People Judge Weight Loss More Harshly When GLP-1 Drugs Are Used, Study Finds
Key Takeaways:
- People using GLP-1 and other anti-obesity medications were consistently judged more negatively than those losing weight through diet and exercise alone.
- Researchers found that anti-obesity medication users were perceived as putting in less effort and were therefore viewed as less moral, competent, warm, and deserving of their success.
- The findings suggest that stigma surrounding obesity treatment may discourage people from seeking effective medical care and reinforce harmful misconceptions about obesity and weight loss.
Study explores social attitudes toward weight loss medication
A recent study published in Scientific Reports has found that people who lose weight using anti-obesity medications (AOMs), including glucagon-like peptide-1 (GLP-1) receptor agonists, are often judged more harshly than those who lose weight through diet and exercise alone.
The research examined how the use of anti-obesity medication influences perceptions of effort, morality, competence, warmth, and deservingness. The findings suggest that social attitudes toward obesity treatment remain strongly shaped by beliefs about personal effort and self-control.
With more than one billion people worldwide living with obesity, the researchers noted that how a person loses weight can significantly influence how others perceive them. Although GLP-1 receptor agonists and other anti-obesity medications have demonstrated substantial effectiveness in treating obesity, they are frequently criticised as an “easy way out.”
According to the researchers, this perception reflects a broader psychological phenomenon known as effort moralization – the tendency to associate greater effort with greater moral worth.
The authors explained that such beliefs may reinforce obesity stigma, discourage people from seeking treatment, and negatively affect both physical and mental health outcomes.
While anti-obesity medications can provide important medical support for people living with persistent obesity, the researchers stressed that understanding the social impact of these perceptions is necessary if the full potential of these treatments is to be realised.
Four studies conducted across three countries
The research involved four pre-registered experimental studies conducted between November 2024 and February 2025 in Belgium, the United States, and the United Kingdom.
In total, 1,205 participants took part in the research. Participants were recruited online through university participant pools and the Prolific platform. Researchers applied several quality-control measures, excluding incomplete responses, failed attention checks, overly rapid responses, and participants with insufficient language proficiency.
Across the studies, participants were presented with descriptions of two individuals who shared identical weight-loss goals and similar experiences with diet and exercise. The only difference between the individuals was that one used an anti-obesity medication while the other did not.
Participants then rated both individuals using Likert-type scales assessing:
- Perceived effort
- Moral character
- Warmth
- Competence
- Deservingness of weight-loss success
- Willingness to cooperate with them in future scenarios
The researchers also explored several additional variables across the studies, including:
- General attitudes toward anti-obesity medication
- Personal or social experience with weight-loss medication
- Beliefs that anti-obesity medication represents a “shortcut”
- Personality traits measured using the Big Five Inventory (BFI)
To analyse the data, the researchers used t-tests, correlations, multilevel modelling, and evidence synthesis techniques.
Anti-obesity medication users viewed more negatively
Across all four studies, the findings revealed a consistent pattern of negative social judgement toward individuals using anti-obesity medication.
Compared with people relying solely on diet and exercise, anti-obesity medication users were perceived as putting in less effort into achieving their weight-loss goals.
This perception of lower effort was strongly linked to harsher moral evaluations. Participants consistently rated anti-obesity medication users as less moral than non-users.
In Study 1, for example, significantly lower perceived effort ratings for anti-obesity medication users were accompanied by similarly large reductions in moral character ratings.
The bias extended beyond morality alone.
Participants also viewed anti-obesity medication users as:
- Less competent
- Less warm
- Less deserving of their success
In addition, participants reported lower anticipated satisfaction with future cooperation involving anti-obesity medication users in a hypothetical training-partner scenario.
According to the paper’s evidence synthesis, most of these effects were large, although the effect relating to warmth was more moderate.
Perceived effort was closely tied to moral judgement
One of the most significant findings was the strong relationship between perceived effort and moral judgement.
Across all four studies, larger differences in perceived effort between medication users and non-users were associated with larger differences in moral evaluations.
The researchers concluded that perceptions of effort appear to play a major role in shaping broader social judgement.
The findings support the idea that many people continue to associate moral worth with visible personal struggle and self-discipline, particularly in relation to body weight and weight loss.
“Shortcut” beliefs intensified negative bias
The study also examined factors that influenced the strength of these perceptions.
Participants who held more positive views toward anti-obesity medications, or who had prior personal or social experience with such treatments, tended to judge medication users less harshly.
In contrast, stronger beliefs that anti-obesity medication represents a “shortcut” to weight loss were associated with more negative moral judgements.
In some analyses, these shortcut beliefs also amplified the relationship between perceived effort and bias.
The researchers found that personality traits such as conscientiousness and extraversion had little overall effect on participants’ judgements. This suggests that the bias is driven more by beliefs about effort and treatment legitimacy than by broader personality characteristics.
One exploratory analysis identified a small association with neuroticism, although this effect was limited.
Meta-analytic evidence synthesis across the studies confirmed that most effects were large, particularly for:
- Perceived effort
- Moral judgement
- Competence
- Cooperation satisfaction
- Deservingness
Effects relating to warmth were moderate by comparison.
Findings highlight social challenges surrounding obesity treatment
The researchers concluded that using anti-obesity medication is not simply a medical decision, but also a social one that may expose individuals to stigma and negative judgement.
According to the findings, people using anti-obesity medications are frequently perceived as putting in less effort and are therefore judged as less moral, less competent, and less deserving of success.
Although the studies were based on vignette scenarios rather than real-world interactions, the researchers stated that the findings point toward a widespread bias rooted in effort moralization.
They suggested that these attitudes could influence interpersonal relationships, healthcare experiences, and broader public perceptions of obesity treatment.
The authors argued that addressing these misconceptions is important for improving healthcare quality and reducing obesity-related stigma.
They also suggested that public education and changes in the way weight loss is discussed may help shift attention away from perceived effort and toward health outcomes and overall well-being.
CCH insights:
Unfortunately, this shows that there is still a very poor understanding of obesity amongst the general public, which means that biased, negative attitudes towards people with excess weight persist. Instead of being seen as medical tools to treat a complex chronic condition, GLP-1 medications are seen by many as short-cut for weight loss cheats. Current evidence suggests these attitudes are common even within the health professions. To improve the quality of obesity care, and to encourage those who need help to seek it, these misconceptions must be addressed.
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Adding Weekly GLP-1 to CBT Further Reduces Heavy Drinking
Key Takeaways:
- A new randomised controlled trial found that weekly semaglutide injections combined with cognitive behavioural therapy significantly reduced heavy drinking days in people living with obesity and alcohol use disorder.
- Participants receiving semaglutide experienced a 41.1% reduction in heavy drinking days, which was notably greater than the reduction seen in the placebo group.
- Researchers say the findings add to growing evidence that GLP-1 receptor agonists may have therapeutic potential beyond weight management, including in the treatment of substance use disorders.
Study suggests GLP-1 therapy may help address alcohol use disorder
A team of researchers from the National Institutes of Health (NIH), Copenhagen University Hospital, and international collaborators has reported the first evidence from a randomised controlled clinical trial showing that a GLP-1 receptor agonist may help reduce heavy drinking in people living with both obesity and alcohol use disorder.
The findings, led by researchers at Copenhagen University Hospital, contribute to a growing body of research suggesting that GLP-1 receptor agonists such as semaglutide may have applications beyond obesity and type 2 diabetes treatment, including potential use in substance use disorders.
Alcohol use disorder remains significantly undertreated worldwide, despite its substantial impact on physical health, mental health, and mortality. Current pharmacological treatment options are limited and often underused in clinical practice.
“Very few medications are currently approved for alcohol use disorder, and these are vastly underutilized. A new option that is more accessible and more effective could be a gamechanger for closing the treatment gap,” said Director of NIH’s National Institute on Alcohol Abuse and Alcoholism (NIAAA) George Koob, Ph.D., a study co-author.
Increasing interest in GLP-1s for addiction and substance use disorders
In recent years, researchers have become increasingly interested in the possible role of GLP-1 receptor agonists in addiction medicine.
GLP-1 drugs were originally developed for type 2 diabetes and later became widely used for obesity management due to their effects on appetite regulation, satiety, and weight reduction. However, emerging research has suggested these medications may also influence the brain’s reward pathways and reduce cravings or compulsive behaviours associated with substance use disorders.
Previous studies examining GLP-1 therapies in alcohol use disorder have produced mixed findings. One recent clinical trial found that a GLP-1 receptor agonist did not significantly reduce heavy drinking across the entire study population. However, researchers observed that participants living with obesity appeared to respond particularly well.
The latest study was designed specifically to investigate this subgroup.
Trial focused on people living with both obesity and alcohol use disorder
The research team enrolled 108 treatment-seeking adults living with alcohol use disorder and comorbid obesity.
All participants received standard cognitive behavioural therapy (CBT), which is a commonly used psychological treatment for alcohol use disorder that aims to help people identify and modify harmful thought patterns and behaviours associated with drinking.
Participants were then randomly assigned to receive either:
- Weekly semaglutide injections
- A placebo injection
The intervention lasted for 26 weeks.
Throughout the study period, researchers collected self-reported alcohol consumption data and monitored several quantitative biomarkers associated with alcohol use. These biological measurements were used to support and validate the participants’ reported drinking behaviour.
Semaglutide group experienced larger reduction in heavy drinking
At the end of the study, the researchers found that participants receiving semaglutide experienced a substantial decline in heavy drinking days.
According to the findings:
- The semaglutide group showed a 41.1% reduction in heavy drinking days
- This represented a 13.7% greater reduction compared with the placebo group
Importantly, biomarker data measuring alcohol exposure supported the self-reported reductions in drinking behaviour, strengthening confidence in the results.
Researchers also observed improvements in several cardiometabolic measures among participants receiving semaglutide. As expected based on previous obesity trials, reductions in body weight and blood pressure were more pronounced in the GLP-1 treatment group.
Researchers note mild and temporary side effects
The study authors reported that semaglutide was generally well tolerated.
Some participants experienced adverse effects, primarily gastrointestinal symptoms, which are commonly associated with GLP-1 receptor agonists. However, the researchers noted that these symptoms were generally mild and transient.
No unexpected safety concerns were highlighted in the report.
Potential clinical impact compared with existing medications
The investigators also evaluated the treatment’s number needed to treat (NNT), a standard clinical metric used to estimate how many people need to receive a treatment for one person to benefit.
In this study, semaglutide achieved an NNT of 4.3.
The researchers noted that currently approved medications for alcohol use disorder typically have an NNT of 7 or higher, suggesting semaglutide may potentially produce clinically meaningful benefits more frequently than existing therapies.
While the authors stressed that further research is needed before definitive conclusions can be drawn, the findings are likely to increase interest in GLP-1 therapies as a possible future treatment option for alcohol use disorder.
“We’re beginning to see some of that potential for GLP-1s to treat drug addiction turn into reality. Questions remain but this is nonetheless very encouraging,” said Director of NIH’s National Institute on Drug Abuse (NIDA) and study co-author Nora Volkow, M.D.
Larger and longer studies still needed
Despite the encouraging findings, the researchers emphasised that additional studies will be necessary to confirm the results.
Future research will need to assess:
- Whether the effects persist over longer periods
- How GLP-1 therapies perform in larger and more diverse populations
- Which patient groups are most likely to benefit
- Whether similar effects are seen in people without obesity
The authors stated that they hope to examine the effects of GLP-1 receptor agonists over a longer duration and in larger study populations in future investigations.
The scientific team was led by first author Mette Kruse Klausen, M.D., and corresponding author Anders Fink-Jensen, D.M.Sc., at Copenhagen University Hospital.
CCH insights:
These results are very promising, suggesting GLP-1 medications offer an effective treatment option for some people with obesity and alcohol use disorder (AUD). However, these patients would need careful monitoring in terms of diet and nutrition. People with AUD are susceptible to nutrient deficiencies because they get most of their calories from alcoholic drinks. If they eat less than usual due to appetite suppression induced by GLP-1 therapy, there is a risk of exacerbating these deficiencies.
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New Study Suggests Semaglutide May Reduce Epilepsy Risk in Adults with Type 2 Diabetes
Key Takeaways:
- Initiating semaglutide was associated with a significantly lower risk of developing epilepsy or seizures compared with other glucose-lowering therapies.
- The observed effect does not appear to be primarily driven by improvements in blood glucose or body weight.
- Findings are preliminary and should be interpreted as an early signal rather than a basis for changing clinical practice.
Background – seizure risk in type 2 diabetes
People living with type 2 diabetes mellitus face a higher risk of developing seizures and epilepsy. This increased risk is thought to be partly driven by inflammatory processes that affect the central nervous system. While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are primarily used for glucose regulation, there has been growing scientific interest in their potential neurological effects.
However, until now, the relationship between GLP-1 RAs and seizure risk has remained unclear.
Study design and population
The findings were presented at the American Academy of Neurology Annual Meeting, held in Chicago from April 18 to 22, 2026.
Researchers conducted a retrospective study using a target trial emulation approach, drawing on data from the National Institutes of Health All of Us Controlled Tier Dataset. The analysis focused on adults aged 18 years and older with type 2 diabetes mellitus who initiated one of the following treatments between December 2018 and December 2021:
- Semaglutide
- Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors)
- Other glucose-lowering therapies
Participants were followed through to December 2023.
To ensure comparability between groups, inverse probability of treatment weighting was applied to balance baseline characteristics. Time-to-event analyses were then used to assess the risk of developing epilepsy or seizures.
Cohort characteristics
A total of 393,596 individuals met eligibility criteria. Within this population:
- 8,533 individuals were included in the semaglutide versus other glucose-lowering drug comparison (2,397 vs 6,136)
- 7,455 individuals were included in the semaglutide versus SGLT2 inhibitor comparison (1,650 vs 3,725)
Key findings – reduced risk of seizures
After statistical adjustment, initiation of semaglutide was associated with a lower risk of epilepsy or seizures compared with both comparator groups:
- Compared with other glucose-lowering drugs:
- Hazard ratio: 0.46
- 95% confidence interval: 0.25–0.83
- P = .010
- Compared with SGLT2 inhibitors:
- Hazard ratio: 0.44
- 95% confidence interval: 0.22–0.86
- P = .017
These findings suggest a meaningful reduction in relative risk among those initiating semaglutide.
Absolute risk reduction and clinical interpretation
Further modelling provided estimates of absolute risk reduction:
- Compared with other glucose-lowering therapies:
- Absolute risk reduction: -0.014
- Number needed to treat: 69
- P < .001
- Compared with SGLT2 inhibitors:
- Absolute risk reduction: -0.008
- Number needed to treat: 129
- P < .001
These results indicate that, while the relative risk reduction is notable, the absolute reduction in risk remains modest.
Mechanisms – not driven by glycaemic control alone
To explore potential mechanisms, the researchers conducted mediation analyses. These analyses assessed how much of the observed effect could be explained by changes in glycated haemoglobin or body mass index.
The results showed that:
- Glycated haemoglobin accounted for only 1.1% of the effect compared with other glucose-lowering drugs and 3.6% compared with SGLT2 inhibitors
- Body mass index contributed 0.3% or less in both comparisons
This suggests that the reduced seizure risk may not be primarily driven by improvements in glycaemic control or weight loss, pointing towards other possible mechanisms.
Expert perspective
Yoonhyuk Jang, MD, PhD, Postdoctoral Fellow in the Department of Immunology at Harvard Medical School, commented on the findings:
“This study suggests that semaglutide may be associated with a lower risk of adult-onset seizures or epilepsy in patients with type 2 diabetes, with the signal appearing more pronounced in late-onset cases among adults aged 60 years or older.”
He added:
“Given that age-associated brain insults are major contributors to adult-onset seizures and epilepsy, these findings may have implications beyond seizure risk alone and raise the possibility that semaglutide could also be relevant to broader brain health; however, because this was a retrospective target trial emulation with a relatively small number of events, it is not yet practice-changing and should instead be viewed as a signal that supports further research into the role of GLP-1 receptor agonists in epileptogenesis.”
Limitations and future directions
The authors emphasised that the study design was observational, despite using advanced statistical methods to emulate a clinical trial. As such, causality cannot be definitively established.
Additionally, the relatively small number of seizure events limits the strength of the conclusions. These findings should therefore be interpreted cautiously and seen as hypothesis-generating.
Further prospective and randomised studies will be needed to determine whether GLP-1 receptor agonists such as semaglutide have a direct role in reducing seizure risk or influencing broader neurological health.
Disclosures
One study author reported affiliations with biotechnology, pharmaceutical, or device companies. Full disclosure details are available in the original study source.
Source: Neurology Advisor
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Can Less Be More? Reduced GLP-1 Dosing May Sustain – and Even Enhance – Weight Loss
Key Takeaways:
- Structured reduction in GLP-1 receptor agonist dosing frequency may allow continued weight loss while lowering treatment burden
- Cardiometabolic improvements achieved during weekly dosing appear to be maintained with less frequent dosing
- Early evidence suggests some individuals may not require high or frequent dosing to sustain weight loss, although larger trials are needed
A new approach to GLP-1 treatment
Emerging evidence suggests that reducing the frequency of glucagon-like peptide-1 receptor agonist (GLP-1 RA) dosing may still deliver sustained benefits for people living with obesity. Data presented at the Obesity Medicine Association’s annual conference indicate that a structured, gradual de-escalation strategy could maintain, and in some cases enhance, weight loss outcomes while reducing the burden of ongoing treatment.
This finding challenges the prevailing assumption that continuous, high-frequency dosing is required to preserve the benefits of these therapies.
Continued weight loss despite reduced dosing
The research, led by Mitch Biermann, MD, PhD, examined outcomes in individuals who transitioned from weekly GLP-1 RA dosing to less frequent schedules. Reflecting on the results, Biermann noted:
“What I found was actually surprising, where in addition to losing weight initially on the weekly regimen, people actually lost further weight on the every-other-week regimen,” Mitch Biermann, MD, PhD, an obesity medicine physician and scientist at Scripps Health, told Healio. “I was just hoping people would break even, not get an additional 2% weight loss.”
This observation suggests that, for some individuals, reduced dosing frequency does not simply preserve prior weight loss but may contribute to further reductions.
Addressing a common patient concern
The study was partly motivated by a frequent question from patients considering GLP-1 therapy. As Biermann explained:
“The No. 1 question patients have when they’re deciding to start one of these medicines is, ‘Do I have to be on this every week for the rest of my life? Do I have to take this forever?’” he said. “Patients ask that about certain medicines and not others. It usually correlates with the stigma around the disease. They always ask about it for weight loss medicine.”
This highlights an important dimension of obesity care – long-term treatment expectations and the role of stigma in shaping patient concerns.
Study design and patient cohort
The analysis was based on a retrospective case series involving 30 adults who had been prescribed either semaglutide (Wegovy or Ozempic) or tirzepatide (Mounjaro). All participants had experienced a plateau in weight loss during standard weekly treatment.
Participants agreed to reduce their dosing frequency while maintaining their effective dose. The adjusted schedules included:
- Every 10 to 14 days (n = 6)
- Every two weeks (n = 17)
- Longer than every two weeks (n = 7)
The mean follow-up period was 36 weeks.
Body composition and weight outcomes
Following the transition to reduced dosing, participants continued to lose weight, with reported reductions of 72.4 ± 2.2 kg (P < .01). In addition to overall weight loss, improvements were observed in body composition:
- Reductions in body fat mass
- Decreases in average percentage body fat
- Lower truncal fat mass
At the same time, skeletal muscle mass increased slightly from 30.33 ± 1.27 to 30.63 ± 1.25, suggesting that weight loss was not associated with disproportionate muscle loss.
Sustained cardiometabolic benefits
Importantly, key metabolic improvements achieved during weekly dosing were maintained after reducing treatment frequency:
- Glycaemic control: HbA1c improved from 5.6% ± 0.13% before treatment to 5.1% ± 0.1% during weekly dosing (P < .001), with no change during reduced dosing
- Triglycerides: Levels decreased from 121 ± 11.3 mg/dL to 84.3 ± 9.6 mg/dL during weekly dosing (P < .001) and remained stable at 74.8 ± 4.1 mg/dL
- Mean arterial pressure: Reduced from 90.5 ± 2 mm Hg to 84.8 ± 2.1 mm Hg (P < .05), remaining stable at 85.1 ± 1.5 mm Hg during maintenance
The proportion of participants meeting criteria for metabolic syndrome also declined, from nearly 83% before treatment to 68% during weekly dosing and 58.6% following dose reduction.
Interpreting the findings
The study authors suggest that lower levels of GLP-1 receptor stimulation may be sufficient to maintain weight loss once it has been achieved. Biermann offered the following interpretation:
“that you don’t need much of these hormones to maintain weight loss, even though you need a lot of them to reduce weight.”
He also drew a parallel with physical activity:
“Exercise doesn’t cause people to lose a ton of weight. It causes people to maintain their weight if they lose it by another method for the most part,” he said. “And that matches this hormone data, because that 30% increase [in hormone levels] you get on GLP-1s from exercise is probably enough to maintain your weight loss.”
Limitations and considerations
The findings should be interpreted cautiously. The study was small, non-randomised, and based on a retrospective case series. In addition, the cohort lacked diversity, with only four participants not identified as white and just two individuals living with class II or III obesity.
These limitations mean that the results may not be generalisable to broader populations.
Implications for clinical practice
Despite its limitations, the study offers a potentially important insight into long-term obesity management. Gradual dose reduction may represent a viable strategy for some individuals seeking to balance efficacy with treatment burden.
As Biermann concluded:
“I think it’s an option that works for many people, [particularly] when we don’t study how to stop medicine in general,” Biermann told Healio.
“I think it’s nice to have some published data on the average effectiveness of this strategy, even though it’s not a randomized controlled trial,” he said.
Looking ahead
Further research, particularly large-scale randomised controlled trials, will be essential to determine whether reduced dosing strategies can be safely and effectively implemented in routine care. For now, these findings provide an early signal that long-term GLP-1 therapy may not need to follow a one-size-fits-all model.
Source: Healio
Gut Microbiome May Shape Responses to GLP-1 Therapies in Obesity and Type 2 Diabetes
Key Takeaways:
- The gut microbiome may contribute to why people respond differently to GLP-1 receptor agonists, although causality remains unproven
- GLP-1 therapies and associated weight loss can alter gut microbial composition, but findings are inconsistent
- Dietary and behavioural changes during treatment are likely key drivers of microbiome shifts rather than direct drug effects
Emerging link between the gut microbiome and GLP-1 treatment response
A recent review published in the Canadian Journal of Physiology and Pharmacology highlights growing interest in the role of the gut microbiota in shaping responses to glucagon-like peptide-1 receptor agonists, commonly referred to as GLP-1 RAs. These medications are widely used in the management of people living with type 2 diabetes and those living with overweight or obesity.
The analysis suggests that gut microbial communities and their metabolites may contribute to the variability observed in treatment responses. At the same time, GLP-1 receptor agonists may themselves influence the composition of the gut microbiota. This bidirectional relationship positions the microbiome as both a potential contributor to treatment variability and a possible future target for more personalised metabolic therapies.
The gut microbiome as a regulator of metabolic health
There is increasing evidence that gut microbes play an active role in metabolic regulation. Preclinical studies using faecal microbiota transplantation have demonstrated that microbial communities can transfer traits such as glucose regulation and body mass. However, findings in human studies have been less consistent.
Despite the widespread use of GLP-1 receptor agonists, research exploring their interaction with the human gut microbiome remains limited. This is particularly notable given the considerable variation in how individuals respond to these treatments. Differences in microbial composition may partly explain this variability, although a definitive causal relationship has not yet been established.
In the review, researchers examined potential interactions between GLP-1 therapies, diet, gastrointestinal symptoms, body weight, and gut microbial composition.
Interactions between GLP-1 signalling and gut microbes
GLP-1 is a naturally occurring hormone that regulates appetite and blood glucose levels by binding to the GLP-1 receptor. It is released by L-cells in the intestine following nutrient intake. Because this release occurs in the lower intestine, GLP-1 operates in close proximity to the gut microbiota, raising the possibility of direct interaction.
Microbial metabolites such as bile acid derivatives and short-chain fatty acids can influence endogenous GLP-1 secretion and activity. These findings suggest that gut microbes may play a role in modulating GLP-1 signalling pathways. However, direct evidence demonstrating that microbial composition determines treatment response to GLP-1 receptor agonists in humans remains limited.
GLP-1 therapies may also indirectly affect the microbiome through changes in appetite, gastrointestinal motility, and dietary intake.
Clinical effectiveness of GLP-1 receptor agonists and variability in response
GLP-1-based therapies including liraglutide, semaglutide, and tirzepatide are now well established in the treatment of type 2 diabetes and obesity. Clinical trials have demonstrated significant weight loss outcomes:
- Tirzepatide – approximately 11.9–17.8% greater weight loss than placebo over 72 weeks
- Semaglutide – approximately 12.4% greater weight loss over 68 weeks
- Liraglutide – approximately 8.0% weight reduction compared with placebo over 56 weeks
Despite these results, individual responses vary widely. Differences in the gut microbiome have been proposed as one potential contributing factor, although this remains an area of ongoing investigation.
Microbiome changes associated with GLP-1 therapies
GLP-1 receptor agonists may influence gut microbial composition in people living with type 2 diabetes and obesity. Historically, obesity has been associated with a higher Firmicutes-to-Bacteroidetes ratio. Some studies suggest that weight loss is linked to increased microbial diversity and a greater abundance of beneficial genera such as Akkermansia.
Clinical observations include:
- Increased Akkermansia levels after six weeks of liraglutide therapy
- Increased levels of Bacteroidota, Actinobacteriota, and Proteobacteria following 12 weeks of semaglutide
- A reduction in Firmicutes in some cohorts
However, these findings are based on a limited number of heterogeneous studies. Many have involved people living with type 2 diabetes who were also taking other medications such as metformin, which is known to independently influence the gut microbiome.
GLP-1 receptor agonists, when combined with lifestyle modification, can lead to approximately 8–20% body weight reduction over several months to one year. Nevertheless, reported microbiome changes remain inconsistent. Some studies show increased diversity, while others report minimal or no significant changes.
Dietary changes during treatment and their microbiome impact
Evidence suggests that observed microbiome shifts may largely reflect downstream effects of weight loss and metabolic improvement rather than direct drug–microbiome interactions.
GLP-1 therapies are associated with changes in eating behaviour, including reduced appetite, increased satiety, and altered taste perception. People using these medications often improve their dietary patterns, with reduced consumption of refined grains, processed foods, beef, and sugar-sweetened beverages. Caloric intake may decrease by approximately 16–39%.
In 2025, organisations including The Obesity Society, American College of Lifestyle Medicine, American Society for Nutrition, and Obesity Medicine Association issued clinical guidance emphasising the importance of nutritional assessment and management of gastrointestinal side effects during GLP-1 therapy.
This guidance recommends prioritising nutrient-dense foods such as vegetables, fruits, whole grains, lean proteins, seeds, and nuts, while limiting refined carbohydrates, sugar-sweetened beverages, red and processed meats, fast foods, and highly processed snacks. Given the strong influence of diet on gut microbial composition, these dietary changes are likely to play a significant role in shaping the microbiome during treatment.
Future directions and research priorities
The review concludes that current evidence points towards behavioural and dietary changes, alongside weight loss, as the primary drivers of microbiome alterations observed during GLP-1 receptor agonist therapy.
However, the gut microbiome remains a promising area for future research. Microbiome profiling could eventually help predict treatment response more accurately in people living with obesity and type 2 diabetes.
Future studies should include:
- Larger and more diverse populations
- Longitudinal monitoring of microbiome changes
- Inclusion of people living with obesity who do not have diabetes
- Detailed tracking of dietary intake, gastrointestinal symptoms, and treatment adherence
Emerging therapies such as oral GLP-1 receptor agonists and new agents like orforglipron may offer further insight into direct interactions between medications and gut microbes, particularly as orally administered drugs come into direct contact with the gastrointestinal tract.
Understanding these relationships may ultimately support more personalised and effective approaches to obesity and diabetes care.
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Semaglutide and Bimagrumab Combination Shows Greater Weight Loss While Preserving Muscle Mass
Key Takeaways:
- A phase 2 clinical trial found that combining semaglutide with the antibody bimagrumab produced greater overall weight loss while largely preserving lean body mass.
- Participants receiving the two-drug combination lost 22.1% of body weight on average, with over 90% of the reduction coming from fat mass.
- The findings highlight the importance of focusing on body composition rather than weight alone when evaluating treatments for people living with obesity.
Combining two mechanisms to improve obesity treatment
A recent clinical trial has found that combining the GLP-1 receptor agonist semaglutide with bimagrumab, an antibody that blocks activin signalling pathways, may produce greater weight loss while preserving lean body mass.
The findings were reported in the paper “Bimagrumab and semaglutide alone or in combination for the treatment of obesity: a phase 2 randomized clinical trial”, published in the journal Nature Medicine. The study describes the results of the BELIEVE trial, led by Dr Steven Heymsfield of the Pennington Biomedical Research Center.
GLP-1–based therapies have become highly effective tools for reducing body weight in people living with obesity. However, a recognised limitation of these therapies is that up to 40% of the weight lost may come from lean mass, which includes skeletal muscle and connective tissue.
The BELIEVE trial explored whether combining semaglutide with bimagrumab could address this issue by enhancing fat loss while protecting lean body mass.
Why lean mass preservation matters
Historically, obesity treatment has often focused on reductions in body weight as the primary outcome. However, researchers increasingly emphasise the importance of preserving muscle mass, which plays a vital role in both physical function and metabolic health.
Dr Heymsfield explained that maintaining lean mass could be particularly important for people living with obesity who may already be at risk of low muscle mass.
“Obesity treatment has traditionally focused on the number on a scale. Patients with obesity who are at risk for low muscle mass, affecting both physical and metabolic function, may benefit from treatments that maximize fat mass reduction while preserving skeletal muscle,” said Heymsfield, who is an LSU Boyd Professor and director of the Metabolism and Body Composition Laboratory.
He also highlighted the complementary biological mechanisms of the two drugs.
“Bimagrumab and semaglutide work through distinct biological pathways, and when combined, we observed not only a preservation of lean mass but also an additive reduction in fat mass that exceeded what either therapy achieved alone.”
Design of the BELIEVE phase 2 trial
The BELIEVE study was designed as a double-blind, placebo-controlled clinical trial evaluating the effects of semaglutide and bimagrumab used either alone or in combination.
Participants were randomly assigned to several treatment groups:
- Bimagrumab only
- Semaglutide only
- Combination therapy
Each medication was also administered at two different dosing levels:
- Bimagrumab: 10 mg/kg or 30 mg/kg
- Semaglutide: 1.0 mg or 2.4 mg
Because of these dosing combinations, the trial ultimately included nine randomised groups.
Bimagrumab was administered every 12 weeks, while semaglutide was given once weekly. Participants were followed over a 72-week treatment period.
Weight loss and body composition outcomes
The results showed clear differences between the treatment groups in terms of both total weight loss and the composition of that weight loss.
Participants receiving bimagrumab alone experienced an average weight reduction of 10.8%. Notably, all of this reduction was attributable to fat mass, while lean mass increased by 2.5%.
Those treated with semaglutide alone lost an average of 15.7% of body weight, with 71.8% of the weight loss coming from fat mass.
The most striking results were seen in participants receiving the combination therapy. These individuals experienced an average weight loss of 22.1%, with 92.8% of the weight reduction attributable to fat mass, while lean mass was largely preserved.
These findings suggest that the combination therapy may offer a way to achieve substantial reductions in body weight while maintaining the muscle mass that supports metabolic health and physical function.
Improvements in metabolic and inflammatory markers
Beyond weight loss and body composition, the study also identified several favourable metabolic changes.
Participants experienced up to an 83% reduction in high-sensitivity C-reactive protein (hsCRP), an inflammatory marker that is associated with increased cardiovascular risk.
The study also reported a substantial increase in adiponectin, a hormone that plays an important role in:
- Improving insulin sensitivity
- Supporting fat metabolism
- Promoting anti-inflammatory processes
Among participants who had indicators of prediabetes at baseline, some of the groups receiving the two-drug combination experienced complete reversion to normoglycaemia, meaning all participants in those groups moved from a prediabetic state to normal blood glucose levels.
Safety and tolerability
Overall, the drug combination was generally well tolerated by participants. Reported side effects were broadly consistent with the known safety profiles of the individual drugs.
However, researchers noted that participants receiving bimagrumab experienced some common adverse events, including:
- Mild-to-moderate acne
- Muscle spasms
The study authors emphasised the need for continued clinical development and further investigation to better understand these effects.
Moving beyond the number on the scale
The BELIEVE trial also underscores a broader shift in how obesity treatments may be evaluated in the future.
Rather than focusing solely on weight or body mass index, researchers increasingly argue that body composition measures, such as the proportion of fat mass and lean mass, provide more meaningful insight into treatment effectiveness and overall health outcomes for people living with obesity.
Funding and study oversight
The study was funded by Eli Lilly and Company. The trial was originally designed by Versanis Bio, a wholly owned subsidiary of Eli Lilly.
Versanis Bio oversaw the clinical trial and provided partial funding before its acquisition by Lilly.
CCH insight:
The results for bimagrumab are very exciting. Although overall weight loss was less for bimagrumab than semaglutide, the amount of fat lost was very similar, but with retention or even increase of muscle mass. As muscle is an important metabolic tissue, you can argue that in this case the lesser weight loss is a better outcome than the higher weight loss, because the weight that is retained is muscle, not fat.
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Semaglutide’s Cardioprotective Effects Extend Beyond Weight Loss, SELECT Trial Confirms
Key Takeaways:
- Semaglutide significantly reduced major adverse cardiovascular events (MACE) in adults with overweight or obesity and established cardiovascular disease, regardless of baseline body weight.
- Reductions in waist circumference contributed partly – but not fully – to the observed cardioprotective benefits, suggesting mechanisms beyond weight loss.
- Early divergence in cardiovascular outcomes between the semaglutide and placebo groups indicates that benefits emerge rapidly after treatment initiation.
Semaglutide’s impact on heart health goes beyond weight loss
A landmark study published in The Lancet has revealed that semaglutide, a Glucagon-Like Peptide 1 Receptor Agonist (GLP-1RA), offers cardiovascular protection in people with overweight and obesity that cannot be explained by weight loss alone. The findings come from the large-scale SELECT trial, which explored the drug’s effect on major adverse cardiovascular events (MACE) in individuals without diabetes but with established cardiovascular disease.
GLP-1 receptor agonists were originally developed for glycaemic control in type 2 diabetes but have since demonstrated additional benefits, including weight reduction and decreased cardiovascular risk. Obesity itself increases cardiovascular mortality and morbidity through metabolic, inflammatory, and haemodynamic pathways. However, simple measures such as body weight fail to differentiate between fat and lean mass or between subcutaneous and visceral fat – the latter being more strongly associated with cardiovascular disease.
Until now, the relationship between changes in adiposity induced by GLP-1RAs and subsequent cardiovascular outcomes has remained unclear.
About the SELECT trial
The SELECT trial was a randomised, double-blind, placebo-controlled, phase 3 study evaluating whether semaglutide, used alongside standard care, could reduce cardiovascular events in adults with overweight or obesity. The trial enrolled 17,604 participants aged 45 years or older with a body mass index (BMI) of at least 27 kg/m² and established cardiovascular disease (defined as a history of myocardial infarction, stroke, or symptomatic peripheral artery disease).
Participants were randomly assigned to receive either once-weekly semaglutide injections or a placebo, with a gradual 16-week dose escalation to a target of 2.4 mg from week 17 onwards. The primary endpoint was MACE – a composite measure including non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death.
Researchers analysed both baseline measures of adiposity (including waist circumference and body weight) and treatment-induced changes over time. Associations between these factors and MACE were assessed using a Cox proportional hazards model, with additional analyses distinguishing early (week 20) and long-term (week 104) effects.
Key findings
The mean follow-up period was nearly 40 months, with participants exposed to semaglutide for an average of 33.3 months and placebo for 35.1 months. Across all baseline body habitus measures, semaglutide reduced MACE incidence compared with placebo.
Higher baseline BMI was associated with female sex, younger age, non-Asian nationality, higher blood pressure, prediabetes, and greater inflammatory burden. Within both study arms, individuals with lower baseline adiposity had a lower MACE risk. In the semaglutide group, MACE risk fell by approximately 4% for every 5 kg reduction in baseline weight, although this trend was not significant in the placebo group. For waist circumference, both groups showed a 4% lower risk per 5 cm smaller baseline measurement.
By week 20, the rate of first MACE events had already diverged between the groups (hazard ratio [HR] 0.58), demonstrating an early cardioprotective effect.
At this point, mean changes in body weight and waist circumference were −6.4% and −5.0 cm in the semaglutide group, compared with −0.8% and −1.1 cm in the placebo group. These early changes accounted for about 70% of the total reductions seen at week 104. Importantly, 11% of all MACE events occurred within the first 20 weeks of treatment.
In the semaglutide group, greater reductions in waist circumference were associated with a lower subsequent MACE risk (HR 0.91; 95% CI 0.84–0.98; p = 0.02), while weight loss alone was not linearly linked to reduced risk. Among placebo recipients, those who lost at least 5% of their weight experienced higher MACE incidence and all-cause mortality, possibly reflecting unintentional or illness-related weight loss.
At week 104, semaglutide recipients who achieved the greatest weight loss had the lowest MACE incidence, whereas placebo recipients with comparable weight loss had the highest.
Waist circumference emerged as a stronger predictor
Analyses indicated that waist circumference reduction was a partial mediator of semaglutide’s cardiovascular benefits. Accounting for early changes in waist circumference reduced the treatment hazard ratio from 0.80 to 0.86 – suggesting that about one-third (33%) of the cardioprotective effect could be attributed to reduced abdominal fat, while the remainder likely involves other physiological mechanisms.
Crucially, time-varying changes in overall weight did not mediate the observed cardiovascular outcomes, underscoring that semaglutide’s heart-protective properties extend beyond simple weight loss.
Implications and limitations
The authors concluded that semaglutide was superior to placebo in reducing cardiovascular risk across all baseline weight and waist circumference levels, and that its benefits became evident early in treatment. They emphasised that early body weight reductions did not independently explain these benefits.
They cautioned, however, that analyses performed after randomisation were exploratory and not causal. The predominantly White, male study population also limits generalisability to broader groups, including women and ethnically diverse populations.
Despite these caveats, the findings strengthen the evidence that semaglutide’s cardioprotective effects go beyond adiposity reduction, pointing to additional metabolic, vascular, or anti-inflammatory mechanisms.
The SELECT trial was funded by Novo Nordisk, and is registered under ClinicalTrials.gov identifier NCT03574597.
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Higher Dose of Semaglutide Delivers Greater Weight Loss and Metabolic Improvements
Key Takeaways:
- Tripling the standard dose of semaglutide led to significantly greater weight loss and improved metabolic outcomes, without an increase in serious adverse effects.
- Participants on the higher dose achieved clinically meaningful reductions in body weight, waist circumference, and HbA1C levels, with nearly one-third losing 25% or more of their starting weight.
- Side effects were mostly mild and transient, suggesting that the higher dose may be a safe option for people requiring more intensive obesity treatment.
Landmark findings from the STEP UP trials
Tripling the standard dose of semaglutide – a widely prescribed glucagon-like peptide-1 receptor agonist (GLP-1RA) – resulted in markedly greater weight loss and cardiometabolic benefits, according to results from two large multicentre clinical trials led by UT Southwestern Medical Center. The studies, published in The Lancet Diabetes & Endocrinology, indicate that patients may be able to safely take a higher semaglutide dose than currently approved if they need to lose additional weight.
“Semaglutide and other drugs in its class have been life-changing for people living with obesity around the world. Our new findings suggest that increasing the dose can lead to even greater benefits and may be appropriate for some patients,” said study leader Dr Ildiko Lingvay, Professor of Internal Medicine in the Division of Endocrinology and in the Peter O’Donnell Jr. School of Public Health at UT Southwestern.
Context: The global obesity challenge
Obesity affects nearly one billion people worldwide, according to the World Health Organization, and is a major driver of conditions such as Type 2 diabetes, cardiovascular disease, certain cancers, and liver disease. GLP-1RAs, first authorised in the early 2000s, have transformed the management of Type 2 diabetes and, more recently, chronic weight management and cardiovascular risk reduction.
Semaglutide received approval from the US Food and Drug Administration (FDA) in 2017 for people with Type 2 diabetes and has since been approved at a 2.4 mg weekly dose for weight management in both the United States and European Union. While this dose can produce significant weight loss, many patients do not achieve their treatment goals.
The STEP UP trials: Design and participants
To explore whether higher doses could deliver additional benefits, researchers conducted two phase 3b clinical trials – STEP UP Diabetes and STEP UP Obesity – to compare the effects of a weekly 7.2 mg dose of semaglutide with the standard 2.4 mg dose and placebo.
In the STEP UP Diabetes trial, 512 adults with both obesity and Type 2 diabetes were randomly assigned to three groups:
- 307 participants received 7.2 mg semaglutide weekly.
- 103 participants received 2.4 mg semaglutide weekly.
- 102 participants received placebo.
Participants were followed for 72 weeks at 68 trial sites across eight countries in Europe, southern Africa, and North America, including UT Southwestern. All participants received counselling every four weeks to encourage reduced-calorie diets and increased physical activity.
Results: Substantial weight loss and metabolic gains
Weight loss outcomes
As seen in earlier studies, the standard 2.4 mg dose produced a mean weight loss of 10.4% of starting weight, compared with 3.9% in the placebo group. However, participants taking the higher 7.2 mg dose achieved an even greater mean weight loss of 13.2%.
In addition, those receiving 7.2 mg were significantly more likely to:
- Reach a 20% reduction in waist circumference – a key measure of cardiometabolic health.
- Achieve superior improvements in HbA1C, an indicator of blood sugar control.
Outcomes in people without type 2 diabetes
The STEP UP Obesity trial, which focused on people with obesity but without Type 2 diabetes, showed even more striking results. Nearly one-third of participants on the higher dose lost 25% or more of their starting weight, compared with 15% of those on the standard dose and none on placebo.
Safety profile and side effects
The most frequently reported side effects were gastrointestinal symptoms, such as nausea, diarrhoea, and constipation. These affected approximately half of participants taking semaglutide and about a quarter of those on placebo. Most symptoms occurred during the dose-escalation period and tended to diminish over time.
The only side effect reported more frequently in the higher dose group was dysaesthesia (a change in touch sensation), experienced by approximately 20% of participants taking 7.2 mg, compared with 5% of those on the lower dose. Importantly, there was no increase in serious adverse events associated with the higher dose.
“These findings reinforce the promise of semaglutide and other GLP-1RAs, with benefits that appear to increase at higher doses without compromising patient safety,” Dr Lingvay concluded.
Funding and disclosures
Both STEP UP trials were funded by Novo Nordisk A/S, the manufacturer of semaglutide. Dr Lingvay reports receiving personal consulting fees from Novo Nordisk.
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