Study D: evaluation of anti-obesity drug treatment in children and adolescents

Russell M Viner; Sanjay Kinra; Deborah Christie; Tim J Cole; Silvia Costa; Helen Croker; Tam Fry; Yingfen Hsia; Lee Hudson; Anthony S Kessel; Steve Morris; Irwin Nazareth; Dasha Nicholls; Min Hae Park; Sonia Saxena; Barry Taylor; Billy White; Ian C Wong

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Viner RM, Kinra S, Christie D, et al. Improving the assessment and management of obesity in UK children and adolescents: the PROMISE research programme including a RCT. Southampton (UK): NIHR Journals Library; 2020 Mar. (Programme Grants for Applied Research, No. 8.3.)

Improving the assessment and management of obesity in UK children and adolescents: the PROMISE research programme including a RCT.

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Chapter 5Study D: evaluation of anti-obesity drug treatment in children and adolescents

Abstract

Background

Three drugs were approved for obesity treatment in the UK between 1998 and 2006 (although the last two were subsequently withdrawn from the market): orlistat (Alli^®; GlaxoSmithKline plc, Brentford, UK), sibutramine (Meridia^®; Abbott Laboratories, Abbott Park, IL, USA) and rimonabant (Acomplia^®; Sanofi, Paris, France). In 2014, the revised NICE guidelines recommended that orlistat was appropriate for obesity management in children and adolescents aged ≥ 12 years in certain circumstances.¹² The aims of this study were to (1) gain a better understanding of young people’s and families’/carers’ experiences of using AODs, (2) use this improved understanding to develop interventions that optimise AOD usage in young people and (3) analyse GP prescribing patterns of AODs and compare their prescribing to current recommendations.

Methods

To assess the aims, a series of studies were conducted: (1) a systematic review and meta-analysis evaluating the efficacy and safety of AODs from published RCTs in children and adolescents; (2) cohort studies to investigate prescribing patterns [for orlistat, sibutramine, metformin (Glucophage^®; Merck Serono, Darmstadt, Germany)] to young people in primary care settings; (3) a survey study to determine current practice in prescribing these drugs to young people for obesity treatment, with examining GP-completed questionnaires across UK general practices (in England, Scotland, Wales and Northern Ireland); and (4) semistructured interviews with young people (i.e. aged 13–18 years) and their parents from three specialist obesity clinics, to understand children’s and families’ perspectives of treatments.

Key results

Evidence from published RCTs showed that orlistat and sibutramine (in combination with behavioural therapy) significantly reduced BMI compared with placebo in young people.

Prescribing of AODs (orlistat, sibutramine) to children and adolescents increased 15-fold between 1999 and 2006, but approximately 45% of orlistat and 25% of sibutramine prescriptions were discontinued after 1 month of treatment, and before patients could see any weight benefits.

There was also a steady increase in metformin prescribing to obese and overweight young people, particularly in girls aged 16–18 years.

In 121 returned questionnaires (80% response rate), 61% of GPs reported issuing the drugs to their patients without secondary or tertiary care team advice. Despite comprehensive guidance provided in the NICE guideline, GPs expressed a need to develop a new guide for prescribing AODs to young people.

Young people and parents described side effects as a significant experience and few adhered to prescribed regimens, independently changing lifestyle and dosage to tolerate medications.

Conclusions

General practitioners require more support from a specialist in managing the treatment of obesity in children in the community. Pharmacological treatment is unlikely to be effective without further assistance, such as lifestyle modification or psychological support. There should be further research to develop a collaborative, prospective, obesity management surveillance network for children and adolescents across other specialist centres in the UK. This could examine effectiveness, safety and prescribing patterns of medications along with other interventions (e.g. psychological intervention, bariatric surgery) for weight management in clinical practice.

Key findings across study D

Evidence from published RCTs has shown that orlistat and sibutramine significantly reduce BMI compared with placebo in young people: orlistat together with behavioural therapy reduced BMI by 0.83 kg/m², with a large number of gastrointestinal adverse drug reactions. Sibutramine with behavioural therapy reduced BMI by 2.20 kg/m². The pooled analysis based on 12 RCTs showed a BMI reduction of 0.64 kg/m² with metformin treatment compared with placebo after 6 months of treatment.
The majority of AOD prescriptions were rapidly discontinued, before patients could see any weight benefits: prescribing of AODs (e.g. orlistat, sibutramine) to children and adolescents increased 15-fold between 1999 and 2006. However, approximately 45% of orlistat and 25% of sibutramine prescriptions were discontinued after 1 month of treatment. This indicates that these drugs are poorly used in the general population.
There was a steady increase in metformin prescribing to obese and overweight young people: the use of metformin increased fivefold between 2000 and 2010 in primary care, particularly in girls aged 16–18 years.
Use of AODs in primary care is rare, particularly in males and those aged < 16 years. High rates of discontinuation were seen, primarily in those prescribed orlistat. Over half of GPs who initiated pharmacological treatment to obese and overweight young people did not consult a specialist for advice. Rates of compliance with NICE guidance for orlistat were low and GPs report low confidence in the use of AODs in this age group. Improved training and support for GPs is needed to guide AOD use in primary care, for both current and future generations of drugs.
Use of AODs is challenging and complex for many adolescents, and few young people describe positive experiences. Few adhered to prescribed regimens, independently changing lifestyle and dosage to tolerate medications. Improved clinician–patient partnership in decision-making and better patient education and subsequent support are likely to improve medication concordance and maximise efficacy.

Background

There has been a dramatic rise in the prescription of AODs in children and adolescents¹⁴⁷ in response to the global epidemic of childhood obesity. It is estimated that the global prevalence of child and adolescent obesity in 2006, using conservative definitions by World Health Organization (WHO) region, varied from 3% in South-East Asia to 8% in Europe, rising to 13% in the Americas.¹ Clear evidence of high levels of current and future comorbidity associated with childhood obesity has driven a search for effective treatments of both childhood obesity and related comorbidities, including problems of glucose-insulin homeostasis, dyslipidaemia, hypertension and other metabolic and psychological problems.¹⁴⁸^,¹⁴⁹ Although attention has focused appropriately on lifestyle modification interventions, a role has been identified for AODs in the treatment of older children and adolescents.¹⁵⁰ In both the USA¹⁵¹ and the UK,¹¹ AODs are recommended for those in whom lifestyle modification has failed or who have significant obesity-related comorbidities. There are few data on the scale of AOD use in children and adolescents.

At the time of planning the PROMISE programme, there were two medications internationally approved for obesity treatment in adults: orlistat (a gastric and pancreatic lipase inhibitor) and sibutramine (a serotonin and noradrenergic reuptake inhibitor). Rimonabant, a selective cannabinoid receptor 1 (CB1) antagonist, was withdrawn worldwide in 2008 because of severe psychiatric side effects.

The US Food and Drug Administration approved the use of orlistat in obese adolescents aged ≥ 12 years, and sibutramine in obese young people aged ≥ 16 years. In the UK, NICE guidance¹¹ identified orlistat and sibutramine as appropriate second-line treatments for those aged ≥ 12 years with significant obesity comorbidities. In 2007, orlistat was approved for over-the-counter (OTC) use in the USA, and in October 2008, the European Medicines Agency (EMA) recommended that orlistat be made available OTC in Europe as well.¹⁵² However, each of these recommendations was based on a limited evidence base, with a small number of RCTs for each drug. Two recent reviews⁴²^,¹⁵³ of obesity treatment in children and adolescents did not adequately address pharmacotherapy for paediatric obesity.

Prior work by this research team had shown that prescribing of AODs for children and adolescents aged ≤ 18 years rose 15-fold in the UK between 1999 and 2006.¹⁵⁴ Notably, this occurred largely before the publication of the NICE guidance in 2006, which endorsed the use of AODs in children and adolescents for the first time. There is a need to have compelling evidence to support AOD use in children.¹⁵⁰

The overall aims of this study were to (1) gain a better understanding of young people’s and families’/carers’ experiences of using AODs, (2) use this improved understanding to help inform future interventions that optimise AOD usage in young people and (3) analyse GP prescribing patterns of AODs and compare their prescribing to current recommendations.

Subsequent to the commencement of PROMISE, sibutramine was withdrawn in Europe (in January 2010) and the USA (in October 2010) as a result of concerns about cardiovascular side effects. Because of this, the use of metformin for non-DM uses in children and adolescents was included as part of this study. Metformin is the most commonly used drug in the management of childhood obesity, although it is not classed as an AOD because it is used as an insulin-sensitising agent in DM.

Substudy 5.1: systematic review and meta-analysis to evaluate the efficacy and safety of anti-obesity drugs

This work was reproduced and published as Russell M. Viner, Yingfen Hsia, T. Tomsic, and Ian C. K. Wong. ‘Efficacy and safety of anti-obesity drugs in children and adolescents: systematic review and meta-analysis’. Obesity Reviews, 2010;11:593–602. https://doi.org/10.1111/j.1467-789X.2009.00651.x.¹⁵⁵

Licence to reproduce number (John Wiley & Sons): 4675940164204.

As part of the preparation for the anti-obesity drug (AOD) workstream of PROMISE, we undertook a systematic review and meta-analysis of AOD use in children and adolescents. This was conducted and submitted after the award of the programme, and we therefore include it in the programme outputs. The findings reported here are substantially those reported in the published paper.

Copyright © Queen’s Printer and Controller of HMSO 2020. This work was produced by Viner et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

Aim

The aim of this substudy was to systematically review the literature and investigate the efficacy and safety on AOD in children and adolescents.

Methods

Literature search

Search strategies drew on published optimal search strategies for drug trials.¹⁵⁶^,¹⁵⁷ The following databases were search between January 1996 and July 2008 for clinical trials investigating AOD and body weight reduction: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL). We also searched the trial registers: the metaRegister of Controlled Trials (www.controlled-trials.com), WHO clinical trial registered (www.who.int/ctrp/en/) and the Clinical trials government (www.clinicaltrials.gov/). Hand-searching was also carried out to examine the reference lists of identified studies.

Eligibility criteria

The inclusion criteria for systematic review were published double-blind randomised placebo-controlled clinical trials investigating the effects and safety of AOD (orlistat, sibutramine, rimonabant) for body mass index (BMI) reduction in children and adolescents aged < 20 years, with duration ≥ 6 months. We excluded quasirandomised, open-label crossover trials and studies published only in abstract form. There was no restriction on language. Note that, given that a range of definitions of childhood obesity exist, we included any trials which used an established definition of overweight or obesity (BMI ≥ 85th, 95th or 98th centile; BMI > International Obesity Taskforce definitions).¹⁵⁸ Given our age range, we examined BMI reduction rather than weight loss as the primary outcome, as growing children with a stable weight may exhibit reduced BMI.

Data extraction and quality assessment

Two reviewers (YH, TT) performed the electronic searches and screened the articles independently. Articles that clearly did not meet eligibility criteria were rejected on initial review. Articles marked for potential inclusion were then obtained electronically or in paper copy, and assessed again for inclusion. Disagreement was resolved by consensus.

Those included studies deemed to meet inclusion criteria by both reviewers were appraised. A standardised form was used to record all details of the papers reviewed.¹⁵⁹ The standard form included study design, blinding status, trial duration, mean age of participants, gender, number of participants in treatment and placebo group, interventions and the assessment of intention-to-treat (ITT) analysis. The Quality of Reporting of Meta-analyses (QUOROM) guideline was used for reporting our review.¹⁰⁶

Statistical analysis

We expressed the primary outcome as change in raw BMI rather than in BMI standard deviation score (SDS), as use of BMI SDS masks significant loss of body mass in the very obese during adolescence.¹⁰⁶ We calculated weighted mean differences for continuous outcomes (e.g. BMI) and risk difference for dichotomous outcomes at the end of study follow-up. The meta-analysis used a random-effects model with RevMan 5.0.16 (The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark). The primary outcome analysis (BMI) was based on ITT data from the completion of the randomised trial, prior to any crossover or open-label extension. However, data on secondary outcomes and adverse events were taken from the same trial end point as the BMI data, using the highest-quality data reported in each trial (whether the ITT population or for completers). Where SDs were not reported, these were obtained from standard errors, confidence intervals (CI), t-values or p-values that relate to the differences between means in two groups. The DerSimonian and Laird Q-test was performed to assess the degree of heterogeneity between studies, and the I²-statistic was used to describe the percentage of total variation across studies due to heterogeneity. Owing to the small number of studies, we were unable to assess publication bias by inspection of Funnel plots. Secondary outcomes were included in the meta-analysis if each outcome was reported in more than two studies for each drug. Findings were reported in accordance with the QUOROM consensus statement.¹⁰⁶

Results

The review flow chart is shown in Figure 11. The initial search identified 101 studies, of which 85 were excluded after reviewing the abstracts. The most common reasons for exclusion were study participants were aged > 20 years, review article or ineligible primary outcome. Sixteen studies were appraised in detail and assessed for inclusion in the meta-analysis.

FIGURE 11

Review flow chart. Source: Viner et al.

Two were identified as subgroup analyses and excluded. Details of the remaining 14 studies are shown in Table 24. Of eight appraised studies of sibutramine, four were excluded from the meta-analysis: two were open-label studies without a control (placebo) group,¹⁶⁰^,¹⁶¹ one randomised controlled trial had a study duration of only 3 months¹⁶² and one randomised controlled trial excluded subjects with primary or nutritional obesity.¹⁶³ Of six studies of orlistat, four were excluded: three were open-label uncontrolled studies,¹⁶⁴^–¹⁶⁶ and one was an open-label non-blinded randomised controlled trial.¹⁶⁷ Two studies of orlistat and four of sibutramine were identified as eligible for meta-analysis (Table 24).

TABLE 24

Appraised trials of sibutramine and orlistat for weight reduction in children and adolescents

Subjects and co-interventions

Subjects across all trials included in the meta-analysis had similar demographic profiles: the majority were aged 12–18 years, mean BMI was between 30 and 40 kg/m² and subjects were predominantly white or Hispanic. In each trial, subjects with secondary causes of obesity were excluded, as were those with DM. All trials included a standardised low-fat, low-energy diet and encouragement to exercise, with a variable element of behavioural modification in some trials.

Methodological quality

Studies were all of similar quality. All studies included an ITT analysis, reported eligibility criteria, and co-interventions were similar in intervention and control arms. The main limitation to quality was moderately high attrition rates, averaging 19% for sibutramine studies and 25% for orlistat studies. Most studies did not describe the randomisation process nor comment on allocation concealment or blinding of outcome assessors. Because there was little variation in quality, we did not perform sensitivity analyses according to study quality. Secondary end points were reported inconsistently, and frequently in a subgroup of patients or not in an extractable fashion.

Orlistat

Two studies fulfilled criteria to be included in the meta-analysis, with a total sample size for BMI outcomes of 573 adolescents (see Table 24). One ran for 6 months and one for 12 months. Each used the recommended dose of 120 mg three times daily, and participants also received behavioural, dietary and exercise counselling. Participants in both studies also received multivitamin supplements.

Figure 12 shows the pooled estimate of mean BMI change with orlistat was a reduction of 0.83 kg/m² (95% CI 0.47 to 1.19 kg/m²) compared with placebo. There was no evidence of heterogeneity. We were unable to undertake an analysis of proportions achieving 5% and 10% reductions in BMI or weight as this was reported in only one study.

FIGURE 12

Mean reduction in body mass index (kg/m²) with sibutramine and orlistat. IV, instrumental variable. Source: Viner et al.

Secondary outcomes for orlistat compared with placebo are shown in Table 25. There were no significant differences in fasting lipids, glucose or insulin between the orlistat and placebo groups. As waist circumference, body fat and blood pressure were each reported in only a single study, these outcomes were not included in the meta-analysis. The effect of orlistat and placebo on changes in vitamin A, D and E levels was not included in the meta-analysis as the dose of multivitamin used in each trial was not specified; however, neither study reported any significant difference in levels of each vitamin between groups during the trial. We were unable to undertake sensitivity analyses for orlistat due to the low study numbers.

TABLE 25

Secondary outcomes and adverse reactions with orlistat

Adverse reactions for orlistat compared with placebo are shown in Table 25. Those taking orlistat were significantly more likely to experience a range of gastrointestinal side effects. It was not possible to assess the risk of any gastrointestinal event or study discontinuation due to gastrointestinal side effects.

Sibutramine

Data from four randomised controlled trials were included in the meta-analysis, with a total sample size for BMI outcomes of 686 adolescents (see Table 24). Three studies ran for 6 months and one study for 12 months. Two studies used a dose of 10 mg sibutramine per day,¹⁶⁸^,¹⁶⁹ one study used 10 mg per day for the first 6 months, increasing the dose to 15 mg per day for the second 6 months if subjects had failed to lose ≥ 10% of initial BMI,¹⁷⁰ and one study used a dose which increased from 5 to 15 mg over the first 7 weeks.¹⁷¹ Figure 12 shows that the pooled estimate of mean change in BMI for sibutramine was a reduction of 2.20 kg/m² (95% CI –2.83 to –1.57 kg/m²). There was no significant heterogeneity. Secondary outcomes for sibutramine compared with placebo are shown in Table 3. Sibutramine treatment increased the absolute percentage of 5% and 10% BMI responders by 45% and 39% respectively, and decreased waist circumference by nearly 6 cm on average, compared with placebo.

Sibutramine was associated with significant improvements in triglycerides and high-density lipoprotein (HDL)-cholesterol compared with placebo (two studies each). Data on the effect of sibutramine on body composition (e.g. fat mass loss) were unavailable. Sensitivity analyses for sibutramine: we conducted sensitivity analyses for study duration (6 or 12 months) and for the use of a behaviour therapy (BT) programme as a co-intervention. A BT co-intervention was used for all study participants in two¹⁷⁰^,¹⁷¹ of the four sibutramine studies. Sibutramine plus BT co-intervention produced a mean BMI reduction of 2.23 kg/m² (95% CI –3.12 to –1.34 kg/m²) compared with placebo and BT. Sibutramine without BT produced a mean BMI reduction of 2.04 kg/m² (95% CI –3.50 to –0.58 kg/m²). The ITT analysis was undertaken at 6 months in three studies and at 12 months in one study. Sibutramine produced a mean BMI reduction of 2.60 kg/m² (95% CI –3.16 to –2.04 kg/m²) in the single 12-month study³² and 1.95 kg/m² (95% CI –2.81 to –1.08 kg/m²) in the three 6-month studies. We repeated the 6-month analyses with the addition of intermediate non-ITT data from 6-month assessments in the single 12-month study; mean BMI reduction across the four studies at 6 months was largely unchanged: –2.02 kg/m² (95% CI –2.49 to –1.55 kg/m²). It was not possible to undertake analyses by sibutramine dose. Adverse reactions for sibutramine compared with placebo are shown in Table 26. Those receiving sibutramine had higher systolic (1.4 mmHg) and diastolic (1.7 mmHg) blood pressure and heart rate (4.7 beats per minute). As hypertension was not an exclusionary condition in all studies, and because of variable data presentation, we were unable to assess trial withdrawal due to hypertension across the studies. Those taking sibutramine were also significantly more likely to experience dry mouth but no other adverse events.

TABLE 26

Secondary outcomes and adverse reactions with sibutramine

Discussion

Meta-analysis of randomised controlled trials of AODs in children and adolescents with primary obesity showed that both orlistat and sibutramine result in significant BMI reduction compared with placebo over 6–12 months: 0.83 kg/m² for orlistat and 2.20 kg/m² for sibutramine. As the SD for BMI in overweight and obese adolescents is approximately 3.5 kg/m² in US and UK populations,⁶⁵^,¹⁷⁴ for sibutramine this therefore equates to an 0.63-SD reduction in BMI. This is a clinically meaningful effect size; recent longitudinal epidemiological data suggest that each additional BMI SD at age 13 years increases risk of non-fatal cardiovascular events by 11–17% and of fatal cardiovascular events by 23–24%.¹⁴⁸ Sibutramine also increased the absolute percentage of those achieving a ≥ 10% BMI loss by approximately 40%, reduced waist circumference by a mean of 5.8 cm compared with placebo (an effect size of approximately 0.6 SDs)¹⁷⁵ and minimally improved HDL-cholesterol. Sensitivity analyses suggested that the addition of BT programmes to sibutramine minimally increased mean BMI loss (by approximately 0.2 kg/m²), and that a longer duration of sibutramine use may increase BMI loss by approximately 0.6 kg/m². Adverse reactions with sibutramine included significant but small increases in systolic and diastolic blood pressure and heart rate. Sibutramine did not increase the risk of other adverse events except for dry mouth.

The effect size for orlistat was smaller and of borderline clinical significance at 0.24-SD reduction in BMI. Orlistat had no beneficial or adverse effects on metabolic outcomes. Orlistat was associated with an approximately 50% increase in minor gastrointestinal adverse events, such as oily spotting, and an 8–17% increase in the absolute incidence of more major gastrointestinal events, such as flatus with discharge and faecal incontinence.

Comparison with the literature

Our findings are similar to another meta-analysis of AODs in children and adolescents, by McGovern et al.,¹⁵³ who reviewed drug trials as part of a wider systematic review of childhood obesity treatment. They reported a mean BMI reduction for sibutramine of 2.4 kg/m² from three randomised controlled trials, similar to our finding of 2.2 kg/m², and a mean BMI reduction for orlistat of 0.7 kg/m², again similar to our finding of 0.83 kg/m². However, this review included unblinded studies, failed to identify eligible trials, included sibutramine and orlistat as subcategories within a larger random-effects meta-analysis and did not undertake sensitivity analyses or examine secondary outcomes in detail. A second (Cochrane) systematic review by Oude Luttikhuis et al.⁴² reported similar findings for orlistat (mean reduction: 0.76 kg/m²). This review included only two small studies in the meta-analysis for sibutramine, reporting a mean reduction of 1.66 kg/m², which is considerably lower than our estimate. Neither of these studies undertook a meta-analysis of adverse events with orlistat or sibutramine. Our findings also align with an update of the Cochrane review in November 2016,¹⁷⁶ which again reported similar findings for orlistat but noted the poor overall quality of the literature.

We are unable to directly compare our findings with adult studies of AOD, either in terms of absolute BMI loss or proportions who lost ≥ 5% or ≥ 10% of initial weight. We did not include weight loss in our review, as BMI reduction is the goal of treatment in childhood and adolescence,¹⁷⁷ growing children may lose BMI while gaining weight, and BMI centiles continue to shift in later adolescence even after height growth has ceased.⁶⁵ However, approximate comparisons can be made for older adolescents who are at or near final height. Meta-analyses in adults show that weight loss from sibutramine and orlistat are limited to 3–4 kg over 12 months.¹⁷⁸ In contrast, the weight loss corresponding to a loss of 2.2 kg/m² related to sibutramine use in 14- and 15-year-old adolescents with a height on the 50th centile for sex is approximately 6 kg for both boys and girls, a relationship that holds true across the obese BMI range. The corresponding weight loss for orlistat is approximate 2.3 kg. These figures suggest the possibility that sibutramine therapy may be more effective in obese adolescents than in adults. The reasons for this are unclear. This may be an artefact of the paucity of data on adolescents and the lack of long-term data. Alternatively, this may suggest that sibutramine is more potent in suppressing appetite in adolescents, possibly because of developmental immaturity in hypothalamic appetite control systems.

We found sibutramine to have modest beneficial effects on triglycerides and HDL-cholesterol, similar to findings in adults.¹⁷⁸ However, we found no evidence of beneficial metabolic effects associated with orlistat use, in contrast to meta-analysis in adults, which suggests that orlistat has small beneficial effects on LDL and total cholesterol.¹⁷⁸ The reasons for this difference are unclear but may relate to the modest BMI loss seen with orlistat in adolescents and the small number of studies.

Study quality was relatively high; attrition rates (19% for sibutramine and 25% for orlistat) were moderately high, but lower than those reported in a meta-analysis of adult trials of these drugs (30% for orlistat, 40% for sibutramine).¹⁷⁸ However, the number of studies of each drug in adolescents is small, and trials have all been undertaken in secondary care settings, limiting the generalisability of findings. We identified no published studies with a duration ≥ 12 months, so we were unable to examine long-term maintenance of BMI loss.

Our findings apply to young people with simple or primary obesity. However, we note that our BMI effect size finding for sibutramine is similar to the 0.7-SD BMI reduction reported by Danielsson et al.¹⁶³ in a randomised controlled trial of sibutramine for 20 weeks in adolescents with secondary or monogenic obesity that was not eligible for our meta-analysis.

Safety

The safety profile of orlistat was similar to that noted in adults (i.e. a marked increase in unpleasant and anti-social gastrointestinal experiences but there was little evidence of significant health risk). Theoretical concerns about fatsoluble vitamin deficiencies were not supported although subjects in both trials were given multivitamins. In contrast, sibutramine was generally well tolerated by subjects but was associated with small rises in systolic and diastolic blood pressure and resting heart rate. The magnitude of these changes is highly similar to that seen in adult studies; a recent meta-analysis found that sibutramine increased adult systolic blood pressure by 1.7 mmHg, diastolic blood pressure by 2.4 mmHg and heart rate by 4.5 beats/minute.¹⁷⁸ Even small increments in blood pressure can have an adverse impact on cardiovascular risk in the long term, particularly in at-risk groups, such as obese adolescents, who often have high blood pressure compared with peers.

Authorities note that the long-term safety of anorectic agents has not been established in children and adolescents.¹⁵⁰ However, the clinical significance of small blood pressure increments over a short treatment period remains unclear, particularly when balanced against the beneficial cardiovascular effects of successful weight reduction.

Strengths and limitations

We undertook a rigorous systematic review and meta-analysis using independent reviewers adhering to the established Cochrane Collaboration methodology. In contrast to adult studies,¹⁷⁸ studies in our review included a range of non-white ethnic groups.

However, our findings have several limitations which need to be considered. First, all published studies have demonstrated efficacy of BMI and body weight reduction in both orlistat and sibutramine. This suggests the possibility of publication bias; however, there were too few studies for either drug to warrant the generation of funnel plots to assess publication bias. Second, there was moderate but non-significant statistical heterogeneity between studies in BMI outcomes from sibutramine use. This was addressed by using a random-effects meta-analysis. It is likely that this heterogeneity is the result of differences in co-interventions, study duration and study populations. We included studies of differing length in the meta-analysis, as it was not possible to standardise duration owing to the differing timings of the ITT analysis. We did not have access to individual patient data to investigate the cause of this heterogeneity. Third, for sibutramine, we excluded one trial from the meta-analysis as study duration was only 3 months and an ITT analysis was not performed.¹⁶² Repeating the meta-analysis for BMI including this study reduced the estimate of BMI reduction to –1.8 kg/m² (95% CI –2.65 to –0.95 kg/m²). Fourth, all included studies were conducted in specialist environments, and the generalisability of these findings to more general populations of obese adolescents is unclear. Finally, our analyses included only data that were extractable from studies, which may be a source of bias as studies may publish only secondary outcomes that differed significantly from placebo. This was the case for the largest included trial of sibutramine, by Berkowitz et al.,¹⁷⁰ which published only metabolic outcomes that differed significantly between sibutramine and placebo, and we were unable to include this study’s data on other not significantly different secondary outcomes in our analyses. However, we believe that this is unlikely to have been important, as we found no significant mean difference for any of these secondary outcomes in the studies that were included in meta-analyses for these outcomes.

Conclusion

Sibutramine together with behavioural support in obese adolescents produces a clinically meaningful reduction in BMI of 0.6–0.8 SDs and is well tolerated. In contrast, orlistat together with behavioural support has limited utility as a weight reduction treatment in adolescents, producing a small effect (0.24 to 0.3 SDs) with frequent gastrointestinal side effects. Further studies of the effectiveness of sibutramine in a range of clinical populations of young people are needed to assess effectiveness and longer-term maintenance of BMI loss.

Substudy 5.2: current practice in the prescription of anti-obesity drugs

The unlicensed use of metformin in children and adolescents in the UK

This work was reproduced and published as Hsia Y, Dawoud D, Sutcliffe AG, Viner RM, Kinra S, Wong IC. Unlicensed use of metformin in children and adolescents in the UK. Br J Clin Pharmacol 2012;73:135–9. https://doi.org/10.1111/j.1365-2125.2011.04063.x.¹⁷⁹

Licence to reproduce number (John Wiley & Sons): 4675940922641.

Background

Metformin is the most commonly prescribed oral antidiabetic drug for DM in children and adolescents in the UK.¹⁸⁰ As metformin has been shown to be effective in reducing testosterone concentrations and improving irregular menstrual cycles,¹⁸¹ it has also been prescribed for the treatment of polycystic ovarian syndrome (PCOS) in women of reproductive age.¹⁸²^,¹⁸³ However, there is still controversy regarding metformin use in PCOS. Two large randomised controlled trials (RCTs) did not show metformin to be more efficacious than placebo in adult women with PCOS.¹⁸⁴^,¹⁸⁵ In adolescents, RCTs have shown the effectiveness of metformin treatment in girls with PCOS.¹⁸⁶^–¹⁸⁸ In contrast to these findings, a recent RCT did not show benefit from metformin treatment along with lifestyle modification in adolescents with PCOS.¹⁸⁹ Despite the controversy, metformin is still recommended as one of the therapeutic options for PCOS in teenage girls.¹⁸¹ In addition to PCOS, metformin is also effective as an anti-obesity drug due to its effect on insulin resistance.¹⁹⁰ Metformin may also have other effects on weight loss, as it reduces hepatic glucose production, inhibits fat cell lipogenesis, increases peripheral insulin sensitivity and may reduce food intake.¹⁵⁰ Studies have shown that metformin is associated with moderate BMI reduction in obese non-diabetic adolescents.¹⁹¹^,¹⁹² In the UK, metformin is licensed for children over the age of 10 years with T2DM who have failed strict dieting.¹⁹³ At present, metformin is not licensed for the treatment of PCOS and obesity in adults or children in the UK.¹⁹³^,¹⁹⁴ Little is known about the extent to which this drug has been used in young people in UK primary care.

Aims

To examine metformin prescribing patterns of general practitioners (GPs) for children and adolescents in the UK primary care setting.

Methods

A retrospective cohort study was conducted using a primary care database, the IMS Disease Analyzer (IMS DA) database. This database contains approximately two million anonymous patient records and over 95 million prescriptions from about 125 general practices and more than 500 GPs.¹⁹⁵ In the UK, virtually all patient care is managed by GPs in primary care. When patients are seen in secondary care (e.g. hospital), consultants or specialists will make the diagnosis and initiate treatment, and GPs will usually continue to monitor patients and issue prescriptions. Electronic medical records are routinely used in UK general practice. GPs usually enter diagnosis and prescription information into the electronic medical records to assist them in patient management.¹⁹⁶

Information held on the database includes patient demographics, indications for treatment and prescription details. Prescribed drugs are coded based on the Anatomical Therapeutic Chemical classification issued by the European Pharmaceutical Market Research Association,¹⁹⁷ and medical diagnoses are coded in accordance with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10), codes.¹⁹⁸ The database has been shown to be of high quality and is widely used in paediatric pharmacoepidemiological studies.¹⁹⁹^–²⁰¹ This study consisted of children and adolescents aged 0–18 years registered with a GP who contributed data to the IMS DA between January 2000 and December 2010. All subjects needed to have a minimum of 6 months’ valid data in the database. Age bands were based on the modification of the International Conference of Harmonisation as follows: < 2, 2–11, 12–15 and 16–18 years.²⁰² Prevalence was calculated as the total number of subjects with at least one prescription of metformin during each year of investigation divided by the total number of study subjects registered on the database in the same year, stratified by age and gender. Annual prevalence of metformin prescribing was calculated using Poisson distribution with a 95% confidence interval (CI). A chi-squared test (Cochran–Armitage test for trend) was used to examine the yearly trend of metformin prescribing. As IMS DA directly links prescriptions to medical indications, the following indications were examined for metformin prescriptions: DM (ICD-10 codes E10–E14), PCOS (ICD-10 code E282) and obesity (ICD-10 code E66).¹⁹⁸ Analyses were carried out using Stata, version 11.0.

This study protocol was approved by the IMS Independent Scientific and Ethical Advisory Committee.

The PRISMA guidelines were followed in undertaking the review and reporting.

Results

A total number of 2674 metformin prescriptions were issued to 337 children and adolescents between 2000 and 2010, 80% of whom were female (n = 270).There were no metformin prescriptions issued to children aged < 2 years. The majority of children were taking metformin for DM treatment were aged 2–11 years. The metformin prescribing started at age 5 years for DM treatment. The number of female adolescents aged 12–18 years who received metformin treatment steadily increased over time (Table 27). The annual prevalence of metformin prescribing increased from 0.03 per 1000 person-years (95% CI 0.02 to 0.05 per 1000 person-years) to 0.16 per 1000 person-years (95% CI 0.12 to 0.20 per 1000 person-years; p = 0.001) (Figure 13).

TABLE 27

Numbers of study subjects and total person-time by sex between 2000 and 2010 by calendar year

FIGURE 13

Overall prevalence of metformin prescribing in children and adolescents (age: 0–18 years), between 2000 and 2010. Source: Hsia et al.

There were a total of 290 patients with at least one diagnosis of DM, PCOS or obesity in their medical records, of whom 235 patients were female (81%) (Table 28). Of 290 patients, 120 female patients were prescribed metformin for the treatment of PCOS and obesity. There were 23 female patients with DM, PCOS and obesity diagnoses who received metformin treatment during the study period. There were 22 patients (7.6%, 22/290) who were prescribed metformin for obesity treatment alone. A total of 47 patients were prescribed metformin without specific relevant diagnosis. After scrutinising their medical records, the most common diagnosis for prescribing ‘unknown and unspecified causes of morbidity’. As IMS DA contains data only from GPs, there is no hospital record in the database to verify diagnoses for these prescriptions.

TABLE 28

Demographic characteristics

Discussion

Our study showed that the use of metformin in the paediatric population increased markedly between 2000 and 2010 in primary care, with prescribing prevalence increasing from 0.03 to 0.16 per 1000 person-years. This increase was particularly marked among girls aged 12–18 years.

There are limited data on paediatric metformin prescribing patterns in the UK. As some prescribing databases do not have links with indications for prescribing, an added strength of this study was that we were able to identify the disease indication for metformin therapy. However, our findings are subject to some limitations. First, the IMS DA records only prescriptions issued in primary care, excluding prescriptions dispensed from hospitals. It is possible that our data did not include a small number of initial hospital prescriptions. While the great majority of these would have been continued in primary care, unfortunately there are no data to investigate the extent of metformin prescribing in hospitals. Second, we were unable to identify whether subjects were treated with lifestyle modification along with metformin, as healthy diet and exercise are mainstays of the treatment for obesity, PCOS and T2DM.¹⁸¹^,¹⁸³ Third, we have no information on diagnostic criteria used for any of the conditions under study as diagnoses are often made in secondary care and as the data set does not record criteria for those made in primary care. While diagnostic criteria for T2DM are internationally accepted, a number of different definitions exist for obesity and PCOS. Fourth, the IMS DA does not contain data on ethnicity and socioeconomic status and thus their impact on prescribing patterns remains unstudied.

Our finding that PCOS was the main indication for metformin prescribing in female adolescents was unexpected. This indicates that the use of metformin for PCOS in teenage girls is increasing in general practice. It has been well documented that adolescent obesity is increasing in population-based studies in the USA²⁰³ and UK.¹⁴⁷ In addition, a previous study found an increased prevalence of T2DM in adolescents aged 12–18 years in the UK.¹⁸⁰ Therefore, it is possible that the prevalence of PCOS in adolescents may also have increased. Although metformin has been shown to be of benefit in teenage girls with PCOS in a number of studies,¹⁸⁶^–¹⁸⁸ the current evidence is limited and inconsistent. The efficacy of metformin treatment in adolescents with PCOS remains to be confirmed by well-designed RCTs. In addition, to extrapolate treatment from adults to adolescents with PCOS is questionable since the risks and benefits are unclear. There were a small number of patients who received metformin for obesity treatment in our study. This prescribing trend may increase in the next few years. In January 2010, the European Medicines Agency recommended removing sibutramine from all markets in the European Union because of the risk of developing cardiovascular events in adults.²⁰⁴ Consequently orlistat is the only licensed AOD in the European Union. As there is limited drug choice for obesity treatment, metformin is likely to gain in popularity for obesity treatment. In addition, a systematic review on economic consequences of obesity treatments found that metformin appeared to be a cost-saving treatment for obese patients with T2DM,²⁰⁵ To date, metformin has not yet received a paediatric licence for PCOS or obesity treatment. As it is mainly prescribed for these unlicensed indications in the paediatric population, more studies are needed to demonstrate its efficacy and safety in this population.

In conclusion, metformin prescribing in children and adolescents has increased substantially in the past decade. An increased number of teenage girls are receiving metformin for PCOS treatment in general practice. As metformin is not licensed for PCOS and obesity treatment in the paediatric population, further studies are required to investigate its long-term efficacy and safety for these conditions.

Anti-obesity drug prescribing for obese children and young people in the UK

Adapted from White et al.²⁰⁶ © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.

Abstract

Aims

Primary care databases show rising prevalence of AOD prescribing to CYP, but these prescriptions are frequently short-lived.

Methods

A primary care database (with 5.7% UK population coverage), The Health Improvement Network (THIN) Additional Information Service (AIS), was used to identify CYP aged ≤ 18 years who were prescribed an AOD between 31 May 2010 and 31 May 2012. A mailed questionnaire to GPs was used to ascertain patient demographics and comorbidities, indications for treatment, and outcomes. We audited against NICE guidance.

Results

A total of 151 patients were identified as receiving orlistat or metformin during the study period. The response rate was 78.9% (119/151). Ninety-four per cent of subjects were eligible for this study. Of these, 86.2% (n = 81) were female. In terms of AODs, 46.8% were prescribed metformin, 58.5% were prescribed orlistat and 5.3% were prescribed both drugs.

Of all orlistat prescriptions, 89.1% (49/55) were initiated in primary care, independent of specialist advice; for metformin, this was 27.3% (12/44). Orlistat was largely prescribed in those aged > 16 years without physical comorbidities. Metformin was initiated for treatment of PCOS (70.5%), insulin resistance (25.0%) and impaired glucose tolerance/impaired fasting glucose (9.1%).

Drug cessation was high, with 5% of orlistat and 57% of metformin prescriptions active at the time of the survey. Median supply of metformin was 10.5 months [interquartile range (IQR) 4.0–18.5 months], compared with 2.0 months (IQR 1.0–4.0 months) for orlistat (p = ≤ 0.001). The proportion of all orlistat treatment lasting a single prescription was 45.5%; none lasted more than 1 year. The majority of all drug terminations were due to families not requesting repeat prescriptions (96.2% for orlistat and 89.5% for metformin) rather than medically led terminations.

Adherence to NICE paediatric guidance for prescribing of orlistat was low: 17% of prescriptions were initiated in the specialist setting and 56% had evidence of obesity-related comorbidity.

General practitioners reported lower confidence in prescribing AODs to CYP than to adults (10-point Likert score median 3 vs. 8; p < 0.0001). GPs requested additional support in the management of childhood obesity, both lifestyle interventions and drugs.

Conclusions

Prescribing of AODs in childhood is rare, with the majority of orlistat prescribing ocurring in those aged > 16 years. GPs requested more support in managing obesity in this group.

Introduction

Little is known about the use of medication for obesity in children and adolescents in the UK, particularly use in primary care. Orlistat is currently the only licensed AOD in the UK since sibutramine was withdrawn owing to concerns about cardiovascular safety.²⁰⁷ However, the most commonly used AOD in CYP is metformin, an anti-diabetes drug used off-licence to treat the metabolic sequelae of obesity in CYP,¹⁹²^,²⁰⁸ although not formally an AOD. Both orlistat and metformin appear to offer small benefits for BMI reduction in CYP; systematic reviews show small reductions in BMI, compared with placebo, for orlistat (by 0.83 kg/m²)¹⁵⁵ and metformin (by 1.4 kg/m²).¹⁹¹ Fewer data exist for the cardiometabolic benefits of these drugs, with only half of the studies of metformin in the systematic review reporting cardiometabolic outcomes.

In the UK, NICE¹² recommends community-based lifestyle modification programmes as the first tier of weight management for childhood obesity, with pharmacotherapy as a second-line treatment. NICE guidance covers only usage of orlistat, which should be prescribed only in exceptional circumstances for those with obesity-related comorbidities (life-threatening in those aged < 12 years) and prescribed only by teams with expertise in these conditions.

Randomised trial data on orlistat and metformin come from specialist clinical settings and largely outside the UK. Very little is known about how these AODs are prescribed and used in actual practice. Pharmacoepidemiology studies of AOD prescribing in primary care in the UK show increasing use of AODs, but also high levels of drug discontinuation, with approximately half of the prescriptions of orlistat not being continued beyond 1 month.¹⁵⁵ The one qualitative study²⁰⁹ examining adolescent use of AODs showed frequent cessation by families independent of their doctors, usually because the perceived advantages did not outweigh the side effects, often with minimal professional support. These data suggest that the effectiveness of AODs in real-life settings may be considerably less than shown in trials, and suggest a need for further research in order to identify strategies to improve the effectiveness of AODs for CYP.

A questionnaire survey of GPs prescribing AODs was undertaken to better understand the use of AODs in primary care in the UK. The aims were to characterise patient demographics, quantify adherence to NICE guidance and identify primary care perceptions of AODs with the long-term aim of optimising AOD prescribing and efficacy.

Methods

Routinely collected primary care data from the THIN database were used to identify general practices that prescribed orlistat or metformin to CYP aged ≤ 18 years between 31 May 2010 and 31 May 2012. THIN covers ≈ 5.7% of the UK population, with 3.6 million active patients from 587 general practices using the Vision General Practice System (In Practice Systems, London, UK).²¹⁰ These practices are broadly representative of practices in the UK in terms of patients’ demographics and characteristics.²¹¹ Questionnaire administration was undertaken by THIN AIS, an independent research organisation affiliated with THIN, with data protection firewalls. Patients prescribed metformin for T2DM were excluded.

A paper questionnaire was sent to all identified general practices. The questionnaire was designed by a multidisciplinary study team comprising an academic GP, two paediatricians, a pharmacist and a GP representative. The questionnaire contained questions regarding patient demographics and comorbidities, outcomes and GP experiences and opinions related to AOD usage in children (see Report Supplementary Material 4 for full questionnaire). GPs prescribing AODs were contacted up to three times over 3 months until the questionnaire was returned. GPs received a £35 payment for each completed and returned questionnaire. THIN AIS anonymised questionnaires prior to analysis by the study team.

A patient’s year of birth, practice identification and practice region were provided by THIN AIS. All other data were provided by individual GPs within prescribing practices. BMI was calculated from GP-derived height and weight measurements when available, and zBMI was calculated using the least mean squares (LMS) method and UK reference data.⁶⁵ AOD termination was assumed if no prescription had been issued within 3 months of the survey. Age at first prescription was calculated from the mid-point of birth year, as month and day of birth were not provided owing to data protection restrictions. Orlistat use was audited against NICE 2006 recommendations,¹¹ which remain unchanged in the 2014 update,¹² bar some text clarifications. For audits against NICE, an assumed birth date of 1 January was used to ensure that no subjects were misclassified as children if they were aged 18 years.

Analyses

Analyses were conducted using Stata 11.0. Simple descriptive statistics were used for the majority of data, including chi-squared test and t-test (paired and independent) for parametric data, and Wilcoxon–Mann–Whitney and Wilcoxon-signed rank tests for unpaired and paired non-parametric data. Thematic analysis was used to analyse qualitative responses.²¹²

Governance

The study was reviewed and approved by the National Research Ethics Service (NRES) Committee London – Surrey Borders [Research Ethics Committee (REC) reference number 11/LO/1020].

Results

Patient demographics

Figure 14 summarises patient sampling. A total of 151 patients were identified by THIN as having received orlistat or metformin during the study period. GP response rate was 78.8% (119/151). GPs identified 21 out of 119 patients as being ineligible for the study. An additional four subjects were excluded after inspection of questionnaires, owing to duplicate questionnaires received for the same drug with inconsistent responses (n = 1), missing patient demographics and drug details (n = 2), and an empty questionnaire (n = 1).

FIGURE 14

Patient sampling. Adapted from White et al. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted. This is an (more...)

A total of 94 subjects were eligible for this study, of whom 86.2% (n = 81) were female. GPs identified ethnicity as British for 44.7% of patients (29 white, three Pakistani, one mixed, one British-African, one mixed African-white British and seven British), white for 30.9% (n = 29), Asian for 4.3% (n = 4) and other for 4.3% (n = 1 each from the Caribbean, Turkey, Iran and Afro-Caribbean/white mixed); 16.0% (15/94) were of unknown ethnicity. The majority of subjects came from England (78.7%, n = 74); the remainder came from Wales (11.7%, n = 11), Scotland (7.4%, n = 7) and Northern Ireland (2.1%, n = 2).

A total of 99 AOD initiations occurred in the 94 subjects (five subjects were prescribed both orlistat and metformin), consisting of 44 metformin (46.8% of sample) and 55 orlistat (58.5%) prescriptions. Drugs were initiated in 68 practices, with 46 practices prescribing one drug each, 15 practices prescribing two drugs each, six practices prescribing three drugs each and one practice prescribing five drugs.

Table 29 summarises baseline demographic and comorbidities by drug. Comorbidities appeared higher in those taking metformin. Sufficient data were provided to calculate BMI and zBMI during the study period for 90.9% (40/44) of those prescribed metformin and 89.1% (49/55) of those prescribed orlistat. All had a BMI above the 98th centile (> 2 SDs). Of the remaining 10, one had no recorded measurements, seven had no height data and two had no drug start date provided by GPs.

TABLE 29

Demographics and comorbidities by drug

Drug initiation

Figure 15 summarises the frequency of drug prescription by age and drug initiator.

FIGURE 15

Bar graph summarising age at AOD initiation, by drug and prescriber. Adapted from White et al. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted (more...)

Of 55 orlistat prescriptions, 89.1% (n = 49) were initiated in primary care, independent of specialist advice. Of this 89.1% of prescriptions, 66.7% were to those aged 12–15.9 years, 93.1% were to those aged 16–17.9 years and 94.1% were to those aged > 18 years. Orlistat was not prescribed to any patient aged < 12 years. In the case of orlistat treatment initiated in primary care on specialist recommendation, the recommending specialist was a paediatrician in three cases (50%) and an adult physician, a lipid clinic and a dietitian in one case each (16.7%).

Of 44 metformin prescriptions, 27.3% (n = 12) were initiated in primary care, independent of specialist advice. Of these, none was for those aged < 12 years, 23.5% were for those aged 12–15.9 years, 25% were for those aged 16–17.9 years and 51.5% were for those aged > 18 years. When metformin was initiated in primary care on recommendation of a specialist, 59.4%(19/32) of recommendations were from a paediatrician, 21.9% (7/32) were from a gynaecologist, 12.5% (4/32) were from an adult physician and 3.1% (1/32) were from an endocrinologist (some had multiple/joint consultations).

Indications for metformin initiation were obesity together with (1) PCOS (70.5%, 31/44), (2) insulin resistance (25.0%, 11/44), (3) impaired glucose tolerance/impaired fasting glucose (9.1%, 4/44) and (4) obesity without known comorbidity (6.8%, 3/44).

Drug monitoring

Of the 61 prescriptions initiated independently by a GP, 67.2% (n = 41) were subsequently reviewed by a GP (75% of metformin prescriptions and 65.3% of orlistat prescriptions), including three that were additionally reviewed by their practice nurse. One was reviewed by a gynaecologist, but not the GP, after drug initiation to confirm appropriateness of the drug prescription.

Of the 38 prescriptions initiated by a GP on specialist recommendation, 26.3% (n = 13) of patients had a GP consultation related to the drug for ‘supervision’ (n = 1), weighing (n = 2), psychological support (n = 1), prescribing (n = 2), answering queries (n = 1) and to discuss efficacy (n = 6). No patients discussed side effects with their GP. GPs were aware of monitoring by a clinician in 84.2% (32/38) of cases, of whom 81.8% (18/22) were followed up by paediatricians and 40% (2/5) were followed up by adult physicians.

General practitioners were made aware of adverse drug effects by two patients, both prescribed metformin: one had diarrhoea and the other had nausea.

Drug duration and termination

Duration of drug prescription is summarised in Figure 16.

FIGURE 16

Kaplan–Meier survival curve demonstrating treatment duration of metformin and orlistat. Figure shows proportion still actively prescribed AOD for orlistat and metformin by time since initiation, beginning from time 0 (100% active prescriptions) (more...)

Over half of metformin prescriptions (25/44), but only 5.5% of orlistat prescriptions (3/55), were active at the time of the survey; an active prescription was defined as a new prescription issued within the preceding 3 months. Twenty-seven patients had only a single prescription issued from primary care, being 45.5% (25/55) of all orlistat and 4.5% (2/44) of metformin treatments. The median duration for supply of metformin was 10.5 months (IQR 4.0–18.5 months), compared with 2.0 months (IQR 1.0–4.0 months) for orlistat (p ≤ 0.001). None of these single prescriptions was issued in the 3 months prior to the survey, and all were given a maximum of 1 month’s supply, making ongoing use highly unlikely. There was a disparity between the reported length of drug prescription and the amount of drug prescribed, suggesting non-continuous use at the prescribed dose.

The majority of all drug terminations were due to families not requesting repeat prescriptions (96.2% of all orlistat terminations and 89.5% of metformin terminations), rather than medically led terminations. GPs reported that in three cases orlistat cessation may have been due to a lack of drug supply in pharmacies. Of four prescriptions actively terminated by a doctor (n = 2 for metformin and n = 2 for orlistat), two were caused by lack of efficacy, one by lack of drug adherence and the other two for reasons unknown.

Adherence to the National Institute for Health and Care Excellence’s guidance

The compliance analysis by NICE¹² was restricted to recommendations for children (Box 1). Using 1 January as their assumed birthday, 23 subjects were definitely aged < 18 years at drug initiation (different age criteria to analyses above).

BOX 1

Summary of 2014 NICE guidance for prescribing of orlistat to CYP

The following criteria were fully met. First, all subjects were aged > 12 years (recommendation 1.8.4). Second, no participants were prescribed orlistat for more than 12 months (1.9.11).

The following criteria were partially met. Four (17.4%) patients were prescribed orlistat following specialist advice (recommendation 1.8.5; see Box 3). Recommending specialists were paediatricians (n = 3) and an adult physician, with one known to be part of a specialist multidisciplinary team (MDT) (1.8.7). All prescriptions recommended by specialists were continued in primary care (1.8.8).

Comorbidities were reported in 56.5% of the sample (13/23), despite NICE requiring comorbidities to be present (recommendation 1.8.6; see Box 3). Comorbidities were emotional distress (7/23), hypothyroidism (3/23), T2DM (1/23), medulloblastoma (1/23), PCOS (1/23) and worsening of another chronic disease secondary to obesity (1/23). No patients had sleep apneoa. Low levels of comorbidity screening in primary care were reported, suggesting that higher numbers of comorbidities may have existed (6/23 were screened for psychosocial distress, five were screened for hypertension, two each for T2DM and dyslipidaemia, and one each and none for sleep apnoea).

No patient was prescribed a multivitamin (1.9.2). Screening for micronutrient intake was not assessed, nor was risk of vitamin deficiencies.

Improving prescribing in primary care

General practitioners reported their confidence in prescribing AODs using a 10-point Likert scale (10 = highest). Confidence was higher for prescribing to adults (median 8, IQR 8–9) than to children (median 3, IQR 1–5; p < 0.0001). There was no difference in confidence between prescribing orlistat or metformin in children (p = 0.8).

The most popular resources used by GPs to support prescribing were NICE guidance¹² (orlistat, n = 20; metformin, n = 7), British National Formulary¹⁹³^,¹⁹⁴ (orlistat, n = 17; metformin, n = 8), local prescribing guidelines (orlistat, n = 8; metformin, n = 11) and specialist guidance (orlistat, n = 1; metformin, n = 7).

General practitioners perceived that 27.3% (n = 12) of patients prescribed metformin and 12.7% (n = 7) prescribed orlistat benefited from the drug; half (50% of those prescribed metformin and 52.7% of those prescribed orlistat) reported not knowing if there had been any benefits for the patient.

Thirty-five GPs provided free-text reflections of their experiences of prescribing orlistat (n = 20) and metformin (n = 14). Three main themes arose. First, metformin was mostly prescribed to PCOS rather than as a weight loss drug. One GP stated that (s)he ‘wouldn’t normally prescribe this just for weight loss’.

Second, there was controversy about whether or not AODs should be prescribed in primary care in this age group, with one GP saying (s)he would ‘usually not prescribe for children’ and another saying (s)he avoided orlistat ‘where possible’. Either metformin was issued ‘on advice of specialist only’ or the patient received specialist follow-up after initiation.

Third, GPs noted concern about the efficacy of these drugs. ‘Inadequate counselling’, lack of drug availability and patient compliance (‘clearly patient was not able to comply’) were hypothesised reasons for ineffectiveness.

Sixty-two GPs wanted improved support, primarily split into two main themes. First, they requested improved age-related guidance for prescribing AODs that is ‘realistic’, with ‘clear [and] concise’ advice including ‘flow diagrams’ and ‘stepwise advice’. This would include instructions on assessment prior to initiation, indications, contraindications, monitoring, safety advice, duration, targets and indications for stopping treatment. Second, they wanted improved guidance for managing patients with obesity, namely advice about lifestyle management and details of available interventions. GPs requested details of ‘non-drug treatments’ including ‘community support for adolescents’ and ‘special clinics for monitoring and support of patients.’ One GP highlighted that ‘non-drug treatments need to be key alongside drug treatment.’

Discussion

This is the first detailed study of primary care prescribing of AODs in CYP at individual patient level. Small numbers of prescriptions were issued in this age group, with most practices surveyed having just a single child or young person on an AOD. However, clear patterns are seen that can help guide prescribing of current and future generations of AODs.

Recipients of AODs were mostly female. Prescribing to those aged < 12 years was rare, with AOD prescribing rates increasing with age. Two-thirds (65%) of the sample was aged ≥ 16 years, including 84% of those prescribed orlistat.

Metformin was mainly prescribed by specialists to those CYP who were obese and had either PCOS or insulin resistance. In contrast, orlistat was mostly prescribed in primary care, independent of specialist advice, to patients with few physical comorbidities.

Drug cessation was high, with only 1 in 18 patients prescribed orlistat continuing to take it at the time of survey, and half requesting only a single prescription. Metformin treatment was more long-standing, with half continuing at the time of survey. Despite well-described side effects associated with these drugs,²⁰⁹ GPs were aware of side effects in only two cases, despite high rates of follow-up. Cessation was almost universally patient led via non-request of repeat prescriptions, independent of medical discussion or decisions. Similar findings have been previously reported.¹⁴⁷^,²⁰⁹

Comparison with NICE orlistat guidelines showed low prevalence of comorbidities and drug initiation without specialist advice. Given that most orlistat prescriptions were for those aged > 16 years, it could be hypothesised that patients were treated as adults, with drugs prescribed in line with adult guidelines that do not necessitate the presence of comorbidities.

General practitioners reported low confidence in prescribing AODs to CYP, despite high levels of confidence when prescribing to adults. They reported a desire for improved guidance not only on drug initiation and monitoring, but also on lifestyle interventions, suggesting possible low overall confidence in managing obesity in children. This fits with findings from this study’s paired qualitative study exploring patients’ experience, which found unease within primary care and pharmacy about AOD usage in CYP, which can result in heightened familial concerns about the use of these drugs.²⁰⁹

Some GPs did not consider metformin an AOD despite it treating the metabolic sequelae of obesity. Low levels of comorbidity screening were found, suggesting that more patients may have benefited from the metabolic benefits of metformin.

Use of AODs in males was low, in keeping with uptake in other obesity interventions. Reasons may include access to primary care, gender differences in acceptance of obesity and other gender norms.

Limitations

This study relied on retrospective, notes-based recall by GPs, increasing the likelihood of missing data. Questionnaire completion rates were variable, with some having only a few questions answered. It was assumed that unanswered questions implied lack of evidence to support the questions. As a result, rates of comorbidities and screening may have been higher than reported. Sequential BMI measurements were sparse, and measurement of BMI changes associated with these drugs was not attempted.

Free-text answers were very brief. Given this, caution was exercised in the analysis of the responses, and themes were kept simple. Future interview studies could allow a better understanding of GP experiences.

The exact age of subjects could not be ascertained, resulting in risk of misclassification bias. Given this, caution was exercised in analysing compliance with NICE guidelines, and it is likely that the number of subjects aged < 18 years who were prescribed orlistat was underestimated.

General practitioners were not asked to justify exclusion of patients from this study. Given some free-text comments about metformin not being an AOD, it is hypothesised that some patients may have been inappropriately excluded.

The research team are unable to comment on specialist prescribing recommendations, as a result of sampling methods. Further research is needed to understand the prescribing practices of specialists and their use of these drugs.

Conclusion

Use of AODs in primary care is rare, particularly in males and those aged < 16 years. High rates of discontinuation were seen, primarily in those prescribed orlistat. Rates of compliance with NICE guidance for orlistat were low and GPs report low confidence in the use of AODs in this age group. Improved training and support for GPs is needed to guide AOD use in primary care, for both current and future generations of drugs.

Subsudy 5.3: understanding young people’s experiences of anti-obesity drugs

This work was reproduced and published as White B, Jamieson L, Clifford S, Shield JP, Christie D, Smith F, et al. Adolescent experiences of anti-obesity drugs. Clin Obes 2015;5:116–26. https://doi.org/10.1111/cob.12101.²⁰⁹

Licence to reproduce number (John Wiley & Sons): 4675941463435.

Background

The role of medications in the management of obesity in children and young people is unclear. In the UK, NICE suggests that AODs may have a role in treatment of young people over 12 years of age with very high body mass index (BMI) or obesity comorbidities.¹¹ Currently only one drug, orlistat, is licensed in the UK as an AOD in children. In addition, metformin is used off-licence predominantly in obese subjects with insulin resistance.¹⁹¹ There are no current data to compare relative usage of these two drugs; however, it is likely that metformin is more widely prescribed, especially by endocrinologists and gynaecologists in subjects with T2DM, insulin resistance and polycystic ovarian syndrome (PCOS). Systematic reviews of metformin and orlistat show small reductions in BMI: orlistat by 0.83 kg/m² (see Viner et al.¹⁵⁵) and metformin by 1.4 kg/m² (see Park et al.¹⁹¹). While these clinical trials suggest the benefits of AODs may be very small, even small reductions in BMI can be important in growing children and adolescents. Primary care prescribing of these drugs increased 15-fold in the UK between 1998 and 2007.¹⁴⁷

Despite encouraging trial results which have evaluated the safety and efficacy of AOD, pharmacoepidemiological studies show that medication discontinuation rates outside the trial environment are very high in both children¹⁴⁷ and adults.²¹³ Analysis of a national primary care prescribing database found 45% of orlistat prescriptions were discontinued after 1 month, and approximately 10% of children and young people remained on the drug for 6 months after initiation.¹⁴⁷ The reasons for these high rates of discontinuation are unclear. Metformin and orlistat have high rates of gastrointestinal side effects, which may limit their use.¹⁶⁵^,²¹⁴ However, there are no published data regarding patient experience of AODs in young people. Qualitative investigation of young people’s experiences allows the generation of hypotheses regarding reasons for early discontinuation.

Aims

The aim of this substudy was to investigate the experiences associated with AOD prescribing and use in adolescents in the UK, in order to inform potential strategies to improve AOD use and, therefore, efficacy in young people.

Methods

We used a qualitative design utilising an in-depth, semistructured interview schedule for young people and parent/carers developed by a multidisciplinary team (two psychologists, two paediatricians, a pharmacist and a patient representative). The schedule contained questions regarding decision processes to take the AOD, expectations of AOD outcomes, experiences of AOD usage, understanding of mechanism of drug action, outcomes of AOD usage and suggestions for improved outcomes. The study was reviewed and approved by the NRES Committee London – Surrey Borders REC (reference number 11/LO/1020).

Recruitment and sample

Young people aged 12–18 years were eligible if they had BMI ≥ 98th centile²¹⁵ and had been prescribed orlistat or metformin for weight control within the last 3 years. Exclusion criteria were (1) use of metformin for management of T2DM, pre-DM or PCOS in non-obese young people, (2) inability to participate in a face-to-face interview or (3) insufficient mastery of English language to participate. Young people were recruited from three paediatric obesity clinics in England (London, Bristol and Liverpool) through the Medicines for Children Research Network. We anticipated requiring approximately 10–20 families to achieve theme saturation.²¹² Based on our previous difficulties recruiting participants into obesity studies, all 109 subjects fulfilling eligibility criteria were invited by their hospital doctor to enrol in the study. Those consenting were invited to interview, together with one parent, and each given a £10 gift voucher as participation compensation.

Face-to-face interviews were conducted in the participant’s own home by one researcher (LJ) experienced in interviewing young people. Parent/young person dyads were independently interviewed unless either of the dyad opted out or they wished to be interviewed together. Written assent for under-16-year-olds and consent for those over 16 were obtained from both the young person and parent/carer. Interviews were audio-recorded and field notes written immediately after the interview.

Analysis

Audio recordings from each interview were transcribed verbatim and anonymised by LJ. Transcripts and field notes were read and coded independently by LJ, and a subsample coded by BW using a general thematic coding methodology.²¹⁶ Memos were written to summarise and synthesise emerging themes. This initial coding framework was used to code the subsequent transcripts and new codes were added as they emerged using a constant comparative technique to compare new and previously collected data to understand emerging themes. To ensure reliability, BW read all transcripts and reviewed the coding. BW and LJ developed models through an iterative process, in which the initial model was reviewed using constant comparison techniques (in which successive items of data are appraised and compared to ensure that the code is reflective of all) and the models revised accordingly. The qualitative analysis was facilitated by the use of NVivo software [QSR International (UK) Limited, Southport, UK].

Results

The interviews took place between January and May 2013; each lasted between 24 and 95 minutes. Theme saturation was reached after views from 16 families were collected. There were 13 parent and young person dyads, two young people without parents (one carer was not available and one did not speak English) and one parent alone (the young person did not wish to be interviewed). Four families (25%) were recruited from Bristol, one (6%) from Liverpool and 11 (69%) from London. Young people were aged 13 to 18 years, 12 (75%) were female, and 12 identified themselves as white British (the remaining identified themselves as White Jewish, Caribbean, British Bangladeshi, and British African). All carers interviewed were female. Ten participants (63%) were prescribed metformin only; eight continue to take metformin. Four were prescribed (25%) orlistat only; none continue on the drug. Two (13%) were prescribed both metformin and orlistat; two continue on metformin and one continues on orlistat. Self-reported weight change ranged from no change to 12.7 kg loss. Participant-reported comorbidities included insulin resistance, T2DM, asthma, hypothyroidism, epilepsy, androgen excess, obsessive–compulsive disorder, depression and hypertension. Participant demographics are summarised in Table 30.

TABLE 30

Self-reported demographics, comorbidities and weight trajectories while taking anti-obesity drugs

Three conceptual models were developed from the emerging themes and are summarised in Figure 17. Models were (a) the factors influencing the commencement of an AOD, (b) the management of side effects and (c) decision to terminate the drug including balancing efficacy and side effects. Below we relate the emergent themes within each model.

FIGURE 17

Model 1: factors influencing the commencement of an AOD. Source: White et al.

Model 1: factors influencing why young people commenced on an anti-obesity drug

Six themes fed into the decision by young people to take the AOD: passive acceptance of the AOD, enthusiasm and relief at the prospect of a drug treatment, medication as a last resort, fear as a motivating factor, AOD as a way out of obesity and their own perceived uniqueness (Figure 17).

Theme 1: passive acceptance of medication

In all cases the doctor suggested an AOD to the young people. Young people’s views were mixed; many had reservations about initiation but there was a general feeling that they should follow the doctor’s advice. Passive acceptance was especially likely when the doctor medicalised obesity by highlighting the increased risk of comorbidities such as T2DM, and where patients were younger:

At the time I was thinking, well if it is stopping her from becoming totally diabetic, then the best thing for her to do is to take it, I suppose.
Parent 9, young girl

I remember them saying to me ‘you haven’t lost any weight, you have gone up, so let’s use this’ and I am like 12/13 years old, what am I supposed to do at this age?
Young person 12, girl aged 16 years

Theme 2: enthusiasm and relief at the prospect of a pharmaceutical treatment

Many participants wanted a novel solution for obesity control and described the potential of a medicine helping them with weight control as ‘awesome’ (young person 12, girl aged 16 years) and ‘exciting’ (young person 8, girl aged 16 years). One participant described how the doctor ‘made it sound like a miracle cure – he made it sound like it was going to fix all of my problems’ (young person 9, girl aged 17 years). However, some young people felt disappointed that they were not able to lose weight without medication:

I felt incredibly relieved that there was something that could help her.
Parent 14, young girl

Theme 3: medication as a last resort

Timing of drug initiation was an important factor, both in terms of timing in relation to other treatments and in relation to readiness to control obesity. Many viewed an AOD as a ‘last resort’ in obesity management. Some had tried all other treatment modalities with insufficient long-lasting benefits, including changes in diet and exercise, participating in programmes such as Slimming World^® (Alfreton, UK) and Weight Watchers (WW International, New York, NY, USA), and ‘gastric band hypnotherapy’ (young person 5, boy aged 13 years):

I think I was at my wits end so anything was better than nothing.
Parent 13, young girl

In contrast, others felt that they were put on the medication before they had had a chance to fully explore other treatment modalities, including management of eating disorders:

. . . if I wasn’t binge eating I think there would have been an impact [on my weight].
Young person 6, girl aged 14 years

Families saw an AOD as an alternative to, rather than part of, a treatment package that included lifestyle changes:

. . . and it was just about like, well, OK then, if this is the last resort, but in some ways I don’t think it was.
Young person 12, girl aged 16 years

The importance of controlling weight at the time of drug initiation varied. Some believed that they would be able to control weight in the future without a drug whereas others wanted additional support immediately:

. . . if I was referred to it a year later or 2 years later I don’t think it would make too much difference.
Young person 15, boy aged 15 years

Theme 4: fear as a motivating factor

Three types of health-related fears were associated with initiation of AOD treatment. Firstly, parents and young people were both concerned and confused by discussions with clinicians about DM; any mention of DM increased their acceptance of the AOD. Young people’s concerns were amplified if their parents or grand-parents had obesity-related conditions:

It is because I am concerned that [my son] does not set up health problems for himself in later life and if we can avoid diabetes that to me seems a very good thing to do indeed while he is struggling to get his weight down, not only for diabetes itself, but all the related things that come in its wake. So that seemed to be absolutely excellent.
Parent 15, young boy

. . . I know that I have to get the weight off for health reasons, because like family members in the past have had lots of health things, especially on my mum’s side and being overweight will affect those things and make them worse or make me more susceptible to them which I don’t want.
Young person 9, girl aged 17 years

Secondly, some young people described feeling threatened by their doctor, reporting that they were told that they would have to undergo bariatric surgery if weight loss was not achieved; they saw surgery as a ‘last resort’ (young person 6, girl aged 14 years) or ‘final straw’ (young person 9, girl aged 17 years) which they wished to avoid.

Thirdly, participants described a fear of being told off or patronised by clinicians, particularly dietitians, in regard to either continued weight gain, lack of exercise, or diet:

I didn’t really find her [the dietitian] very helpful. I think I need guidelines. And it was just oh, you need to eat healthily. I didn’t really find her useful . . . [she] ask(ed) me what I eat and it made me feel guilty then. I know that that is kinda what the aim is but do that as well as help me. Not just make me feel bad.
Young person 3, girl aged 16 years

For the first 2 years they wanted me to see the dietitian and all you ever got were these really skinny bitches (mind my language) who just patronised you and said eat healthily and I am, like I have been coming here 2 years already, I already know what I am meant to do, and no matter how hard I try nothing is happening and you are not helping.
Young person 9, girl aged 17 years

Theme 5: anti-obesity drug as a way out of obesity

For some young people, an AOD was seen as a ‘way out’ of obesity. Young people had their own personal reasons for wanting to lose weight. Some were emotional, and saw the AOD as a way out of being bullied, feeling self-conscious or a way to alleviate their feeling of ‘desperation’ (young person 9, aged 17 years). Others had lifestyle reasons for wanting to lose weight, which included improved fitness and ability to wear certain clothes:

Just to help me lose weight because at the time I was feeling really self-conscious.
Young person 13, girl aged 13 years

I want to just fit into a medium [sized clothes].
Young person 8, girl aged 16 years

Theme 6: perceived uniqueness

Some young people considered themselves to be ‘unique’ because they had a complex medical history or a genetic tendency to obesity and thus felt they needed specialised treatment to help them with their weight. Some believed that they were unlike other overweight young people, in that they did not have a sedentary lifestyle or poor diet, but were incorrectly judged by others as doing so:

It is not that I eat a lot, it is just because of my . . . I can’t remember what it is called, they think it has something to do with my complex medical issues ‘cos I don’t eat that much.
Young person 13, girl aged 13 years

Model 2: management of side effects

The overall themes in model 2 can be seen in Figure 18.

FIGURE 18

Model 2: management of side effects. Source: White et al.

Side effects from AOD were a key issue for many young people, although a minority did not experience any. Side effects of both metformin and orlistat were usually gastrointestinal, particularly abdominal cramps and diarrhoea. For some, this involved spending ‘many, many hours on the loo’ (young person 15, boy aged 15 years, using metformin), and ‘really weird, intense pain’ (young person 1, girl aged 18 years, using metformin). Some were taken aback by the severity of the side effects; one young person reported ‘I have never seen diarrhoea like it’ (young person 6, girl aged 14 years, using orlistat), while another said ‘we were told that there could be mild stomach upsets or whatever but I didn’t expect it to be as uncomfortable as it was’ (young person 15, boy aged 15 years, using metformin). A few young people attributed unusual symptoms to metformin, including hand tremor, headaches and change in moods.

Parents expressed concern about their children having to experience such unpleasant side effects. One mother felt that it was ‘totally wrong’ for her daughter to have such side effects at her age (parent 6, young girl using orlistat):

It was awful and he would do it [faecal incontinence] in his trousers and he would phone me up and say Mum, I need to come home.
Parent 5, young boy

Nearly all young people were prepared to endure some side effects as their doctor had forewarned them. However, there was personal variation as to how much each individual tolerated these side effects; some continued taking the medication despite episodes of faecal incontinence while others stopped with much milder side effects. Some young people were more resilient than others in coping with side effects.

Some initiated self-devised lifestyle strategies or changes in drug regimen to minimise side effects; we identified a number of key likely mediators that influenced how these side effects were managed.

Regimen change to minimise the side effects

Regimen changes were devised and initiated by both doctors and families. Some young people used orlistat flexibly and omitted doses to minimise side effects at predetermined important times. Firstly, this allowed them dietary freedom at special occasions such as birthdays and, secondly, it minimised side effects in certain environments or events, such as school time or during exams:

I stopped [the medication] because I didn’t want to take them during the exams in case I had a bad stomach it would take time off [the exam] . . .
Young person 2, girl aged 17 years

At times, doctors recommended changes in formulation, dosage and frequency to minimise side effects:

They [doctors] changed her metformin dose and changed it to slow release. Then after that they changed the time she was taking it. It would help her a bit more.
Parent 1, young girl using metformin

With the higher [initial] dosage I was vomiting more . . . by breaking it down to two in the morning and two in the evening, I think it [vomiting] is a lot better.
Young person 8, girl aged 16 years, using metformin

In contrast, some young people reported discussing side effects with their doctors but were told that their symptoms would improve if they continued with the current regimen:

. . . [I was] just told to take it and get on with it really.
Young person 5, boy aged 13 years

Alternative self-initiated strategies to manage side effects

Families reported a range of self-initiated strategies to cope with the side effects, particularly diarrhoea and faecal incontinence. These included taking spare clothes to school in case of incontinence, not leaving the house or taking additional medication to counteract the effects.

. . . she would start taking loperamide [anti-diarrhoeal medication] to counteract the effects of it . . . a few times because she was like, I have got to go to school, I have got the runs and I can’t keep going out of the lessons, so it was a bit difficult that one.
Parent, young girl using orlistat

I was asked to bring in spare things because she kept having accidents [faecal incontinence]. She had [already taken] a few herself which she had taken in her bag.
Parent, young girl using orlistat

It made me stop going out for a while as I was worried that it might come over me and I might have to dash off and it would be embarrassing.
Young person, boy aged 16 years, using orlistat

Only a minority of young people taking orlistat recognised that the ‘side effects’ they were experiencing were the result of the fat they had consumed and changed their diet:

I went back to the really healthy stuff.
Young person 13, girl aged 13 years, using orlistat

Mediators in dealing with side effects

Young people identified certain mediators which influenced how side effects were managed.

Reluctance to discuss side effects with clinicians

Despite reporting trust in their doctors, some participants were disinclined to talk to them at planned appointments or initiate additional interim appointments. Some did not feel their GP had sufficient expertise to support AOD usage:

I probably would have liked more support – however, my consultant is very good and I do prefer her to the local GP. She [consultant] sees loads of people with the same condition. Helping them to change their ways and this and that. But at the GPs they do loads of different things . . .
Young person 10, girl aged 14 years

Few turned to other health-care professionals, such as pharmacists, for support, and sometimes these interactions heightened familial concerns, particularly if the professional questioned the appropriateness of the medication:

. . . when I picked up his prescription the pharmacist said ‘the child is only 13’ and I thought oh, is there a reason . . . He just thought it was unusual, it was normally for older people. He thought it was a bit odd and he said maybe you should ask that question. And he also said it would be helpful for me to give him some feedback after he takes them.
Parent 7, young boy

Understanding mechanism of action

Understanding of food content, in particular fat content, was also variable, and some young people reported not having received any dietetic advice prior to commencement of the AOD. This included patients prescribed orlistat. Many had familial experience of AOD usage that increased their own understanding; this was often grandparents taking metformin for control of T2DM or mothers who had taken orlistat for weight control.

Some perceived their drug-related symptoms as ‘side effects’ while others realised that they were a consequence of high fat intake. The majority of participants who correctly understood the mechanism modified either their diet or drug regimen:

. . . if I was eating the fat, I would have to go to the toilet.
Young person 3, girl aged 16 years, using orlistat

Age

Young people reported that if they had been early adolescents at the time the AOD was introduced, they did not listen to the information given by the doctor, preferring to leave understanding to the parent:

I was at that age where I don’t need to know.
Young person 6, girl aged 14 years

Concerns about safety

A few had concerns about the safety of the medicine because of the side effects while others felt that the medicines must be safe because a doctor had prescribed them:

I thought that it couldn’t be, like, safe if it was keeping me awake all night and making me like go a lot.
Young person 5, boy aged 13 years, using metformin

Environmental influences

Many had heightened awareness of toilet facilities, particularly their proximity and the impact of sharing toilets. This was driven by concerns about faecal urgency, risk of incontinence and the embarrassment related to the staining of toilets with oily faeces:

She felt she couldn’t be comfortable taking them at school and college, because she just couldn’t rush out, and when she said she did, it was like an orangey/yellow oil that goes into the toilet and it doesn’t flush away. So that is very embarrassing if you are out somewhere.
Parent 1, young girl using orlistat

Model 3: drug continuation – efficacy versus side effects

The overall model for the decision to continue or stop taking the prescribed AOD is shown in Figure 19.

FIGURE 19

Model 3: patient-led decision process regarding drug continuation. Source: White et al.

Participants continued with the medication for between 1 month and 8 years. Nine out of 12 were prescribed metformin, and one of six participants prescribed orlistat continued beyond 6 months. Seven young people discontinued an AOD. The decision to either continue with, or stop, the AOD was frequently based on a decisional balance between the efficacy of the AOD and ongoing side effects. The decision to terminate treatment was frequently described as a balance between the perceived benefits of the AOD and its side effects. Various mediators influenced this decision, including perceived benefits and expectations, lack of support and understanding of drug action:

I don’t want to take something that I don’t think was working and making me ill.
Young person 6, girl aged 14 years

I just thought what is the point of taking it if it is not working and I am not eating the rubbish foods, there is no point as it weren’t really doing anything.
Young person 3, girl aged 16 years

Participants described efficacy in terms of body weight, body shape and metabolic parameters. Individual goals varied from going down a clothes size to weight stabilisation. Most young people had expectations of weight control that were aligned with published outcomes, although some hoped for outcomes that were faster, more extreme or more guaranteed. Weight stabilisation was acceptable for some participants, and they continued to take it, fearing that their weight would increase faster if they stopped taking the medicine:

He [clinician] said that they may help me lose weight and my mind crossed out the word ‘may’ and replaced it with the word ‘will’.
Young person 9, aged 17 years

It is keeping her weight not going up.
Parent 10, young girl

There was significant variation in the understanding of drug action, in terms of mechanism and efficacy. Some perceived that the AOD required a restricted diet and increased exercise to be effective, while others believed that lifestyle changes were not necessary. These views seemed to be unrelated to the drug prescribed. Some described the futility of taking an AOD as they were unable to undertake healthy behaviours, and subsequently stopped the drug:

. . . they said this [the medicine] is not a miracle worker it doesn’t help you lose weight. You help yourself to lose weight and it just gives you a little pat on the back every so often to help you carry on what you need to do . . .
Young person 10, girl aged 14 years

I don’t know whether the tablet actually makes you lose weight or just because it makes you stop eating, it makes you lose weight.
Young person 2, girl aged 17 years

Drug termination was an active decision by young people and their families, and not by their doctor. The decision was taken by the young person alone, or with the advice and support of their parent. Very few young people or parents reported adequate drug monitoring and support from the obesity specialist; this influenced their decision to independently stop the drug:

She [Mum] advised me not to take them because it wasn’t very nice for me experiencing this.
Young person 6, girl aged 14 years

Young person:
I just stopped taking them, went cold turkey.

Interviewer:
What put you off ringing up the clinic to discuss it?

Young person:
I just didn’t think it was important.
Young person 15, boy aged 15 years

Support was a theme that spanned across all three models. One mother described the period taking the AOD as a ‘lonely’ time. Few reported adequate support from their obesity specialist, primary care physician or pharmacist. Two participants described disheartenment after being discharged from a specialist service due to inadequate progress, and reported subsequent weight gain. General practitioners mostly only issued repeat prescriptions. Many young people said that they would be happy to be monitored by their GP if they could not get an appointment at the specialist clinic, yet others felt that GPs had insufficient experience to support them. Emotional support mainly came from friends and family. Parental supervision, usually from a mother, ensured that younger adolescents took the medication. As young people matured, parents were more likely to step back and let the young person take responsibility for their medication:

I think there were times when she tried skipping it, but she had a dragon as a mother. So as long as I am aware it happens, and what I do now is put it all out in individual pill boxes for the day.
Parent 13, young girl

Discussion

These are the first published qualitative data on adolescent experiences of AOD use. In this sample, AOD prescriptions were uniformly suggested and initiated by specialist paediatricians, with passive acceptance by young people and families. After initiation, families mostly described receiving minimal support from the specialist prescriber as well as from local clinicians including GPs and pharmacists. There was a wide variation in the experience and tolerance of side effects, which were largely managed by families independently of clinicians using self-directed strategies. Although doctors made the decision to start the drug, we saw that patients decided to terminate the drug, usually because of insufficient benefit to justify the side effects.

Participants had a range of comorbidities, including depression and hypothyroidism, which may have impacted on their experience of AOD usage. Owing to the wide range of comorbidities and small numbers of each, it was not possible to explore more fully the interaction between these individual conditions and AOD usage.

Similar findings have been demonstrated in the adult studies exploring AOD usage. Qualitative study participants from three primary care practices reported that doctors initiated AOD, giving patients little choice in the decision and inadequate information about the drugs and related lifestyle changes.²¹⁶ Similar patterns of use have been reported in adults. Two previous studies showed that side effects were a major factor influencing adherence, and many adults report using the medication flexibly to fit in with their lifestyles, and minimise side effects at inappropriate times.²¹⁷^,²¹⁸ The highly visual side effects also encouraged some adults to consider their behaviour as a cause of their obesity and to adopt a healthier diet.²¹⁸ Similar themes for drug discontinuation were reported in these previous studies; participants who benefited from the drug continued with, or adapted, the medication, and those participants who did not lose weight abandoned it.²¹⁷ Similar themes have also been demonstrated in the adolescent adherence literature, with insufficient clinician support, embarrassment, insufficient belief in drug efficacy, interference with usual activities and side effects all being reported as barriers to medication adherence in other chronic conditions.²¹⁹

Results from this study offer insight into the experiences of young people who are taking AOD, and offer potential targets for change that could potentially improve drug adherence and outcomes in this patient population. They suggest that more careful approaches are needed to improve drug initiation and ongoing support. Potential strategies are summarised in Box 2.

BOX 2

Potential strategies to improve AOD initiation and ongoing support

Obesity is likely to be a lifelong disease for this cohort, given that current treatments have modest efficacy. Long-term drug use is likely to be an integral treatment modality in addition to behaviour modification strategies at both the individual and population level. Effective prescribing habits are needed to support both current and future generations of anti-obesity medications.

Limitations

Participants were recruited from three hospital clinics in England, with the majority from one hospital in which two of the authors are clinicians. This has the potential of limiting generalisability and introducing bias. However, AODs in young people are largely initiated in specialist centres, and those centres included in this study were among the largest of a very small number of specialist paediatric obesity clinics in the UK. To minimise bias, all data were collected by an independent researcher not part of any clinical team and responses were anonymised before analysis. Delays in the study may have led to problems with recall for those patients who stopped the medication some time previously. As with all qualitative studies, the researcher’s presence during interviews could have affected the subjects’ responses; every effort was made to reassure the participants that the researcher was both non-judgemental and not part of the clinical team, and their responses would be fully anonymised prior to analysis by the team. We aimed to include patients who were prescribed an AOD but never took it. However, no such young people responded to recruitment invitations. We are therefore unable to comment on those participants who were prescribed an AOD but who never initiated medication. Only a small minority of eligible subjects enrolled in the study, despite thorough attempts to contact them using clinical research nurses. It is highly possible that those with negative experiences felt more motivated to participate in the study. Largely negative responses indicate that participants are likely to have felt reassured about their anonymity, and did not fear reprisal from their clinicians.

Conclusion

Use of AOD is challenging and complex for many adolescents, and few young people in our study described positive experiences. Multiple factors were identified that could be targeted to improve medication concordance and maximise efficacy, including improved clinician–patient partnership in decision-making, and better patient education and subsequent support. Many of these are not unique to the current generation of AOD, and are likely to be relevant to novel drugs.

Bookshelf ID: NBK555455

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Viner RM, Kinra S, Christie D, et al. Improving the assessment and management of obesity in UK children and adolescents: the PROMISE research programme including a RCT. Southampton (UK): NIHR Journals Library; 2020 Mar. (Programme Grants for Applied Research, No. 8.3.) Chapter 5, Study D: evaluation of anti-obesity drug treatment in children and adolescents.
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