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A study published in Nature Medicine and an accompanying conference abstract and poster looks at long term weight loss effects of semaglutide in obesity without diabetes.
Commenting on both the Nature Medicine paper on semaglutide and longer-term weight loss; and the MACE unpublished abstract and poster looking at cardiovascular benefits:
Prof Bryan Williams OBE MD FMedSci, Chief Scientific and Medical Officer, British Heart Foundation, said:
“I think there are two aspects to this story that are important. First that longer term use of this approach for the treatment of obesity appears safe for up to four years. Second that the treatment is reported to significantly reduce the risk of death from heart diseases. The latter confirms what we have long suspected, notably, that the increase in the risk of a number of cardiovascular diseases associated with obesity will be reversed is weight is reduced. This is likely to relate to a number of mechanisms, including improved blood fat profiles, lower blood pressure, less diabetes and less inflammation related to all of the above.
“A lot has been made of the potential benefit “beyond weight loss” but my view is that in reality, this is all likely to be due to the reversal of the abnormal and damaging biology of obesity by reversing the weight gain.”
Commenting on both the Nature Medicine paper on semaglutide and longer-term weight loss; and the MACE unpublished abstract and poster looking at cardiovascular benefits:
Prof Tricia Tan, Professor of Metabolic Medicine & Endocrinology, Imperial College London, said:
“SELECT was a well conducted randomised controlled trial which looked at the effects of semaglutide on cardiovascular disease events in people without diabetes, who were overweight or obese (body mass index >27) and with pre-existing cardiovascular disease.
“It is remarkable that they were able to do this trial in a wide range of people all over the world, although people from the African continent continue to be under-represented as they are in many other international trials. Nevertheless, the results are highly applicable to many people across the world and more importantly to UK and its multi-ethnic communities.
“It is very encouraging that continued treatment for 4 years or so is effective in helping people to lose weight at a clinically significant level of 10% on average. Previously, the only evidenced and effective long-term treatment for obesity was weight loss surgery where we have evidence that surgery is capable of giving long-term weight loss for 20 years or so. This trial helps to support the idea that Semaglutide is effective at least in the medium-term.
“The implication of these results for people in the UK is as follows: firstly, I feel that we need to update our NICE guidelines for semaglutide treatment, which presently only mandate treatment for up to 2 years, to increase the length of funding to at least 4 years if not more. Secondly, we also need proper funding from the NHS to implement the specialist clinics necessary for us to effectively deliver these life-saving and cost-effective medications.
“It is also encouraging to see that people who are technically ‘”overweight” as defined by a body mass index <30 also benefit from protection from cardiovascular disease events as well as those who are obese (body mass index >30). Not only that, even people who do not lose >=5% of weight seem to benefit as well. This is important, as it tells us that there may be beneficial effects of semaglutide (and other similar medications) on heart disease which do not depend on weight loss. This has an implication for our current NICE guidance, which tells us to stop semaglutide treatment in people who have not lost more that 5% of weight when reviewed at 6 months. It may be that we should continue treatment in people who have had cardiovascular disease, even if they don’t lose as much weight as we would like.
“In summary: these new results, although not yet published, have important implications for our current practice in the UK. Based on these findings, I feel that NICE recommendations should now be changed to take into account these important findings, and we should properly treat obesity as a long-term condition that requires long-term treatment.”
Commenting on just the unpublished abstract and poster looking at cardiovascular benefits:
(please note Prof Wilding was an author on the Nature Medicine paper looking at longer-term weight loss with semaglutide (also part of the SELECT trial); here he is commenting only on the MACE study on cardiovascular outcomes) Prof John Wilding, Professor of Medicine & Honorary Consultant Physician, Department of Cardiovascular and Metabolic Medicine, University of Liverpool, said:
“This is a robust analysis of a large clinical trial with over 17000 participants from over 40 countries so is relevant to many people with overweight / obesity who have cardiovascular disease. It is consistent with the results seen in similar studies with semaglutide and other GLP1 RA in people with type 2 diabetes and now extends these findings to people without diabetes.
“This detailed analysis of the SELECT data shows that the effects of semaglutide on cardiovascular disease go beyond the effects on weight and BMI and provide further evidence (in addition to that which already exists for semaglutide and other GLP1RA in diabetes), that these medicines have significant benefits for people with pre-existing CVD that are at least partly independent of weight loss.”
Commenting on the unpublished abstract and poster looking at cardiovascular benefits:
Prof Rameen Shakur, Professor of Genomics and Precision Cardiovascular Medicine, University of Brighton, said:
“This convincing dataset from the SELECT trial has a lot of implications on how we manage chronic disease in global populations as we battle obesity and the ancillary implications of it. One point I would like to state is that although this data is part of the SELECT trial, this new data is looking at additional outcomes as part of that trial. We are unclear on the mechanism and biological process by which semaglutide might reduce cardiac mortality per se. One could argue this was to be expected given if you improve diabetes control and also reduce weight – which are drivers of a pro inflammatory process involved in not just cardiovascular but also most cancers – then one should see a reduction. I don’t think it is commercially realistic to put whole populations on a medical therapy until you know how the biological system works. Interestingly, there remains a risk of pancreatitis and some rare thyroid cancers which is often not stated and this should also be monitored during the course of patient use.”
Prof Sir Martin Landray, Chief Executive Officer, Protas, said:
Context:
“The UK has one of the highest prevalences of obesity in Europe. In 2021, more than a quarter of middle-aged adults in England were classified as obese and a further 40% as overweight. Survey data suggest that the prevalence of obesity is not evenly distributed across the country, with higher rates in the North and Midlands than London and the South. Prevalence appears to be higher in areas of greater deprivation and among people with disabilities, lower levels of education or of Black ethnicity. In 2020, there were almost 11,000 hospital admissions directly attributable to obesity. Within England, there has been a significant increase in obesity among the most deprived communities and rates of obesity-related hospital admissions are 2-3 times greater in the most deprived areas compared to the least deprived areas. Obesity is associated with an increased risk of multiple co-morbidities including cardiovascular disease, diabetes, musculoskeletal disorders, cancers, polycystic ovary syndrome, COVID-19, depression and anxiety, and an increased risk of overall mortality. [Please note that among people with lower than normal BMI, the relationship between BMI and health outcomes is quite different – in other words the lowest risks are among those in the normal range with risks increasing for those with BMI below that or – as is the case in the population in this trial – above that. It is a U-shaped relationship.]
What’s already known?
“Previous trials of the GLP-1 agonist weight loss drugs have largely focused on patients with diabetes. The results of the SELECT trial were first published in November 2023. It included over 17,000 patients who (a) were overweight or obese, (b) did not have diabetes and (c) already some form of cardiovascular disease. The main trial results (from last November) showed that semaglutide (the GLP-1 agonist being studied) reduced the risk of a composite major adverse cardiovascular events (defined as death from cardiovascular disease, non-fatal myocardial infarction or non-fatal stroke) by comparison with placebo. That is good news.
What’s new?
“This new report of the same trial now looks at those results and asks the question of whether the size of those effects differs markedly depending on baseline body mass index. In other words, does this treatment work similarly across the range of BMI studied? The answer is yes – the proportional reduction in major adverse cardiovascular events is similar across the range studied. The results are in line with what is seen in observational studies of the relationship between higher BMI and higher risk of cardiovascular disease: A meta-analysis of prospective studies by the Global BMI Mortality Collaboration, mostly in high-income countries, of 4 million never-smokers without chronic disease found that each 5 kg/m2 increase in BMI above 25 kg/m2 (the upper limit of the normal range) was associated with 31% higher all-cause mortality and 42% higher cardiovascular mortality. The results are important since they suggest that, if the drug were affordable and widely available, then it could be used to reduce the risk of cardiovascular events among a very broad range of people who already have cardiovascular disease in order to prevent future cardiovascular events (much like we do with statins and treatments for blood pressure).
“This is a subsidiary analysis of a large randomised trial. The findings relating to treatment effects for people with different levels of BMI at baseline are appropriate and reasonably convincing. I am much less convinced about the appropriateness of the analyses based on the level of weight loss achieved – these appear to be non-randomised assessments (there aren’t suitable control groups).
So what don’t we know?
“Importantly, this trial opens up the question: To what extent might these new GLP-1 agonist weight loss drugs impact the broader range of potential clinical and potentially societal / economic benefits (e.g. on symptoms of breathlessness and arthritis, the need for major joint replacements) among the much greater number of people who have neither diabetes nor cardiovascular disease? Could this treatment be useful in primary prevention – reducing the risk of not just cardiovascular events but many other diseases in people who are overweight or obese but who have not (yet) had cardiovascular disease? Answering that question will require suitably large, inclusive and long-term trials. The answers could change the way we treat obesity in much the same way that our approach to hypertension and cholesterol has evolved over the last few decades.
Diet and non-pharmacological measures?
“Although this and other results relating to the GLP-1 agonist drugs are remarkable, we must accelerate the pursuit of non-pharmacological policy efforts to improve diet and reduce the development of obesity in the first place.”
Commenting on the Nature Medicine paper looking at longer-term weight loss:
Dr Simon Cork, Senior Lecturer in Physiology, Anglia Ruskin University, said:
“This is an important study because it adds further evidence to the discussion on the decision (certainly by the UK health service) to limit prescription to 2 years. We know that weight regain is very common in patients who stop taking semaglutide after this time, but we didn’t (until now) have any safety data or proof that weight would remain off. It was assumed that weight plateau would continue but hasn’t been shown until now. Importantly one of the decisions by the UK health service to limit to 2 years was because of questionable long term cost effectiveness. That this data demonstrates improved cardiovascular and metabolic parameters continuing to 4 years may go some way to negating that argument.
“This study also neatly demonstrates that obesity is a lifelong condition and the decision by NICE to limit prescription to 2 years (whilst they acknowledge its limitations) does a disservice to patients suffering with obesity.”
Nature Medicine paper: ‘Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial’ by Donna Ryan et al. was published in Nature Medicine at 23:01 UK time on Monday 13 May.
DOI: https://doi.org/10.1038/s41591-024-02996-7
Unpublished conference poster and abstract: ‘Relevance of Body Weight and Weight Change on Cardiovascular Benefit with Semaglutide: A Pre-specified Analysis of the SELECT Trial’ was also presented at the conference with the same embargo time of 23:01 UK time on Monday 13 May 2024. There is no full paper but the abstract and poster are available.
Declared interests
Prof Bryan Williams: “No conflicts related to this.”
Prof Tricia Tan: “I am a former shareholder and founding member is Zihipp Ltd, an imperial college spin out company that develops similar drugs for obesity.”
Prof John Wilding: “I am not an author of the Deanfield study. I was an investigator for SELECT trial and also an author of the weight loss in SELECT manuscript that was published in Nature Medicine at the same time as the Deanfield study.
John Wilding reports consultancy / advisory board work for the pharmaceutical industry contracted via the University of Liverpool (no personal payment) for Altimmune, AstraZeneca, Boehringer Ingelheim, Cytoki, Lilly, Napp, Novo Nordisk, Menarini, Pfizer, Rhythm Pharmaceuticals, Sanofi, Saniona, Tern, Shionogi & Ysopia; research grants for clinical trials from AstraZeneca and Novo Nordisk and personal honoraria / lecture fees from AstraZeneca, Boehringer Ingelheim, Medscape, Napp, Novo Nordisk and Rhythm.
He is past president of the World Obesity Federation, a member of the Association for the Study of Obesity, Diabetes UK, EASD, ADA, Society for Endocrinology and the Rank Prize Funds Nutrition Committee. He is national lead for the Metabolic and Endocrine Speciality Group of the UK NIHR Clinical Research Network.”
Prof Rameen Shakur: “I have no pharma declarations.”
Prof Sir Martin Landray: “Protas is a non-profit company established to facilitate large clinical trials to address common diseases
No current conflict of interest in relation to treatments for obesity.”
Dr Simon Cork: “No CoI to declare.”