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Learning objectives
After reading this feature you should:
- Be familiar with the mode of action of GLP-1 receptor agonists
- Understand the NICE guidance on their use in weight management
- Be aware of the possible side-effects of these treatments and how to counsel patients to minimise them.
The term ‘obesity’ describes a condition characterised by an excessive or abnormal disposition of fat that presents a risk to health. It is defined in terms of body mass index (BMI) – a ratio of an individual’s weight (in kg) divided by their height (in metres squared).
The World Health Organization (WHO) classifies adults with a BMI greater than or equal to 25 as overweight and obese if their BMI is greater than or equal to 30. Among those defined as obese, there are three subdivisions: class 1 (BMI 30-34.9kg/m2); class 2 (BMI 35-39.9kg/m2) and class 3 (BMI of 40kg/m2 or more).
Over the last 20 years, obesity has become a worldwide public health crisis, with global prevalence having more than tripled since the 1970s. According to WHO, in 2022 one in eight adults (some 890 million people) were living with obesity. But obesity is not just an adult problem. In 2022, the WHO also estimated that around 160 million children aged between five and 19 years were living with obesity.
For some time now, the standard advice for those living with overweight or obesity has been to lose weight through dieting and increased physical activity. Although weight loss does occur through dieting, evidence suggests that the effects are relatively small. For instance, in a recent review of 14 randomised trials, the pooled mean difference in weight loss was only 2.4kg for interventions lasting between 13 and 26 weeks.
Key facts
- Over the last 20 years, obesity has become a global health crisis
- Demand for the latest class of anti-obesity medicines, the GLP-1RAs, is enormous
- These drugs have been shown to cause weight loss when used alongside a low calorie diet and physical activity.
Medicinal approaches to weight loss
In addition to dieting and higher levels of physical activity, there are a number of medicines that have been developed to aid weight loss.
In recent years, largely due to social media and celebrity endorsement, there has been global interest in the latest anti-obesity class of medicines, the glucagon-like peptide-1 receptor agonists (GLP-1RAs). Demand for these drugs has been enormous, with the worldwide market estimated to be worth 46.70 billion US dollars in 2024 and predicted to reach a staggering 322.85 billion US dollars a year by 2034.
A recent poll among US adults revealed that roughly one in eight said they had taken one of these drugs, and a survey of 1,000 UK women revealed that 72 per cent were considering using GLP-1RA drugs as an aid to weight loss in 2025.
Widening treatment access — will it happen?
In June 2023, the Government announced the creation of a two-year pilot that would examine the expansion of specialist weight management services outside a hospital setting.
On the face of it, the rationale for widening access to weight loss treatments appeared sensible. Any such service,
if successful, should result in a commensurate decrease in the number of individuals developing obesity-related complications, so reducing healthcare expenditure.
To date, however, it remains unclear whether or not the pilot study will begin. Given how NICE has endorsed primary care use of tirzepatide, this appears to have led to a huge number of online pharmacies offering all of the GLP-1RA drugs to patients, together with weight management support.
GLP-1 breakthroughs
The origin of GLP-1s can be traced to 1906, when researchers became aware that an extract from the intestine could lower blood glucose. Interest in this extract faded, however, following the discovery of insulin in 1921.
Renewed interest did not occur until 1986, when scientists identified how the intestinal extract contained GLP-1, a hormonal cleavage product of glucagon, which is secreted by the pancreas in response to a fall in blood glucose levels. Glucagon acts on the liver, stimulating the breakdown of glycogen and causing blood glucose levels to rise.
In 1987, it was shown that infusion of GLP-1 into healthy, fasted volunteers caused insulin levels to rise, with a subsequent reduction in plasma glucose. This was the first proof that our intestines were able to produce an incretin – i.e. something that could stimulate the pancreas to release insulin. At the time, whether incretins might be of value in the management of type 2 diabetes was unclear.
It wasn’t until the early 1990s that studies established how GLP-1 could be used as a type 2 diabetes treatment. A curious observation then found that intracerebroventricular injection of GLP-1 profoundly reduced food intake among fasted rats, suggesting that the hormone may also have a role in weight management.
While GLP-1 could potentially have a dual therapeutic role, researchers faced an enormous challenge: the plasma half-life of GLP-1 was only one to two minutes. Much effort was therefore directed towards modification of the molecule into a more stable analogue.
The first GLP-1RA, exenatide, was introduced in 2004, followed by liraglutide in 2009. Although liraglutide controlled type 2 diabetes and led to weight loss, early trials found that the drug gave rise to unacceptable side-effects, such as nausea. However, it was soon realised that these effects could be mitigated by slowly increasing the dose.
In 2015, a landmark trial published the New England Journal of Medicine showed that a once daily subcutaneous injection of liraglutide produced a more than 10 per cent weight loss in a third of those living with obesity and without type 2 diabetes.
Further modification of GLP-1 led to the creation of semaglutide and together with liraglutide, both drugs were later approved for type 2 diabetes and weight loss. In addition, the weight loss effect of semaglutide also improved cardiometabolic risk factors such as hypertension and cholesterol levels.
Today, there are five GLP-1RA agents available in the UK: dulaglutide, exenatide, liraglutide, lixisenatide and semaglutide. While the GLP-1 receptor was perceived as a primary target, other work focused on a second incretin that acted on the glucose-dependent insulinotropic polypeptide (GIP) receptor.
The drug tirzepatide (Mounjaro) was created and found to work as a dual GLP-1-GIP agonist, with trials suggesting that it could reduce body weight by more than 20 per cent.
How do GLP-1s work?
GLP-1 is a gut hormone released in response to food intake. Following a meal, GLP-1 stimulates insulin release and reduces glucagon secretion, hence its value in treating type 2 diabetes. But a second effect, which is relevant to weight loss, is that GLP-1 also acts to delay gastric emptying creating a sense of fullness, reducing appetite and calorie intake, and ultimately leading to weight loss.
Although there are several GLP-1RA drugs available, all of which are indicated for managing type 2 diabetes, only three are currently licensed for weight loss, as shown in Table 1 (above).
Managing adverse effects
Despite the potential for substantial weight loss, patients often find the adverse effects of GLP-1RA drugs intolerable. Typically, patients can experience nausea, vomiting, constipation, gastroparesis, dehydration and gallstones. It is worth remembering, however, that many of these adverse effects occur because of the drugs’ actions.
Delaying gastric emptying leads to feeling fuller for longer, but slowed digestion causes food to sit in the gut, leading to unpleasant symptoms.
This is why the dose of drug is increased gradually over several weeks, so that while patients do lose weight, they are not overwhelmed by the side-effects. Food intake may also need to be adjusted; eating smaller meals throughout the day avoids becoming too full, which may reduce nausea and other gastrointestinal adverse effects.
NICE guidance
Advice on the use of the three GLP-1 receptor agonists described in Table 1 has been provided by NICE.
In 2020, NICE recommended liraglutide to help manage overweight and obesity alongside a reduced calorie diet and increased physical activity in adults with a BMI of at least 35kg/m2 and non-diabetic hyperglycaemia. Liraglutide could also be used in those with a high risk of cardiovascular disease, based on risk factors such as hypertension and dyslipidaemia.
In 2023, NICE issued similar guidance for semaglutide, although this time, the duration of treatment was restricted to a maximum of two years and the drug could only be provided within a specialist weight management service.
The most recent guidance (December 2024) was for tirzepatide. While recommendations for use were similar, this time NICE suggested that the drug could be used in primary care as well as through specialist weight management services.
GPhC issues new guidance for online prescribing of weight loss drugs
Guidance from the General Pharmaceutical Council (GPhC) for pharmacies supplying medicines online was issued in 2022.
This advised pharmacists to carry out a risk assessment to identify whether treatment requests were appropriate and to ensure that staff were able to check the identity of patients. At the time, the list of medicines the GPhC felt were inappropriate for online supply did not include weight loss drugs.
However, revised draft guidance last year did include “medicines used for weight management and those known to be misused to achieve weight loss” as not suitable to be prescribed by a questionnaire model alone. There was a recommendation not to supply unless further safeguards had been put in place.
This month, the GPhC firmed up its recommendations in published guidance confirming that online pharmacies can no longer prescribe high-risk medicines, including weight loss drugs, based solely on information
from questionnaires. From now on, when someone requests such a medicine, the prescriber must do one of the following:
- Speak to the patient by phone or video call
- Access their clinical records
- Contact the patient’s GP, usual prescriber or a third-party provider.
For weight loss medicines, this means online prescribers must independently verify a person’s weight and/or BMI before making the decision to prescribe.
However, despite these additional safeguards, it remains impossible for online pharmacies to ensure that patients adhere to the dietary or physical activity advice included in the NICE guidance.
Is this an effective solution?
It is clear that this new class of anti-obesity drugs provides effective weight loss when used alongside a hypocaloric diet and increased physical activity.
In fact, trial data indicates how patients can lose as much as 5 per cent of their initial weight after only four weeks of treatment. Furthermore, although NICE has suggested restricting use of GLP-1RA drugs to only two years, evidence to date shows that adherence becomes suboptimal long before 12 months of use.
One recent study, for example, found that GLP-1 persistence was 46.3 per cent at 180 days and 32.3 per cent at one year. There is also considerable evidence revealing that once patients stop taking GLP-1RA drugs, they invariably regain lost weight.
A further and more relevant point is how obesity is inextricably linked to socioeconomic and demographic factors.
The GLP-1RA drugs can only ever serve to address the consequences and not the root causes of obesity. Nevertheless, if patients are able to lose some weight with these drugs, it might provide the necessary drive for them to persevere with lifestyle modification.
On the other hand, simply relying on pharmacotherapy without appropriate lifestyle changes is unlikely to counter the unhealthy habits that contributed to the weight gain in the first place. Consequently, the GLP-1RA drugs alone are unlikely to solve the obesity crisis.
The only way that GLP-1RA agents might provide a societal benefit to the obesity crisis is if they are provided via adequately funded multi- disciplinary primary care weight management services that also include behavioural support, access to exercise facilities and nutritional advice. Only then can such services be expected to have a noticeable effect on levels of obesity and, ultimately, its health-related consequences.
What’s on the menu...
Does calorie labelling encourage people to eat less when dining out?
In April 2022, it became a legal requirement for all larger restaurants and cafes to include calorie labelling on their menus.
At the time, it formed part of the Government’s obesity strategy and recognised the fact that diet – or at least eating too much – was a major cause of obesity and a contributor to the wide range of obesity-related co-morbidities. There is certainly some evidence to support this legislative change.
In a Cochrane review published in 2018, it was concluded – albeit from a small body of low quality evidence – that nutritional labelling of calorie or energy information on menus may reduce energy intake from food purchased in restaurants.
It has been a legal requirement for menus in the US to have calorie labelling since 2018, and it does appear to have made a difference.
In an analysis of over 330 million fast food items purchased in US chain restaurants, after 12 months the average calorie content of meals was 4.7 per cent lower than would have been expected if calorie information was not included.
Calories and composition
On the face of it, providing calorie information does seem likely to reduce people’s intake of food. However, while the calorie content of food has some value, it is much more important to consider the amount of protein, fat, salt and sugar contained within a food.
A problem with focusing solely on calories is the underlying and incorrect assumption that obesity is simply the result of an individual ingesting more calories than they expend. This simplistic explanation is not strictly correct.
The dietary composition of what we eat critically influences the accumulation of body fat more than calorie balance alone. Processed foods and those consumed in restaurants and cafes are often very energy dense, with a high glycaemic load and unhealthy amounts of dietary fat, sugar and salt. It seems that these foods can cause a hormonal imbalance in which there is sustained insulin secretion, and this leads to fat accumulation.
But what do diners think of calorie information and do they use it? One US study with 788 men and 1,042 women found that while 52.7 per cent said they noticed calorie information when buying a meal or snack in a restaurant, more than a third (38.2 per cent) said they did not use this information when deciding what to order.
When they did use the calorie information, it was to help them avoid high calorie food items (50.1 per cent).
Latest research
The most recent analysis was published in January by researchers from the Cochrane Library. The researchers included 25 studies, 18 of which were randomised controlled trials. Most were undertaken in real world settings such as restaurants and cafes, mainly in the US and UK.
The findings suggest that providing calorie information does lead to a selection of items that results in modestly reduced calorie intake.
The data found that for an average 600 kilocalorie (kcal) meal, adults exposed to calorie labelling would be more likely to select foods that were on average 11 kcal less and consume roughly 35 kcal less – the equivalent of around two teaspoons of sugar. Unfortunately, the researchers were unable to assess the impact of calorie labelling on people’s choices of alcoholic drinks, but they were confident in their conclusions based on the quality of the evidence.
The point of the latest analysis was to determine whether the provision of calorie labelling on menus influenced consumer behaviour and in the right direction. That is, when presented with calorie information, were individuals more likely to go for lower calorie food options?
While the average reduction in energy intake was small, if this behaviour was continued over time, there is a likelihood that individuals would ultimately take in less energy and potentially lose weight.
The findings are consistent with other research and therefore provide a rationale for adding calorie information to menus. Perhaps the next stage would be to use the traffic light system utilised for pre-packed processed foods, to provide individuals with even greater nutritional composition information to enable a more informed choice of meals.
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