Managing obesity with semaglutide

Semaglutide is a synthetic analogue of glucagon-like peptide one (GLP-1). GLP-1 is a hormone produced in the distal part of the small intestine – the ileum – in response to the presence of food. It stimulates insulin release from the pancreas and it acts as a satiety hormone to signal fullness to the brain.

The STEP1 trial was a randomised, placebo-controlled trial of semaglutide for obesity in people who did not have diabetes. The results showed that participants achieved a 16 percent weight loss after one year compared with about two percent weight loss on placebo.  At the time of publication this was “the most effective medication available for weight loss …….. it changed our thinking about obesity, it changed our expectations of obesity treatments”, says Professor Miras. The trial also showed that semaglutide 2.4 mg was well-tolerated with a favourable safety profile.

NICE appraisal of semaglutide for obesity

The GLP-1 agonists, first liraglutide (Saxenda) and now semaglutide, represent “a major revolution in the treatment of obesity”, says Professor Miras.

A single technology appraisal carried out by the National Institute for Health and Care Excellence (NICE) assessed the efficacy and cost-effectiveness of Wegovy (semaglutide) 2.4 milligrams for the treatment of obesity. It recommended that the medication should be available to people who have a body mass index over 35 kg/m² and at least one weight-related comorbidity.  It is also recommended for people with body mass indices of 30 to 35 kg/m² who also meet the criteria for referral to specialist weight management services.

The NICE guidance limits treatment to two years as semaglutide was not shown to be cost-effective for longer periods.  “That will create some more questions and some difficulties and challenges because we do not stop treatment for any other chronic disease and therefore there is no reason why we should do that for obesity”, says Professor Miras.

Obtaining and using semaglutide for obesity

Ideally, people seeking semaglutide treatment for obesity should be referred by their GP to a specialist weight management centre for treatment via the National Health Service. If this involves long delays some people may wish to seek a supply in the private sector. Professor Miras stresses the importance of having the support of a specialist weight management team in either situation.

Semaglutide will work on its own, without other measures, such as dietary changes, exercise or psychological interventions, but the combination can be additive or even synergistic.  The medication works is because it makes people change their diet. “The diet changes because of the drug ……. the vast majority of people will eat pretty much the same foods that they were eating before taking the medication but they would just eat less”, says Professor Miras. He also notes that the best way of enhancing the release of GLP-1 naturally is to eat high-protein meals.

Could semaglutide prevent cardiometabolic disease?

Obesity is a disease in which the mechanisms that normally control hunger and fullness are disrupted because of genetic mutations. The biological drivers that control body weight are very powerful. Approximately 70 percent of anyone’s body weight is determined by their genetic makeup and the other 30 percent depends on other environmental factors. It follows that treatment needs to be lifelong and not just for two years.

The SELECT trial is expected to show whether semaglutide has an impact on hard clinical outcomes. SELECT is a four-year trial, involving 17,000 participants with established cardiovascular disease, who were randomised to receive semaglutide 2.4 mg or placebo. The results are expected in Autumn 2023.

Disclosures:
Grants/Research Support: Fractyl, Novo Nordisk, Randox.
Other Financial or Material Support/Honoraria: Novo Nordisk, GI Dynamics, AstraZeneca, Boehringer Ingelheim, Currax Pharmaceuticals

Read and watch the full series on our website or on YouTube.

“Obesity in my opinion, and in the opinion of many scientific colleagues in the field, is clearly a disease”, says Professor Miras.  However, there is still controversy about this, he acknowledges.  He explains the factors driving obesity as follows:

“The reason why obesity is a disease is because we know that the biological drivers that control our body weight are very, very powerful. So, what we know is that approximately 70 percent of anyone’s body weight is determined by their genetic makeup and the other 30 percent depends on other environmental factors – therefore we cannot ignore such a big number. The genetic makeup of our appetite-regulation system sits in the brain and it sits in areas that control hunger and fullness. ……In the disease of obesity, the circuits that control hunger and fullness are disrupted because of genetic mutations. As a result, this causes the symptoms of obesity and the symptoms of obesity are high hunger and low fullness. …. Lots of us that are of normal weight are just lucky, we are not smarter and we are not more educated or hard working or have more willpower than those that do not. Now I’ve talked about the biological drivers but this doesn’t mean that we should ignore the other 30 percent or so of the environmental drivers of obesity. There are many of those and the correct way of treating the disease would be to address them, for example through healthy nutrition, access to physical activity, psychological support, social support etc.”

At the same time, environmental issues need to be addressed for the prevention of obesity in order to reduce the number of people that develop the disease in years to come.  “This is not just about treatment and it is not just about prevention, it is about doing both”, he adds.

One important question is whether the two-year treatment recommended in the NICE Technology Appraisal will effectively ‘retrain’ eating habits so that continuing treatment is not needed.  “I get asked this question about medications a lot as to whether our appetite centres in the brain can be trained with the medication or any treatment for obesity and the answer is largely no. We know not only from our own experience but also from randomised, controlled clinical trials that when the medication is stopped the vast majority of people regain the weight that they have lost. This is because, unfortunately, the medication or even bariatric surgery does not train the appetite centres of the brain to behave in a certain way”, he says. The drugs only work while they are there, similar to the way in which anti-hypertensive treatment works.  “Therefore, that means that the people who suffer with the disease of obesity need to be treated for life”, he emphasises.  This may involve different medications or even other forms of treatment. Whichever route is selected the effective treatments – be they medication, nutritional, psychological, or physical activity – need to be continued long term, he explains.

SELECT trial

The next logical question is whether the use of semaglutide for obesity might prevent cardiometabolic problems in future.  Professor Miras says:

“The great thing about what we have already discussed is that these medications for obesity, including semaglutide, have already been shown to reduce the number of people who develop diabetes, for example, they reduce blood pressure, cholesterol etc so their metabolic profile is very good”. The results of the SELECT trial are expected in Autumn 2023 and these should show whether semaglutide has an impact on hard clinical outcomes.  SELECT is a four-year trial, involving 17,000 participants with established cardiovascular disease, who were randomised to receive semaglutide 2.4 mg or placebo. “I was privileged to be to be contributing to this trial in my unit. This trial is coming to an end as we speak and we’re really looking forward to the results because they will really change the way that we deal with obesity – and we will now have evidence not only for risk factors for cardiovascular disease but actual hard outcomes”, he says.

Disclosures:
Grants/Research Support: Fractyl, Novo Nordisk, Randox.
Other Financial or Material Support/Honoraria: Novo Nordisk, GI Dynamics, AstraZeneca, Boehringer Ingelheim, Currax Pharmaceuticals

Read and watch the full series on our website or on YouTube.

“Since [semaglutide] is going to become available in the National Health Service I can see no reason why [interested people] should not seek a referral from the general practitioner to a specialist Weight Management Centre in order to be assessed and, hopefully, be given the medication”, says Professor Miras. If this option is not available or involves a long delay, then people may wish to seek a supply in the private sector. However, “If they are to do that, I would stress the importance of having a specialist weight management team that looks after them because it’s not about taking the medication for six months and then stopping it and seeing how things go”, he adds. People suffering from the disease of obesity need long-term treatment, ideally with the support of a multidisciplinary weight-management team, he emphasises. “So, again, I stress the importance of not using the DIY model of care”, he says.

Pharmacy supply

Supply of semaglutide at NHS expense, via a community pharmacy, could be possible if the community pharmacist is part of a specialist weight management team. The good thing about the NICE guidance is that it has deliberately left the details of the specialist weight management teams vague. Professor Miras hopes that some GPs will now set up weight management teams in the community in order to increase the access to the medication.

Natural stimulation of GLP-1 secretion

There is not yet a ‘natural’ way to stimulate the release of GLP-1.  Professor Miras explains that the hormone is produced in a group of cells predominantly found in the distal part of the small intestine – the ileum. These are entero-endocrine cells that respond to the presence of food in the lumen of the gut by secreting the hormone (GLP-1). “Now the best way we have at the moment of enhancing the release of GLP-1 is eating protein because what has been shown is that, as opposed to fat or sugar, high protein meals [elicit secretion of] more of this hormone for the same [number] of calories. So, protein is satiating and that’s why protein can cause weight loss and weight loss stability.  But apart from …. having a diet which is high in protein, at the moment we do not have anything else we can naturally do to produce more of that hormone, but I’m sure that that will also come”, he says.

Inevitably, some people will seek to use semaglutide on its own, without lifestyle modification but how well might this work? Professor Miras explains that the reason why the medication works is because it makes people change their diet. “The diet changes because of the drug ……. I mean that the vast majority of people will eat pretty much the same foods that they were eating before taking the medication but they would just eat less.  There is a smaller proportion of people that may also change the type of foods that they eat and this may enhance their weight loss”, he says.  Nevertheless, the support and guidance of a multidisciplinary team can personalise the treatment to optimise and enhance the biological effects of the drug. The combination of the drug with nutritional advice and physical activity has additive, and possibly synergistic effects, he concludes.

Disclosures:
Grants/Research Support: Fractyl, Novo Nordisk, Randox.
Other Financial or Material Support/Honoraria: Novo Nordisk, GI Dynamics, AstraZeneca, Boehringer Ingelheim, Currax Pharmaceuticals

Read and watch the full series on our website or on YouTube.

The GLP-1 agonists represent “a major addition” to the list of weight loss drugs. “You need to remember that since the 60s or so we’ve had some successes and many many failures in the field of obesity”, says Professor Miras.  “You also need to remember that in the UK, at least for approximately 10 years, the only medication we could use for obesity was orlistat which was not the easiest medication for people to take. So, since the introduction of Saxenda, and now with the introduction of Wegovy, we’re seeing a major revolution in the treatment of obesity taking place as we speak.  There is a lot more to do but the semaglutide addition is a really good step in the right direction”, he continues.

NICE technology appraisal

The National Institute for Health and Care Excellence (NICE) in the UK is an organisation that successes not only the efficacy but also the cost effectiveness of new therapies for any kind of disease and what they did in this single technology appraisal is that they assessed the efficacy and cost-effectiveness of Wegovy (semaglutide) 2.4 milligrams for the treatment of obesity, explains Professor Miras.  NICE guidance applies in England but it is also used in Wales and in Northern Ireland.   Because of the robustness of the appraisal process it also serves as a guide to many other countries, he notes.

The recommendation from this appraisal was that the medication should be available to people who have a body mass index over 35 Kg/m² and at least one weight-related comorbidity.  It is also recommended for people with body mass indices of 30 to 35 kg/m² who also meet the criteria for referral to specialist weight management services.  Adjustments for ethnicity need to be made in some cases.

Semaglutide will be available through specialist weight management centres – that is a group of clinicians that are trained in the in the treatment of obesity, explains Professor Miras.  “What is important to understand is that this group of clinicians does not necessarily have to [be based] in a hospital setting – they can be anywhere including primary care”, he says.  “This contrasts with the guidance for Saxenda, which very specifically said that it should be available from what is called tier 3 services in the UK, which are predominantly in secondary care. So, this is a major change and it [means that] the access to the medication will hopefully increase”, he adds.  It’s also important to note that eligibility for the drug will not be exactly the same as set out in the Summary of Product Characteristics (SPC) – which says that the drug is indicated for people with a BMI over 27kg/m² with a comorbidity or people with a BMI over 30 kg/m². “It’s important that people do not confuse the two and the second important thing to say is that the medication will be available for two years based on the cost effectiveness of the drug”, he says.  Beyond two years NICE calculated that it is no longer cost-effective and should be discontinued. “That will create some more questions and some difficulties and challenges because we do not stop treatment for any other chronic disease and therefore there is no reason why we should do that for obesity”, says Professor Miras.  “Overall, even though this is not perfect guidance, it is good guidance and we’ll just need to work around the challenges that it creates”, he concludes.

Disclosures:
Grants/Research Support: Fractyl, Novo Nordisk, Randox.
Other Financial or Material Support/Honoraria: Novo Nordisk, GI Dynamics, AstraZeneca, Boehringer Ingelheim, Currax Pharmaceuticals

Read and watch the full series on our website or on YouTube.

Semaglutide is a synthetic analogue of glucagon-like peptide one (GLP-1). It is a hormone produced in the intestine when we eat. “It does two things. It makes our pancreas produce insulin to reduce our blood glucose but it also signals to the brain fullness – so it is a satiety hormone”, explains Professor Miras. Experience of GLP-1 agonists over the past 16 years in the treatment of diabetes has shown that people not only see reduced glucose levels but also weight loss. The satiety-inducing effect therefore underpins the use of GLP-1 receptor analogues for the treatment of the disease of obesity.

Liraglutide, another GLP-1 receptor agonist, was launched some time ago and it differs from semaglutide in several respects. The use of this group of drugs started with products that had to be injected twice a day. Liraglutide was approved for obesity with the brand name of Saxenda, and this is injected once a day whereas semaglutide is injected once a week.

“What we know is that while this development has been taking place, the efficacy of the medications has been increasing.  So, liraglutide (Saxenda) …… can cause approximately eight percent weight loss at three milligram dose, …… whereas Wegovy, which is semaglutide 2.4 milligrams can cause almost 16 percent weight loss at one year”, says Professor Miras.

The STEP1 trial was a randomised, placebo-controlled trial of semaglutide for obesity in people who did not have diabetes.  “What they found was that the total percent weight loss at approximately a year or so after initiation of treatment was 16 with the medication is about as opposed to about two percent or so with placebo”, he explains.  At the time of publication this was “the most effective medication available for weight loss …….. it changed our thinking about obesity, it changed our expectations of obesity treatments”, he adds.

Moreover, it also showed that semaglutide 2.4 mg was well-tolerated with a favourable safety profile.  Common side-effects are gastro-intestinal including nausea, diarrhoea or constipation but these disappear with time in most people.  “Less than 10 or even less than five percent of people … have to discontinue treatment because of side effects”, says Professor Miras. There is also a small risk of developing gallstones and cholecystitis, but these are rare, he comments.

Disclosures:
Grants/Research Support: Fractyl, Novo Nordisk, Randox.
Other Financial or Material Support/Honoraria: Novo Nordisk, GI Dynamics, AstraZeneca, Boehringer Ingelheim, Currax Pharmaceuticals

Read and watch the full series on our website or on YouTube.