from the pharmacovigilance risk assessment committee (PRAC) 8-11 April 2024. [Online] 

14. Fernando K, Bain S, Holmes P, Newland-Jones P, and Patel D. Glucagon-like peptide 1 receptor agonist usage in type 2 diabetes in primary care for the UK and beyond: a narrative review. Diabetes Ther 2021;12:2267-2288.

15. Hu W, Song R, Cheng R, Liu C, Guo R, Tang W, Zhang J, Zhao Q, Li X, and Liu J. Use of GLP-1 receptor agonists and occurrence of thyroid disorders: a meta-analysis of randomized controlled trials. Front Endocrinol. 2022;13. doi: 10.3389/fendo.2022.927859

16. Joint Formulary Committee. BNF for Children (Online) London: BMJ Group, Pharmaceutical Press and RCPCH Publications. [Online] 

17. Kadowaki T, Isendahl J, Khalid U, Lee S, Nishida T, Ogawa W, et al. for the STEP 6 investigators. Semaglutide once a week in adults with overweight or obesity, with or without type 2 diabetes in an east Asian population (STEP 6): a randomised, double-blind, double-dummy, placebo-controlled, phase 3a trial. Lancet Diabetes Endocrinol 2022;10(3):193-206.

18. Kelly A, Auerbach P, Barrientos-Perez M, Gies I, Hale P, Marcus C, et al. for the NN8022-4180 Trial Investigators. A randomized, controlled trial of liraglutide for adolescents with obesity. N Engl. J Med 2020;382:2117-2128.

19. Khoo J, Hsiang J, Taneja R, Law N, and Ang T. Comparative effects of liraglutide 3 mg vs structured lifestyle modification on body weight, liver fat and liver function in obese patients with non-alcoholic fatty liver disease: a pilot randomized trial. Diabetes Obes Metab 2017;19:1814-1817.

20. Lavine J, Schwimmer J, van Natta M, Molleston J, Murray K, and Rosenthal P, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011;305(16):1659-1668.

21. Lean M, Leslie W, Barnes A, Brosnahan N, Thom G, McCombie L, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet 2018;391(10120):541-551.

22. Lentferink Y, Knibbe C, and van der Vorst M. Efficacy of metformin treatment with respect to weight reduction in children and adults with obesity: a systematic review. Drugs 2018;78(18):1887-1901.

23. Masarwa R, Brunetti V, Aloe S, Henderson M, Platt R, and Filion K. Efficacy and safety of metformin for obesity: a systematic review. Pediatrics 2021;147(3):e20201610.

24. Merck. Glucophage 500 mg film coated tablets – Summary of Product Characteristics. Electronic Medicines Compendium 2022. [Online] 

25. Newsome P, Francque S, Harrison S, Ratziu V, van Gaal L, Calanna S, et al. Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. Aliment Pharmacol Ther 2019;50:193-203.

26. NovoNordisk. Ozempic 1 mg solution for injection in pre-filled pen – Summary of Product Characteristics. Electronic Medicines Compendium 2021. [Online] 

27. NovoNordisk. Saxenda 6 mg/mL solution for injection in pre-filled pen – Summary of Product Characteristics. Electronic Medicines Compendium 2022. [Online]

28. NovoNordisk. Wegovy 2.4 mg, FlexTouch solution for injection in pre-filled pen – Summary of Product Characteristics. Electronic Medicines Compendium 2024. [Online] 

29. Pala L, Barbaro V, Dicembrini I, and Rotella C. The Therapy of insulin resistance in other diseases besides type 2 diabetes. Eat Weight Disord 2014;19:275-283.

30. Pasternak B, Wintzell V, Hvii A, Eliasson B, Gudbjörnsdottir S, Jonasson C, Hveem K, Svanström H, Melbye M, and Ueda P. Glucagon-like peptide 1 receptor agonist use and risk of thyroid cancer: Scandinavian cohort study. BMJ 2024;385:e078225. doi: https://doi.org/10.1136/bmj-2023-078225

31. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M et al. for the SCALE Obesity and Prediabetes NN8022-1839 Study Group. A randomized controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med 2015;373:11-22.

32. Rubino D, Abrahamsson N, Davies M, Hesse D, Greenway F, Jensen C, et al. for the STEP 4 Investigators. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 Randomized Clinical Trial. JAMA 2021;325(14):1414-1425.

33. Rubino D, Greenway F, Khalid U, O’Neil P, Rosenstock J, Sørrig R, et al. for the STEP 8 Investigators. Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes: The STEP 8 Randomized Clinical Trial. JAMA 2022;327(2):138-150.

34. Ryan P, Seltzer S, Hayward N, Rodriguez D, Sless R, and Hawkes C. Safety and efficacy of glucagon-like peptide-1 receptor agonists in children and adolescents with obesity: a meta-analysis. J Pediatr 2021;236:137-147.

35. Srivastava G, Fox C, Kelly A, Jastreboff A, Browne A, Browne N, et al. Clinical considerations regarding the use of obesity pharmacotherapy in adolescents with obesity. Obesity (Silver Spring) 2019; 27(2):190-204.

36. Storgaard H, Cold F, Gluud L, Vilsbøll T, and Knop F. Glucagon-like peptide-1 receptor agonists and risk of acute pancreatitis in patients with type 2 diabetes. Diabetes Obes Metab 2017;19(6):906-908.

37. Supplementary Appendix to Weghuber D, Barrett T, Barrientos-Pérez M, Gies I, Hesse D, Jeppesen O, Kelly A, Mastrandrea L, Sørrig R, and Arslanian S, for the STEP TEENS Investigators. Once-weekly semaglutide in adolescents with obesity. New England Journal of Medicine 2022;387(24):2245-2257.

38. Tobalqy M and Elkout H. Psychiatric adverse events associated with semaglutide, liraglutide and tirzepatide: a pharmacovigilance analysis of individual case safety reports submitted to the EudraVigilance database. International Journal of Clinical Pharmacy 2024;46(2):488-495.

39. van Boxel E, Rahman S, Lai K, Boulos N, and Davis N. Semaglutide treatment for children with obesity: an observational study. Arch Dis Child 2024. doi: 10.1136/archdischild-2023-326687.

40. Weghuber D, Barrett T, Barrientos-Pérez M, Gies I, Hesse D, Jeppesen O, Kelly A, Mastrandrea L, Sørrig R, and Arslanian S, for the STEP TEENS Investigators. Once-weekly semaglutide in adolescents with obesity. New England Journal of Medicine 2022;387(24):2245-2257.

41. Welling M, de Groot C, Kleinendorst L, van der Voorn B, Burgerhart J, van der Valk E, et al. Effects of glucagon-like peptide-1 analogue treatment in genetic obesity: a case series. Clin Obes 2021;11:e12481.

42. Wilding J, Batterham R, Calanna S, Davies M, van Gaal L, Lingvay I et al. for the STEP 1 Study Group. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021;384(11):989-1002.

43. Wilkinson L, Holst-Hansen T, Laursen P, Rinnov A, Batterham R, and Garvey T. Effect of semaglutide 2.4mg once weekly on 10-year type 2 diabetes risk in adults with overweight or obesity. Obesity (Silver Spring) 2023;31(9):2249-2259.

44. Younossi Z, Reyes M, Mishra A, Mehta R, and Henry L. Systematic review with meta-analysis: non-alcoholic steatohepatitis – a case for personalised treatment based on pathogenic targets. Aliment Pharmacol Ther 2014;39:3-14.

45. Wilson D et al, for the Glaser Pediatric Research Network Obesity Study Group. Metformin extended release treatment of adolescent obesity: a 48-week randomized, double-blind, placebo-controlled trial with 48-week follow-up. Archives of Pediatric & Adolescent Medicine 2010;164(2): 116-123.

Appendix 1 - Summary of drugs for obesity

*Can be considered exceptionally for children from age 10 years.

Rybelsus® and orlistat are not locally approved for paediatric obesity, but are presented here for comparison only. 

Appendix 2 - Drugs which affect weight

The following is not a comprehensive list, but shows examples of common drugs prescribed in paediatrics which may affect body weight. Practitioners should be aware of the effect of these drugs if prescribed. For drugs that cause weight gain, they can discuss with the relevant speciality if an alternative is suitable.

SSRIs (e.g., sertraline, fluoxetine) may cause weight gain or weight loss.

*Atypical antipsychotics and long-term oral corticosteroids induce insulin resistance, which may manifest as drug-induced diabetes mellitus.