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A study published in the New England Journal of Medicine (NEJM) looks at the use of the drug semaglutide to treat obesity.
Prof Keith Frayn, Emeritus Professor of Human Metabolism, University of Oxford, said:
“Attempts to find a drug to aid weight loss have a long history. Many drugs have been tried, but most have been abandoned because of limited effectiveness or because of side-effects. This study shows clinically meaningful weight loss, using a drug of a family with a good safety record in the treatment of Type 2 diabetes. The metabolic improvements observed were impressive, but were largely those expected from the weight loss. It will be crucial now to gather longer-term data to see if that weight loss can be maintained.”
Prof Tom Sanders, Professor Emeritus of Nutrition and Dietetics, King’s College London, said:
“This is a carefully conducted study in severely obese patients and shows that this peptide drug aids weight loss. The limitation is that it needs subcutaneous injections of the drug on a weekly basis and common side effects were nausea and diarrhoea. Gastrointestinal disorders were also much more frequent in those on the active treatment. While this study shows that patients on active treatment do lose a lot of weight it does not show what happens when treatment stops. The challenge post weight loss is to prevent a regain in weight. While drug like this may prove useful in the short term for obtaining rapid weight loss in severe obesity, they are not a magic bullet for preventing or treating less severe degrees of obesity and public health measures that encourage behavioural changes such as regular physical activity and moderating dietary energy intake are still needed. It is rather like the situation we are in with the vaccine, we still need to stick with public health measures and not become overdependent on medicines.”
Dr Baptiste Leurent, Assistant Professor in Medical Statistics, London School of Hygiene and Tropical Medicine, said:
“This study by Wilding and colleagues is a randomised placebo-controlled trial of once-weekly semaglutide injection in obese adults. This international trial enrolled nearly 2,000 participants and found a significantly higher weight loss in the semaglutide group. The results are impressive: after one year the participants receiving semaglutide had lost on average 15 kg, compared to 3kg in the placebo group. Two in three had manage to lose over 10% of their starting weight. The study was very well conducted, with in my opinion no reason to question these findings. Given the nature of the study, this difference can be directly attributed to an effect of the semaglutide treatment. A particular challenge in weight loss trial is to follow-up everyone, to make sure that it is not only the highly motivated who remain at the end. This trial managed to follow 90% of the participants, which is as good as you can get.
“However, there was some side effects related to the treatment, particularly gastrointestinal disorders (nausea, diarrhea, etc.), which will need close monitoring. We also need to better understand what is happening once the treatment is stopped, and whether it could be taken for a shorter period of time.
“In conclusion, this was a well-designed study with unequivocal findings. Semaglutide is indeed likely to be a game changer in the fight against obesity.”
Dr Jennifer Logue, Associate Dean (Research), Faculty of Health and Medicine, and Reader in Metabolic Medicine, Lancaster University, said:
“This is a randomised trial of a medication that is currently used for type 2 diabetes but is also known to decrease appetite and support weight loss for people with obesity. It is an injection, given by the patients at home once per week. In this study they randomly allocated participants to either the medication or a placebo injection and everyone got diet and exercise counselling every 4 weeks and kept a food and activity diary. This means that the results should be free of bias.
“In showing a strong effect (14.9% weight loss on average) and reasonable tolerability (4.5% of people taking the medication had to stop due to side effects, though they were still part of the final results), this medication fills a huge gap in our treatment for people with obesity. Current weight management programmes delivered by local authorities and the NHS aim for a 5% weight loss and there are no other effective treatments in use except for bariatric (weight loss) surgery, which results in a 20% weight loss or more. Many people do not want bariatric surgery, and access is still limited in the NHS, yet most people with obesity have already been on several diets, losing and regaining weight. This medication allows us to have an additional treatment option to help reduce risk, and improve health and quality of life for people with obesity.
“In the UK we will have an issue using this medication as we have a severe shortage of specialist weight management programmes and trained specialists to deliver it. It does not simply need prescribed – we need dieticians, psychologists, physicians and physical activity specialists to ensure that the results seen in this trial are replicated in the NHS. The trial participants were 74% female and 75% white Caucasian which may not represent those at highest risk of diabetes or heart disease, and they are all volunteers who sought out the research opportunity; increased support will be required to get the highest needs populations into services and fully benefitting from these medications. Even without this medication, this is something that needs urgent action; the effect of ignoring obesity treatment has been apparent during the coronavirus pandemic, with people with obesity at higher risk of severe disease, hospitalisation and death.”
Dr Simon Cork, Senior Lecturer in Physiology, ARU, said:
“On the surface, obesity would seem to be a simple condition to treat. Reduce calorie intake and increase calorie expenditure to reduce body mass. However the multiple physiological systems that interplay to regulate appetite and body weight make this remarkably difficult, which is why losing weight through diet and exercise alone is very tough and often leads to disappointingly low levels of weight loss for individuals. The holy grail of obesity treatment is a drug which can utilise our physiology to naturally drive down appetite and body weight.
“The results of this study show that significant body weight reduction with once weekly injections, using drugs that mimic our bodies own appetite suppressing mechanisms offer real promise in reducing body weight in those with obesity. This is a very well conducted study using a large cohort of individuals who have obesity and who have been unable to lose significant weight through lifestyle modifications alone.”
Prof Sir Stephen O’Rahilly MD FRS FMedSci, Director of the MRC Metabolic Diseases Unit, University of Cambridge, said:
Relevant background
“Obesity is an increasingly common condition which can be disabling in itself but also strongly predisposes to premature death and disability from diabetes, cardiovascular diseases and certain cancers.
“Obesity occurs when food intake chronically exceeds energy expended and has become more common largely because palatable food, in large amounts, is more readily available and affordable than ever before.
“People predisposed to obesity find it difficult to achieve and maintain significant weight loss as their biological drives to eat tend to be stronger than those whose tendency is to remain lean. These drives become even stronger after they have lost weight through dieting, which makes keeping weight off very hard.
“For obvious reasons, finding an effective and safe appetite suppressant to treat obesity has been a “holy grail” of obesity research for many decades.
“Many previous promising candidates have failed either because they were not very effective, or if they were, had dangerous side effects.
“The results presented in this paper suggest that semaglutide is very effective as a weight loss agent and that, while it does have side effects, these are predictable, reversible and not sufficiently serious to raise significant alarm.
“The Danish pharmaceutical company, Novo Nordisk, who are the manufacturers of semaglutide, have, for many years, been developing modified forms of a natural hormone GLP-1 for the treatment of Type 2 diabetes. GLP-1 is made by cells in the intestine and levels increase in the blood after a meal, providing some of the signal to the brain that tells us we are “full”. They found that these drugs caused significant loss of weight by suppressing appetite. Semaglutide is their latest version and appears to be a particularly effective suppressor of appetite. They have made it into a form that can be injected weekly.
Results of study
“In a trial of about 1000 people, average age 47, mostly white and about 75% female who were either obese (most participants) or overweight with associated medical problems, two thirds were given a once weekly injection of semaglutide and one third were given a placebo injection. Neither the participants nor the doctors treating then knew who got what.
“After 15 months the people given placebo lost 2.6 kg (nearly 6 lbs) (this commonly happens with placebo in trials for weight loss as people are very motivated to lose weight). The people given semaglutide lost an average of 15.3kg (~34 lbs or more than 2 and a half stones). This weight loss showed significant benefits in all the blood tests which indicate risk of cardiovascular disease and diabetes.
“People given semaglutide did have more frequent side effects, especially nausea, vomiting and diarrhoea through these were mostly classified as mild to moderate and only ~4.5% of people stopped taking the drug because of these. A higher percentage of people in the semaglutide group reported problems with gallstones. Rapid weight loss is known to be associated with the development of gallstones and the complications of having gallstones so it is hard to know whether this side effect is due to the semaglutide or whether it would happen with any agent that produced rates of weight loss of this magnitude. Three people in the semaglutide group and none in the placebo group reported acute pancreatitis, a potentially serious and life threatening condition sometimes caused by gallstones. This is not a statistically significant difference but is worthy of note. Unlike some previous appetite suppressant drugs which caused significant psychological and psychiatric side effects there is no evidence that semaglutide has any adverse effects of that nature.
Conclusions
“In people who are obese, once weekly semaglutide produces highly significant weight loss with major benefits on risk factors for diabetes and heart disease. The amount of weight loss achieved is greater than that seen with any licensed anti-obesity drug.
“This study shows that it is possible to develop an appetite suppressing medicine which can cause sustained weight loss over a period of 15 months, associated with substantial health benefits.
“Side effects are common and while they are mild in most people they can be troublesome in a significant number.
“This is the start of a new era for obesity drug development with the future direction being to achieve levels of weight loss comparable to semaglutide, while having fewer side effects.”
Prof Naveed Sattar, Professor of Metabolic Medicine, University of Glasgow, said:
“This is a large impressive trial result, and could be a game changer. Losing more than around 10kg in weight (achieved by around 70%) can lead to measurable health gains across many diseases, some relatively promptly, with an improvement in physical functioning. The trial drug, semaglutide, as with similar drugs, does lead transient increase in nausea and vomiting but that <5% of people prescribed stopped treatment due to this, suggests the drug is generally well tolerated. Of course, there remains a strong place for lifestyle changes and the community is getting better at helping people lose weight by such measures, but for those who do not lose sufficient weight, or need to lose more, it is reassuring that new classes of drug, like semaglutide are now coming forwards and offer a “chemical” satiety boosting drug or appetite suppressant, that could help achieve greater weight loss than current tools in our armoury. There are other similar drugs in development but these new data are hugely encouraging. Ongoing trials will tell us if these drugs lessen cardiovascular disease and future cost effectiveness analyses are needed to determine relevant criteria for when such drugs are affordably adopted in care.”
Dr Duane Mellor, Registered Dietitian and Senior Teaching Fellow, Aston Medical School, Aston University, said:
“This is a potentially significant clinical trial showing a drug which is already available for use with people with type 2 diabetes can be effective to support people in their efforts to lose weight. However, as with many promises of amazing weight loss, we need to be clear that in this study the weekly injection of semaglutide did not lead to weight loss on its own, people changed their lifestyles as well. All participants in the study followed a 500kcal per day energy deficit (common in many weight loss programme) and were encouraged to increase physical activity to 150 minutes per week. So, it is perhaps better to say this semaglutide can support someone’s efforts to lose weight, and perhaps helps them to lose more weight than they would have done otherwise.
“The study (and the press release) perhaps overplays some of the findings, firstly the idea that more people are losing more than 20% of their body weight when they took semaglutide for 68 weeks; this is an outcome not described on the trials registration. This could suggest this was not a planned result of the study and could suggest a risk of reporting bias. Additionally the claim that 35% of people on semaglutide lost 20% or more of their starting body weight is based on the people that completed the trial, not everyone who took started the study and may have withdrawn for some reason. This is important as they report that around 80% adhered to the study treatment, suggesting 1 in 5 may not have followed the treatment for the 68 weeks. This is important especially when discussing weight loss studies, as many people know losing weight is hard to do, especially over the long term. A more reliable estimate would be the just over 30% of people who completed the study who lost more than 20% of their initial weight, as this accounts for both those who could keep following the treatment, as well as those who could not, for whatever reason. As with many weight loss studies, it should not be forgotten that those on the placebo also did well with over 1 in 10 losing more than 10% of their starting weight which is likely to have given their health a significant boost.
“The study also reported on side-effects, which occurred in both people who took semaglutide and the placebo. However there were more side effects linked to gallstones and nausea with the semaglutide, this is similar to other studies of this drug. It is interesting that the paper did not report on effects of the study on a marker called calcitonin. This was listed as a secondary outcome of interest in trial registration (https://clinicaltrials.gov/ct2/show/NCT03548935) as this is important, as the type of drug semaglutide is, a GLP analogue have been linked to thyroid and similar cancers in studies of similar drugs. So, although there were no links to thyroid cancer, it is unfortunate the details of this marker were not included in this study.
“Overall, it is useful to have a potential option to help people lose weight, however we need to acknowledge that weight loss will still need lifestyle change, and that with any medication or change in lifestyle can bring potential risks and side effects. So, it is always wise to speak to a health professional before trying to lose weight. It also highlights that when trying to lose weight support is important, the people in this study had regular contact and advice during the study which can help people to achieve weight loss, so if you are planning to lose weight it is best not to try to do it alone!”
Dr Amelia Hollywood, a health psychologist from the University of Reading said:
“It is promising to hear that there is another potential weight loss medication that can be offered to patients, as currently the only one that has proved to be safe and effective is orlistat. This will be good news for clinicians and patients. However it is worth noting that individuals did not just simply inject this medication and lose weight, they also had to change their behaviour.
“The trial included a lifestyle intervention which involved diet and physical activity counselling. It would appear that along with orlistat, the key information to note is that they also require behaviour change and the medication is just a tool to facilitate weight loss. Individuals need to be supported to change their behaviour in relation to diet and physical activity, in order to lose weight.”
‘Once-Weekly Semaglutide in Adults with Overweight or Obesity’ by John P.H. Wilding et al. was published in the New England Journal of Medicine at 22:00 UK time on Wednesday 10 February 2021.
Declared interests
Prof Keith Frayn: “I have no conflict of interest to declare.”
Prof Tom Sanders: “Honorary Nutritional Director, HEART UK & Member of Science Committee, British Nutrition Foundation.”
Dr Baptiste Leurent: “No conflict of interest.”
Dr Jennifer Logue: “I an in receipt of consultancy fees from Novo Nordisk.”
Dr Simon Cork: “I have no conflicts of interest to report.”
Prof Sir Stephen O’Rahilly: “SOR has a current research collaboration with Novo Nordisk scientists in an unrelated area. He has, in the past, been a remunerated consultant for the company but is not currently.”
Prof Naveed Sattar: “NS has consulted for Novo Nordisk, Eli-Lilly, Pfizer, Sanofi, and Astrazeneca. He was also a co-investigator in in lifestyle trials such as DiRECT.”
Dr Duane Mellor: “Duane Mellor has previously undertaken research and analysis for Diet Chef and Slimming World as well as supporting clinical trials of a number of weight loss and diabetes medications.”
Dr Amelia Hollywood: “My PhD was funded by Roche (2006-2009) who used to make orlistat, but that drug is no longer under licence and has gone generic.”