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GLP-1 Weight Loss Is Mostly Driven by Fat Loss, Not Muscle

Key Takeaways:

• GLP-1 receptor agonists and dual GLP-1/GIP therapies lead to significant weight loss, primarily through reductions in fat mass rather than muscle.
  
• Improvements in body composition, including reductions in visceral fat, occur as early as three months into treatment.
  
• Although some lean body mass loss is observed, it is relatively modest compared with overall weight loss, suggesting a favourable pattern of change.
  
  
  

GLP-1 therapies in the context of obesity care

A recent study published in the International Journal of Obesity examined how glucagon-like peptide 1 receptor agonists and dual GLP-1/glucose-dependent insulinotropic polypeptide agonists affect body weight and composition in adults living with overweight or obesity.

The global prevalence of obesity has risen substantially in recent decades. This condition is closely linked to a range of cardiometabolic complications that can reduce both quality of life and life expectancy. As a result, effective obesity management typically requires a personalised, multidisciplinary approach. This may include behavioural support, dietary changes, physical activity, pharmacological treatments, and, in some cases, surgical intervention.

GLP-1 receptor agonists and related incretin-based therapies have emerged as an important pharmacological option. These treatments are known to support sustained weight loss and improve obesity-related comorbidities. They have also demonstrated cardioprotective effects. However, while these therapies predominantly reduce fat body mass, they may also lead to some loss of lean body mass, which has raised concerns, particularly for older adults and people at risk of frailty.

Study design and methods

To better understand these effects, researchers conducted a comprehensive evaluation of clinical studies assessing GLP-1-based therapies and their impact on body composition.

Databases including Web of Science, PubMed, and Scopus were systematically searched for relevant studies involving adults with overweight or obesity, with or without type 2 diabetes. Following removal of duplicate records, studies were screened based on titles, abstracts, and full texts to determine eligibility.

The methodological quality of the included studies was assessed using established tools. Meta-analyses were then performed on studies that provided numerical data on changes in body composition and anthropometric measures. Statistical analyses used random-effects models, with subgroup analyses based on drug type and treatment duration. Publication bias was evaluated using Egger’s test.

In total, 36 studies were included in the qualitative review, with 24 contributing to the meta-analyses. Most studies were conducted in Europe and Asia, and many reported outcomes at six months. Twenty-four studies included people living with type 2 diabetes. The most frequently studied medications were liraglutide and semaglutide. Body composition was commonly assessed using bioelectrical impedance analysis and dual-energy X-ray absorptiometry.

Changes in weight and body composition

Early effects at three months

After three months of treatment, participants experienced a significant reduction in body mass of approximately 9 percent. This effect was particularly notable among those receiving beinaglutide.

Substantial improvements in body composition were also observed. Visceral adipose tissue area decreased by 29.25 cm², while fat body mass was reduced by 17 percent. Lean body mass showed a smaller but statistically significant reduction of 2 percent.

In addition, body mass index decreased by 2.96 kg/m² and waist circumference by 9.6 cm.

Outcomes at six months

At six months, body mass remained significantly reduced, with an average decrease of 5 percent.

Both fat body mass and lean body mass declined further, by 6 percent and 1 percent respectively. Skeletal muscle mass showed a modest reduction of 3 percent. Visceral adipose tissue continued to decrease, with a reduction of 32.31 cm².

Body mass index fell by 2.40 kg/m², while waist circumference decreased by 2.3 cm.

Longer-term results at twelve months

At twelve months, body mass was reduced by 4 percent, with continued decreases in body mass index of 1.74 kg/m² and waist circumference of 3.2 cm.

Both fat body mass and lean body mass were reduced by 4 percent. The most pronounced reductions were reported in a study involving liraglutide, although the authors noted considerable variability between studies and advised caution when comparing specific agents.

Egger’s test indicated some publication bias in outcomes reported at three months, but no significant bias was observed at later time points.

Interpreting fat loss and muscle preservation

Overall, the findings demonstrate that GLP-1-based therapies produce meaningful improvements in key measures associated with obesity, including body mass, body mass index, and waist circumference, across multiple time points.

The most rapid and substantial changes occurred within the first three months of treatment. Across all timeframes, reductions in fat mass, particularly visceral fat, were more pronounced than reductions in lean mass.

The authors described this pattern as “quality” weight loss, characterised by a predominance of fat mass reduction with relative preservation of lean tissue. Importantly, no single GLP-1 receptor agonist was found to be superior in preserving lean mass.

Implications for clinical practice and future research

These findings have important implications for clinical care. While some degree of lean mass loss occurs with GLP-1-based therapies, the overall pattern of weight loss appears favourable, particularly given the substantial reductions in fat mass and visceral adiposity.

Future research should focus on optimising treatment strategies that combine pharmacotherapy with lifestyle interventions. In particular, there is a need to explore approaches that support the preservation of lean mass, such as targeted nutritional strategies and resistance training programmes.

Such considerations are especially important for people at higher risk of sarcopenia, including older adults and those with existing muscle loss.

CCH insights:

These results are encouraging, but it is important not to become complacent about lean mass loss during weight loss. The studies analysed here involved average weight losses of less than 10% of body weight, but some people can lose 15-20% of body weight on GLP-1 therapy – do they lose similar proportions of body fat and lean tissue? All patients on GLP-1 therapy should receive advice on lifestyle measures to help minimise lean tissue loss.

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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

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GLP-1 Receptor Agonists Show Potential to Reduce Mental Health Risks in People with Diabetes and Obesity

Key Takeaways: 

• GLP-1 receptor agonists were associated with a reduced risk of worsening mental illness in people living with diabetes and co-existing anxiety or depression
  
• Semaglutide and liraglutide showed the most notable effects, including reductions in depression, anxiety, and self-harm risk
  
• Findings from a large Swedish cohort study highlight potential dual benefits, though randomised trials are still needed
  
  
  

Growing interest in the mental health effects of GLP-1 therapies

A large national cohort study from Sweden, published in The Lancet Psychiatry, suggests that glucagon-like peptide-1 receptor agonists may offer benefits beyond metabolic control. The findings indicate that medications such as semaglutide and liraglutide could help reduce the risk of worsening mental illness in people living with diabetes and co-existing obesity, anxiety, or depression.

GLP-1 receptor agonists are widely used in the management of type 2 diabetes and obesity. However, their impact on mental health outcomes has remained uncertain, with previous research producing mixed results. This study contributes new large-scale evidence suggesting a potentially protective effect.

Mental illness and diabetes – a high-risk overlap

People living with diabetes are known to have a higher risk of mental health conditions, including depression, anxiety, and suicide. This overlap creates a complex clinical picture, where both metabolic and psychological factors influence outcomes.

The researchers emphasised that understanding how commonly prescribed antidiabetic medications affect mental health is essential, particularly in populations already at elevated psychiatric risk.

Study design and population

The study analysed data from Swedish national electronic health registers, covering the period from 2009 to 2022. Researchers identified individuals with diagnosed depression or anxiety who were also receiving antidiabetic treatment.

Participants who used GLP-1 receptor agonists were compared with those who did not use these medications, as well as with individuals taking other second-line antidiabetic therapies.

In total, nearly 95,500 people were included in the analysis. Approximately 60% of participants were female and 40% male, with a mean age of around 50 years. Data on ethnicity were not available.

During the follow-up period, almost 22,500 individuals used GLP-1 receptor agonists.

Outcomes measured

The study assessed several primary and secondary outcomes related to mental health.

Primary outcomes included:

• Psychiatric hospitalisation
• Sick leave exceeding 14 days due to psychiatric reasons
• Hospitalisation due to self-harm
• Death by suicide
  

Secondary outcomes included:

• Worsening symptoms of depression or anxiety
• Substance use disorder
• Self-harm
  

Reduced risk of worsening mental illness

The findings indicated that some GLP-1 receptor agonists were associated with a lower risk of worsening mental health outcomes.

Semaglutide and liraglutide were linked to a 42% and 18% lower risk of worsening mental illness, respectively, compared with people who did not use GLP-1 therapies.

When examining specific outcomes:

• Semaglutide was associated with a 44% lower risk of worsening depression
• A 38% reduced risk of worsening anxiety
• A 47% lower likelihood of worsening substance use disorder

Liraglutide showed a more limited effect, with a 26% reduction in the risk of worsening depression, but no significant impact on other mental health outcomes.

Other GLP-1 receptor agonists, including exenatide and dulaglutide, did not demonstrate meaningful changes in risk.

Impact on self-harm risk

One of the most notable findings was the association between GLP-1 receptor agonist use and a reduced risk of self-harm.

Overall, these medications were linked to a 44% lower risk of self-harm compared with non-use, suggesting a potentially important role in mitigating severe psychiatric outcomes in this population.

Implications for clinical practice

The results suggest that certain GLP-1 receptor agonists may provide dual therapeutic benefits for people living with diabetes and obesity, addressing both metabolic and mental health outcomes.

However, the authors cautioned that observational findings cannot establish causality. They highlighted the need for randomised controlled trials to confirm these associations and better understand the mechanisms involved.

Conclusion

This large Swedish cohort study provides evidence that some GLP-1 receptor agonists, particularly semaglutide and liraglutide, may be associated with reduced risks of worsening mental illness and self-harm in people living with diabetes and co-existing psychiatric conditions.

While further research is required, the findings point towards a potentially valuable role for these medications in addressing the interconnected challenges of metabolic and mental health.

CCH insight:

Yet more positive news about GLP-1 medications. This is very encouraging, particularly as there are so many drugs that have negative side-effects regarding mental health. However, this study only shows an association, and not causation, and did not adjust for the possible effects of losing weight – those on GLP-1 therapy may have experienced improved mood and mental health due to the fact they were losing weight, rather than as a direct effect of the drug. More research is needed to elucidate the complex interactions of obesity and mental health and the effects of GLP-1 medications.

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Weight Loss Drugs May Be Linked to Bone Health Risks, Five-Year Study Shows

Key Takeaways:

• A large observational study suggests a modest increase in osteoporosis and related conditions among people taking GLP-1 receptor agonists over five years
  
• The underlying cause remains unclear, with weight loss itself, rather than the drugs alone, likely contributing to changes in bone health
  
• Despite these findings, the cardiovascular and metabolic benefits of GLP-1 therapies continue to outweigh potential skeletal risks for most people
  
  
  

Growing use of GLP-1 therapies raises new questions

Glucagon-like peptide-1 receptor agonists, commonly referred to as GLP-1 drugs, are widely used to manage type 2 diabetes and support weight loss. These medications are recognised for their ability to reduce body weight, improve glycaemic control, and lower cardiovascular risk.

However, emerging long-term data are beginning to highlight potential concerns relating to bone health. A new study, presented at the 2026 annual meeting of the American Academy of Orthopaedic Surgeons, examined five years of real-world data and suggests that these treatments may be associated with an increased risk of certain skeletal conditions.

The findings are observational and have not yet undergone peer review. They demonstrate association rather than causation. Nevertheless, given the rapid uptake of GLP-1 receptor agonists, researchers emphasise the need for careful, ongoing evaluation.

Study findings – signals of increased skeletal risk

Researchers analysed medical records from more than 146,000 adults living with obesity and type 2 diabetes over a five-year period.

Among those taking GLP-1 therapies, approximately 4 percent developed osteoporosis, compared with just over 3 percent of those not taking these medications.

Additional findings included:

• Osteomalacia, or bone softening, occurred in around 0.2 percent of people using GLP-1 drugs, compared with 0.1 percent in the control group
  
• Gout was slightly more common, affecting 7.4 percent of people taking GLP-1 therapies compared with 6.6 percent in those not taking them
  

Lead researcher Muaaz Wajahath, a medical student at Michigan State University College of Human Medicine, highlighted the importance of emerging long-term data:

“We are just now reaching the precipice where five- and 10-year follow-up data are becoming available for patients taking GLP-1 medications,” Wajahath said. “Any medication that sees this rapid adoption warrants close examination, particularly in orthopedics, where obesity and surgical intervention often overlap.”

Dr Giles Scuderi, an orthopaedic surgeon and vice president of Northwell Orthopedics, commented on the findings:

“The study findings contradict recent assertions of musculoskeletal protection and suggest that GLP-1 RA exposure may confer increased long-term skeletal risk.”

Is the risk driven by the drug or by weight loss?

A key question remains whether the observed risks are directly caused by GLP-1 medications or are instead related to weight loss itself.

People living with obesity and type 2 diabetes already have elevated risks of inflammation and bone fragility. In addition, weight loss – particularly when rapid or substantial – can affect bone metabolism.

Dr James J. Chao explained:

“As with any weight loss, bone remodeling can occur if patients lose weight on these medications.”

Bone remodelling is the continuous process of breaking down old bone and replacing it with new tissue. During periods of calorie deficit, this balance can shift, resulting in net bone loss.

“If patients lose lean mass on these medications, bone health can be affected due to less strain being placed on bones,” he added.

Dr Fernando Ovalle Jr. reinforced that this is not unique to GLP-1 therapies:

“We’ve seen it with bariatric surgery for many years and even with aggressive caloric restriction. That’s not unique to GLP-1s.”

Balancing risks and benefits

Despite these findings, experts continue to support the use of GLP-1 receptor agonists in appropriate patients.

These medications have demonstrated strong benefits, including:

• Improved glycaemic control
• Reductions in blood pressure and lipid levels
• Lower risk of heart attack and stroke
  

“In high-risk patients, those benefits are substantial and often life-saving,” Ovalle said.

As a result, the overall benefit–risk balance remains favourable in most cases. While there may be a modest increase in fracture or gout risk, these risks can typically be monitored and managed.

Scuderi echoed this perspective:

“Since heart disease is a leading cause of death, the potential risk of muscle and bone problems might be less important.”

He also emphasised the importance of active clinical management rather than passive prescribing.

Practical steps to protect bone health

Healthcare professionals can take a proactive role in supporting people receiving GLP-1 therapies.

Recommended strategies include:

• Ensuring adequate protein intake to support muscle mass
• Maintaining sufficient calcium and vitamin D levels
• Engaging in regular resistance and weight-bearing exercise
• Avoiding excessively rapid or unsupported weight loss

“Strength training, in particular, is critical,” Ovalle said. “Preserving muscle mass protects bone. If a patient loses weight but also loses significant muscle, fracture risk can increase regardless of the medication used.”

Certain groups may require closer monitoring:

• Postmenopausal women
• Older adults
• Individuals with a history of fractures
  

Gout risk may also increase temporarily during periods of rapid weight loss.

“Regarding gout, rapid weight loss and changes in uric acid metabolism can transiently increase flares,” Ovalle said. “That’s something we’ve seen even outside of GLP-1 therapy.”

Building the nutritional knowledge to guide patients through these supportive measures – adequate protein, key micronutrients and protecting lean mass during weight loss – is the focus of professional training such as the College of Contemporary Health’s Nutrition & Weight Management Essentials, a CPD-accredited online short course.

For individuals concerned about bone health, targeted supplementation may be considered. Scuderi noted that healthcare professionals may recommend therapeutic doses of dietary supplements to support lean mass retention and reduce inflammation.

A signal worth monitoring, not a cause for alarm

While early long-term data suggest a potential association between GLP-1 therapies and bone-related risks, these findings should be interpreted with caution.

The study does not establish causation, and multiple factors – including weight loss, underlying conditions, and changes in body composition – are likely to contribute.

At present, GLP-1 receptor agonists remain a valuable and often transformative option for people living with obesity and type 2 diabetes, provided their use is accompanied by appropriate clinical oversight and supportive lifestyle measures.

CCH insight

With so many people taking GLP-1 medications, it is important to keep researching the long-term effects, and this study sheds important light on potential risks with regard to bone health. The most important message here, however, is that this reminds us how it is vital that patients on GLP-1 therapy need to be carefully monitored and supported, particularly during the first year or so when weight loss is relatively rapid. If bone health is affected, this can be managed and treated. If bone health is affected, this can be managed and treated. Much of that support is nutritional: CCH’s Nutrition & Weight Management Essentials CPD short course (10 CPD hours, fully online, CPD-accredited) gives healthcare professionals a solid grounding in nutrition and weight management, including how to help patients meet their protein, calcium and vitamin D needs and preserve lean muscle during periods of rapid weight loss.

Explore Nutrition & Weight Management Essentials →

Source: The Epoch Times  

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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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Switching GLP-1 Medications May Improve Long-Term Engagement in Obesity Treatment, Real-World Study Suggests

Key Takeaways:

• Real-world data from nearly 127,000 adults with overweight or obesity found that switching between GLP-1 receptor agonist medications was associated with greater long-term treatment persistence.
  
• Only about one quarter of patients remained on any GLP-1 therapy after one year, highlighting ongoing challenges with long-term adherence.
  
• Researchers suggest that changing medications should be viewed as a normal part of obesity care, rather than as a sign that treatment has failed.
  
  
  

Large real-world study examines how patients use GLP-1 medications

Patients without diabetes who switched between glucagon-like peptide-1 receptor agonist (GLP-1RA) medications for overweight or obesity were more likely to remain engaged with treatment than those who stayed on the same medication, according to new research conducted by investigators at UT Southwestern Medical Center.

The findings were published in JAMA Network Open and provide one of the most detailed real-world analyses to date of how adults with overweight or obesity use these medications over time. The study suggests that switching between drugs within the same therapeutic class is relatively common and may play an important role in sustaining long-term treatment.

The researchers argue that clinicians should not interpret medication changes as treatment failure. Instead, they suggest that switching therapies may represent a pragmatic strategy to maintain continuity of care when patients experience side effects, access issues, or other barriers.

“This study provides one of the largest real-world descriptions to date of how adults with overweight or obesity use and switch GLP-1RAs over time,” said first author Luyu (Amber) Xie, Ph.D., Pharm.D., Assistant Professor in the Peter O’Donnell Jr. School of Public Health and co-Director of the Biostatistics and Data Science Core at UT Southwestern. “It highlights that long-term persistence is low and that switching between medications is a relatively common part of ongoing treatment rather than a sign of failure.”

Tracking medication use in nearly 127,000 adults

To examine treatment patterns, the research team analysed insurance claims data from nearly 127,000 adults in the United States who were living with overweight or obesity and initiated GLP-1RA therapy between 2019 and 2024.

Participants in the study did not have diabetes and were prescribed GLP-1 medications specifically for weight management. The researchers tracked medication use over a 12-month period following treatment initiation in order to understand how patients continued, discontinued, or switched therapies.

The analysis revealed that treatment pathways were rarely straightforward. Instead of remaining on a single medication for the entire year, many patients experienced adjustments to their treatment regimen. These changes were often driven by factors such as side effects, medication availability, insurance coverage, and the introduction of newer therapies.

GLP-1 receptor agonists have become a central component of modern obesity treatment. Medicines in this class include semaglutide, liraglutide, and tirzepatide, all of which act on hormonal pathways involved in appetite regulation and metabolic control. Despite their clinical effectiveness, maintaining long-term adherence has proven difficult for many patients.

Persistence remains a major challenge

The study found that long-term persistence with GLP-1RA therapy remains relatively low.

After one year, only around one quarter of patients remained on any GLP-1 medication. During that same period, approximately one in five patients transitioned from their initial therapy to a different GLP-1RA.

However, the data also revealed an important pattern. Patients who switched medications were more likely to continue treatment overall and demonstrated higher levels of adherence compared with those who remained on their original therapy.

These findings suggest that medication switching may reflect proactive clinical management rather than treatment failure.

“Switching between GLP-1RA medications should be viewed as a normal part of long-term obesity care,” said senior author Sarah Messiah, Ph.D., M.P.H., Professor of Epidemiology and Pediatrics, Associate Dean for Research in the O’Donnell School of Public Health, and Director of the Child and Adolescent Population Health Program. “Persistence should not be judged by staying on a single drug indefinitely, but by maintaining engagement in care and working with clinicians to find sustainable, effective treatment strategies over time.”

Visualising treatment pathways

In addition to analysing persistence and switching rates, the researchers also mapped treatment pathways to illustrate how patients moved between different medications over the course of the study period.

These visualisations showed that newer once-weekly injectable therapies frequently served both as initial treatments and as destinations when patients switched from other medications. This pattern reflects the growing role of these agents in contemporary obesity management.

According to the researchers, these dynamic treatment pathways highlight the evolving nature of obesity pharmacotherapy and reinforce the need for flexible treatment strategies.

“In today’s clinical environment, successful obesity care often involves adapting treatment over time rather than expecting a single medication to meet every patient’s needs indefinitely,” said co-author Jaime Almandoz, M.D., M.B.A., Professor of Internal Medicine in the Division of Endocrinology and Medical Director of UTSW’s Weight Wellness Program.

Setting realistic expectations in obesity care

The findings also underline the importance of setting realistic expectations with patients at the start of treatment.

Clinicians may need to emphasise that finding the most effective long-term medication strategy can involve trial and adjustment. In some cases, more than one medication may be prescribed before a sustainable approach to treatment is established.

By framing medication adjustments as part of routine care, clinicians may help patients remain engaged with treatment and reduce the perception that a change in therapy represents a setback.

Future research on personalised treatment pathways

The authors note that additional research is needed to better understand the factors that shape treatment trajectories in obesity care.

Future work will explore how patient characteristics, specific medications, and the timing of therapy influence patterns of persistence and switching. The goal is to generate insights that can support more personalised and sustainable approaches to treatment.

Study contributors and funding

Additional UT Southwestern researchers involved in the study include Diego Anazco Villarreal, M.D., an Internal Medicine resident; Azucena Herrera Chancay, M.D., an Internal Medicine fellow; M. Sunil Mathew, M.S., Senior Population Science Data Manager; and Jackson Francis, M.P.H., Population Science Project Coordinator.

The research was supported by the UTSW Clinical and Translational Science Award, the National Institutes of Health (1U54TR00236), the Texas Health Resource Clinical Scholar program, and the UTSW Nutrition & Obesity Research Center (NORC).

CCH insight:

This is an interesting study which looks at a very important issue. Obesity is a chronic relapsing disease so ongoing, long-term treatment is necessary. If a patient is struggling with a particular medication, the opportunity to try an alternative is very helpful, and will increase the chances of adhering to treatment. The number of options is gradually increasing, most notably with oral formulations becoming available this year, and new drugs in the pipeline such as petrelintide, which promises slightly less weight loss than Wegovy or Tirzepatide, but minimal gastrointestinal side effects – so far better tolerability. All these developments should help patients find a medication that works for them, enabling long-term treatment compliance and better outcomes.

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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.

Keeping pace with how GLP-1 therapies work and how to weigh emerging trial evidence like this is the focus of professional training such as the College of Contemporary Health’s GLP-1RAs in Focus, a CPD-accredited online short course.

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 because the weight that is retained is muscle, not fat. Making sense of fast-moving evidence like this – and the mechanisms behind it – is exactly what CCH’s GLP-1RAs in Focus – Why Drugs Like Ozempic Work CPD short course (2 CPD hours, fully online, CPD-accredited) is built to support, giving healthcare professionals a clear grounding in how these medications work and how to appraise the evidence with confidence, whether or not they prescribe.

Explore GLP-1RAs in Focus →

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GLP-1 Weight-Loss Drugs Found to Work in Rare Genetic Obesity

Key Takeaways:

• GLP-1–based medicines reduced body weight and improved metabolic health in animals lacking the MC4R receptor, a critical regulator of appetite and body weight
  
• The findings suggest these therapies may work through alternative brain and peripheral pathways, offering potential treatment options for people living with rare genetic obesity
  
• Researchers highlight potential risks linked to lean mass loss, emphasising the importance of long-term monitoring and muscle-preserving treatment strategies
  
  
  

Understanding genetic obesity and loss of appetite control

For individuals born with certain genetic mutations affecting appetite regulation, managing body weight can resemble attempting to stop a vehicle with failing brakes. Despite sustained effort, biological signals governing hunger and energy balance do not respond normally.

One of the most important regulators of food intake is the melanocortin-4 receptor (MC4R), located within the hypothalamus. This receptor plays a central role in maintaining energy balance by responding to hormonal signals that indicate satiety.

When mutations disrupt signalling pathways linked to MC4R, individuals may experience profound dysregulation of appetite. Children affected by these mutations frequently develop severe early-onset obesity, and by adulthood many conventional interventions have produced limited or no sustained benefit.

New research published in the International Journal of Obesity now suggests that widely used GLP-1–based anti-obesity medicines may offer a potential therapeutic approach even when this critical biological pathway is absent.

Testing GLP-1 medicines without MC4R function

The research team investigated whether modern incretin-based therapies could still produce weight-loss effects in the complete absence of MC4R signalling.

To explore this question, scientists used genetically engineered mice lacking the MC4R gene entirely. These animals closely replicate clinical features seen in people living with MC4R pathway deficiency, including:

• Excessive food intake
  
• Rapid fat accumulation
  
• Fatty liver disease
  
• Elevated cholesterol levels
  
• Early insulin resistance
  

Under normal physiological conditions, hunger regulation relies heavily on signalling cascades such as the POMC–MC4R and leptin–MC4R pathways, which transmit satiety signals as the stomach approaches fullness. Disruption anywhere along these pathways can lead to some of the most treatment-resistant forms of obesity recognised in clinical medicine.

The researchers therefore posed a direct question: would GLP-1 therapies still work if MC4R signalling were completely removed?

Three leading anti-obesity drugs evaluated

The study examined three prominent weight-management medicines:

• Semaglutide
  
• Tirzepatide
  
• Retatrutide
  

All belong to the broader class of GLP-1–based therapies, which act on receptors distributed across the brain, pancreas and vagus nerve connecting the brainstem to abdominal organs.

Each drug was administered once daily via injection over a 21-day period.

Despite the absence of functional MC4R signalling, all three treatments produced substantial anti-obesity effects. As the authors reported:

“Our findings demonstrate that all three GLP-1 analogs exhibit significant anti-obesity effects in MC4R KO mice.”

Significant weight and metabolic improvements

Weight reduction occurred across all treatment groups:

• Semaglutide reduced body weight by an average of 19.7 percent
  
• Retatrutide achieved a 24.1 percent reduction
  
• Tirzepatide, which targets both GLP-1 and GIP receptors, produced the largest effect with a 31.6 percent reduction
  

Importantly, these outcomes occurred in animals completely lacking MC4R function.

Food intake declined consistently across groups, accompanied by broader metabolic improvements. Researchers observed:

• Reduced liver injury markers
  
• Lower cholesterol and triglyceride levels
  
• Suppression of liver genes associated with fat production
  

The authors concluded:

“These results suggest that GLP-1 analogs may provide an effective treatment option for patients with MC4R-POMC pathway deficiencies.”

Alternative brain and peripheral mechanisms

The findings indicate that GLP-1 therapies may bypass defective MC4R signalling entirely.

According to the research team:

“GLP-1 analogs appear to exert their anti-obesity effects through central pathways that do not involve MC4R, as well as via peripheral mechanisms involving the vagus nerve.”

This alternative mechanism may explain why the drugs remained effective despite removal of a pathway traditionally considered essential for appetite regulation.

Tirzepatide’s superior performance may relate to its additional action on the GIP receptor, providing dual hormonal signalling that enhances metabolic effects.

Implications for rare genetic obesity disorders

The results carry particular relevance for clinicians caring for people living with rare genetic obesity conditions, including POMC deficiency and Prader–Willi syndrome.

Currently, one approved therapy for some of these disorders, setmelanotide, works by stimulating the melanocortin pathway itself. However, treatment effectiveness depends on partial pathway function, which may limit outcomes in individuals with more severe deficiencies.

GLP-1–based therapies differ in that their effects do not appear dependent on MC4R signalling, potentially expanding treatment possibilities for individuals previously considered difficult to treat pharmacologically.

Lean mass loss and long-term considerations

Alongside reductions in fat mass, researchers observed decreases in lean body mass across all treatment groups. This raises important clinical considerations regarding prolonged therapy.

The authors cautioned:

“Chronic suppression of food intake could lead to muscle loss, potentially resulting in sarcopenia.”

They further noted that:

“Combination strategies, possibly including agents that preserve or increase muscle mass, may help mitigate this effect.”

These findings reinforce growing clinical discussion around muscle preservation during pharmacological weight management.

Early evidence, not yet clinical practice

While the results are encouraging, important limitations remain.

The study:

• Ran for only three weeks
  
• Included only male mice
  
• Lost two animals from the tirzepatide group before completion
  
• Has not yet been replicated in human clinical trials involving individuals with MC4R mutations
  

As such, the findings represent proof of biological concept rather than immediate clinical guidance.

The researchers summarised their conclusion clearly:

“This study provides the first demonstration that GLP-1 analogs can be effective in treating obesity associated with MC4R deficiency.”

A potential shift in understanding obesity treatment

The study contributes to a broader shift in obesity science, suggesting that effective treatment may not depend on restoring a single disrupted pathway. Instead, therapies capable of engaging multiple neural and peripheral systems may overcome even profound genetic drivers of obesity.

For people living with rare genetic forms of obesity, these findings offer cautious optimism that future treatments may succeed where traditional approaches have historically fallen short.

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Tirzepatide Not Linked to Increased Depression or Suicidal Ideation in Obesity Trials

Key Takeaways: 

• A post hoc analysis of three SURMOUNT trials found no evidence that tirzepatide increases the risk of depression compared with placebo over 72 weeks.
  
• Rates of suicidal ideation and behaviour were low and similar between tirzepatide and placebo groups, with most reports assessed as low risk.
  
• Experts emphasise the need for routine mental health assessment in people living with obesity, alongside further research in populations with established psychiatric conditions.
  
  
  

Overview of the analysis

Once-weekly subcutaneous tirzepatide was not associated with an increased risk of depression compared with placebo, according to a post hoc analysis of the SURMOUNT clinical trial programme. The findings were published in Obesity and add to the growing body of evidence examining the psychiatric safety of incretin-based therapies used for weight management.

As previously reported by Healio, in January the Food and Drug Administration requested the removal of warnings related to suicidal ideation and behaviours from the labels of several obesity medications, including liraglutide 3 mg (Saxenda), semaglutide 2.4 mg (Wegovy) and tirzepatide (Zepbound).

In the newly published analysis, researchers reported that adults receiving tirzepatide across three SURMOUNT trials did not experience worsening of depression over the course of the studies.

“The low occurrence of these events with tirzepatide is similar to that observed in pooled analyses of semaglutide 2.4 mg and liraglutide 3 mg, both GLP-1 receptor agonists approved for weight management,” said Thomas A. Wadden, PhD, professor of psychology in psychiatry at the Perelman School of Medicine, University of Pennsylvania, in comments to Healio. “The present report provides the first detailed analysis of the risk of these psychiatric events with tirzepatide.”

Study design and assessment methods

The analysis included data from the SURMOUNT-1, SURMOUNT-2 and SURMOUNT-3 studies. Across all three trials, adults living with obesity or with overweight and at least one weight-related comorbidity were randomly assigned to receive once-weekly subcutaneous tirzepatide or placebo for 72 weeks.

Depression symptoms were evaluated using the Patient Health Questionnaire-9 (PHQ-9). Suicidal ideation and behaviour were assessed using the Columbia-Suicide Severity Rating Scale. In addition, investigators recorded neuropsychiatric adverse events during scheduled study visits.

Depression symptoms over time

A total of 4,056 adults were included in the pooled analysis, of whom 63 percent were women and 74 percent were White. Overall, 2,806 participants received tirzepatide and 1,250 received placebo. At baseline, mean PHQ-9 scores were 2.7 in the tirzepatide group and 2.6 in the placebo group, indicating minimal or no depressive symptoms.

By week 72, participants receiving tirzepatide experienced a 0.6-point greater reduction in PHQ-9 score compared with those receiving placebo.

Among participants who had no or minimal depression symptoms at baseline and received tirzepatide, 79.4 percent remained in that category through the end of safety follow-up. During follow-up, 17 percent reported mild symptoms, 2.9 percent reported moderate symptoms, 0.7 percent reported moderately severe symptoms and 0.1 percent reported severe symptoms.

A smaller proportion of participants in the tirzepatide group moved to a more severe depression category compared with the placebo group, 18.2 percent versus 24.3 percent respectively, with this difference reaching statistical significance (P < .001). Conversely, a higher proportion of those receiving tirzepatide moved to a less severe depression category compared with placebo, 52.4 percent versus 41.8 percent (P < .001).

Suicidal ideation and behaviour

At baseline, a history of suicidal ideation or behaviour was reported by 70 participants receiving tirzepatide and 38 participants receiving placebo. Through the end of safety follow-up, 0.6 percent of participants in both the tirzepatide and placebo groups reported suicidal ideation. Most of these events were classified as low risk.

Moderate-risk suicidal ideation was reported by 0.3 percent of participants receiving tirzepatide and 0.1 percent of those receiving placebo. High-risk suicidal ideation occurred in three participants receiving tirzepatide and one participant receiving placebo.

Suicidal behaviour was reported by two participants in the tirzepatide group and by none in the placebo group.

Treatment-emergent nervous system disorder adverse events occurred in 15.8 percent of participants receiving tirzepatide and 13 percent of those receiving placebo. The investigators reported no difference between groups in the occurrence of treatment-emergent psychiatric disorders overall.

Implications for mental health care in obesity

Wadden noted that he and his colleagues supported the FDA decision to remove warnings related to suicidal ideation and behaviour from the labels of incretin-based obesity medications. However, he stressed that mental health assessment remains essential in the care of people living with obesity.

“Persons with obesity, particularly with a BMI of more than 40 kg/m2, are at substantially increased risk of major depression and anxiety disorders,” Wadden said. “It’s critical that they receive the same mental health care that persons of average weight would when presenting with these conditions.”

He also highlighted the need for further research to better understand the effects of incretin-based therapies in people with established psychiatric conditions.

“Randomized trials of the GLP-1 obesity medications largely excluded persons who, in the past 2 years, had experienced major depression, schizophrenia or bipolar disorder, or who had a lifetime history of suicide attempt,” Wadden said. “GLP-1 medications potentially could be beneficial to individuals who suffer from these conditions. Small, carefully controlled studies would appear warranted, as would a close examination of the FDA’s recent retrospective cohort study of more than 2 million individuals. The FDA’s dataset likely included a far greater range of psychiatric status than found in the randomized controlled trials that evaluated tirzepatide and semaglutide for chronic weight management.”

Disclosures

Wadden reports advising for Novo Nordisk and WW and receiving grants on behalf of the University of Pennsylvania from Eli Lilly, Epitomee Medical and Novo Nordisk. All other relevant financial disclosures are reported in the study.

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Nutrition Gaps Raise Safety Concerns as Use of GLP-1 Weight Loss Drugs Accelerates

Key Takeaways:

• Many people prescribed GLP-1 weight loss medications receive little or no structured nutritional guidance, increasing the risk of preventable vitamin and mineral deficiencies and loss of muscle mass.
  
• New research highlights a lack of high-quality evidence on how diet quality, protein intake, and micronutrient intake are affected during treatment with drugs such as semaglutide and tirzepatide.
  
• Experts warn that without integrated nutritional care, the rapid expansion of GLP-1 drug use could undermine long-term health benefits despite effective weight loss.
  
  
  

Experts from University College London and the University of Cambridge are warning that many people prescribed newer weight loss medications may not be receiving sufficient nutritional guidance to support safe and sustainable weight loss. As a result, some individuals may face avoidable risks, including vitamin and mineral deficiencies and loss of lean body mass, particularly muscle.

The concerns arise from new research published in Obesity Reviews. Led by Dr Marie Spreckley of the University of Cambridge, the review identified limited high-quality evidence on how nutritional advice influences calorie intake, body composition, protein consumption, and patient experiences among people using these medications.

How GLP-1 weight loss drugs work

Drugs such as semaglutide and tirzepatide, sold under brand names including Ozempic, Wegovy, and Mounjaro, work by mimicking the action of glucagon-like peptide-1 (GLP-1). This hormone is released after eating and plays a role in regulating appetite and glucose metabolism. By enhancing feelings of fullness, reducing hunger, and dampening food cravings, these medications can substantially lower energy intake.

Studies suggest that calorie intake may fall by 16–39%, helping to explain why these drugs are highly effective for people living with obesity or overweight. However, the researchers note that there has been very little detailed study of how such reductions affect overall diet quality, protein intake, or micronutrient intake, including vitamins and minerals. Existing evidence indicates that lean body mass, including muscle tissue, can account for as much as 40% of total weight lost during treatment.

Experts warn of risks without nutrition support

Dr Adrian Brown, an NIHR Advanced Fellow at UCL’s Centre of Obesity Research and the study’s corresponding author, described how these medications alter eating behaviour.

“Obesity management medications work by suppressing appetite, increasing feelings of fullness, and altering eating behaviors, which often leads people to eat significantly less. This can be highly beneficial for individuals living with obesity, as it supports substantial weight loss and improves health outcomes.

“However, without appropriate nutritional guidance and support from healthcare professionals, there is a real risk that reduced food intake could compromise dietary quality, meaning people may not get enough protein, fiber, vitamins, and minerals essential for maintaining overall health.”

Without structured support, reduced intake may unintentionally lead to inadequate consumption of nutrients needed to preserve muscle mass, bone health, immune function, and overall physical resilience.

Public guidelines versus private use

Guidance from the National Institute for Health and Care Excellence recommends semaglutide for weight management only for people who meet strict eligibility criteria, such as a body mass index of at least 35.0 kg/m² alongside obesity-related comorbidities including type 2 diabetes or cardiovascular disease. When prescribed through the NHS, the medication is intended to be delivered as part of a comprehensive programme that includes dietary changes and increased physical activity.

In reality, most people currently using GLP-1 drugs in the UK obtain them outside the NHS. An estimated 1.5 million people are now using these medications, with around 95% accessing them through private providers. In these settings, ongoing nutritional advice and follow-up support are not always consistently offered.

Rising use outpaces nutrition guidance

Dr Spreckley, who works at the Medical Research Council Epidemiology Unit at the University of Cambridge, said nutritional care has not kept pace with the rapid uptake of these therapies.

“Use of GLP-1 receptor agonist therapies has increased rapidly in a very short period of time, but the nutritional support available to people using these medications has not kept pace. Many people receive little or no structured guidance on diet quality, protein intake, or micronutrient adequacy while experiencing marked appetite suppression.

“If nutritional care is not integrated alongside treatment, there’s a risk of replacing one set of health problems with another, through preventable nutritional deficiencies and largely avoidable loss of muscle mass. This represents a missed opportunity to support long-term health alongside weight loss.”

Low intakes of essential vitamins and minerals are associated with fatigue, impaired immune function, hair loss, and increased risk of osteoporosis. Loss of lean mass, most commonly muscle, can also raise the likelihood of weakness, injuries, and falls, particularly in older adults.

Limited research leaves major questions unanswered

The review identified only 12 studies that examined diet and nutritional outcomes alongside treatment with semaglutide or tirzepatide. These studies differed widely in how dietary advice was delivered and how nutritional outcomes were measured. Many lacked standardised methods and consistent reporting, making it difficult to draw firm conclusions about best practice.

Despite the rapid expansion of GLP-1 drug use, the researchers found little robust evidence to guide clinicians on how to support people nutritionally during treatment.

Lessons from bariatric nutrition care

Given the urgent need for practical guidance, the researchers suggest that interim lessons could be drawn from nutritional care used after bariatric surgery. Procedures such as gastric banding and gastric bypass lead to similar reductions in appetite and food intake.

Dr Cara Ruggiero, a co-author from the MRC Epidemiology Unit at the University of Cambridge, said established post-surgery principles could help address current gaps.

“While GLP-1 receptor agonists are increasingly used, there remains a clear gap in structured nutritional guidance. In the interim, we can draw on well-established post-bariatric nutrition principles. Our previous work highlights the importance of prioritizing nutrient-dense foods including high-quality protein intake, ideally distributed evenly across meals, to help preserve lean mass during periods of reduced appetite and rapid weight loss.”

Equipping healthcare professionals with the nutritional knowledge to guide patients safely through this kind of rapid weight loss is the focus of professional training such as the College of Contemporary Health’s Nutrition & Weight Management Essentials, a CPD-accredited online short course.

The available evidence did not support recommending strict low-fat diets alongside GLP-1 therapies. However, some observational studies reported that people using these medications consumed relatively high amounts of total and saturated fat, suggesting a potential need for personalised guidance that aligns with national dietary recommendations.

Meal timing was rarely examined in clinical trials. Nevertheless, the researchers note that eating smaller meals more frequently may help manage side effects such as nausea and improve tolerability, particularly during the early stages of treatment.

Studying real-world experiences

The research team also emphasised the importance of incorporating the perspectives of people using GLP-1 medications into future studies. Understanding what types of information and support individuals find most helpful could improve real-world care and long-term outcomes.

To address this, the team has launched AMPLIFY – Amplifying Meaningful Perspectives and Lived experiences of Incretin therapy use From diverse communitY voices. The project aims to explore how people experience next-generation weight loss medications in everyday life.

“These medications are transforming obesity care, but we know very little about how they shape people’s daily lives, including changes in appetite, eating patterns, well-being, and quality of life,” Dr Spreckley said. “That’s what we’ll explore, working in particular with people from communities historically under-represented in obesity research, to help shape the future of obesity treatment.”

The research was funded by the National Institute for Health and Care Research, with additional support from the Medical Research Council and the NIHR UCLH Biomedical Research Centre.

CCH insights:

GLP-1 medications are licensed for the treatment of diabetes and obesity and they should be used alongside diet and lifestyle advice to improve cardiometabolic health. However, they are now commonly known as ‘weight loss drugs’, implying their primary aim is for people to lose weight. But this is kind of missing the point – the weight loss outcome is one of the mediating effects of the drugs which leads to improved health. However, if weight loss is not accompanied by a move to a healthy diet, which provides adequate levels of essential nutrients, then health outcomes will be compromised, as highlighted by this study then health outcomes will be compromised, as highlighted by this study. Closing that gap starts with clinicians themselves being confident in the fundamentals: CCH’s Nutrition & Weight Management Essentials CPD short course (10 CPD hours, fully online, CPD-accredited) gives healthcare professionals a solid grounding in nutrition and weight management, including how to help patients meet their protein and micronutrient needs and preserve lean muscle during weight loss.

Explore Nutrition & Weight Management Essentials →

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GLP-1 Receptor Agonists Linked to Lower Mortality After Diabetic Foot Ulcers, Nationwide French Study Finds

Key Takeaways:

• Nearly one in seven people experienced death within one year of a first diabetic foot ulcer, highlighting the severity of risk following ulcer onset.
  
• Treatment with GLP-1 receptor agonists was independently associated with improved survival, including after major lower-limb amputation.
  
• Multidisciplinary care and early specialist involvement were associated with better outcomes, reinforcing the importance of structured follow-up.
  
  
  

Background and study aims

Diabetic foot ulcers remain one of the most serious complications of diabetes, often signalling advanced disease and a high burden of comorbidity. Despite advances in diabetes care, mortality following a first diabetic foot ulcer continues to be substantial.

This nationwide observational study set out to identify factors associated with one-year mortality after a first recorded diabetic foot ulcer using data from the French National Health Data System (SNDS). A secondary objective was to examine mortality within one year following major lower-limb amputation in the same population.

Study design and data sources

Researchers conducted a retrospective cohort analysis using the SNDS, a comprehensive national database that captures hospital admissions, outpatient care, prescribed medications, and long-term disease registrations across France.

Adults with a first incident diabetic foot ulcer recorded between January 2017 and December 2018 were included. Case identification combined hospital discharge diagnoses and community care records, allowing capture of people diagnosed both in hospital and in outpatient settings. All individuals were followed for 12 months after ulcer identification.

To examine associations with mortality, the researchers used Cox proportional hazards models. These models adjusted for a wide range of variables, including demographic characteristics, clinical comorbidities, diabetes treatments, major amputation, and access to specialist care.

Mortality and amputation outcomes

In total, 133,791 people with a first diabetic foot ulcer were identified. Within one year of diagnosis, 14.6% died, underlining the high short-term mortality associated with this complication. During the same period, 3.5% underwent a major lower-limb amputation.

Outcomes following amputation were particularly poor. Among those who had a major amputation, 28.8% died within one year, indicating a markedly elevated risk compared with people who did not undergo amputation.

Factors associated with increased mortality

Several factors were independently associated with a higher risk of death within one year of a first diabetic foot ulcer. These included male sex, increasing age, and ulcers identified during a hospital admission rather than in the community.

Clinical and treatment-related predictors of higher mortality included insulin use, major lower-limb amputation, and a range of comorbid conditions. Cardiovascular disease, cancer, dementia, end-stage kidney disease, and liver disease were all strongly associated with poorer survival.

Similar patterns were observed when analysing mortality after major amputation, suggesting that underlying health status and disease severity play a central role in outcomes across the care pathway.

Protective factors and the role of GLP-1 receptor agonists

Several factors were associated with a lower risk of death. Use of lipid-lowering therapy emerged as a protective factor, as did prior contact with specialist healthcare professionals. People who had consulted diabetologists, ophthalmologists, or podiatrists before ulcer onset experienced better survival, pointing to the benefits of ongoing, multidisciplinary diabetes care.

Notably, treatment with glucagon-like peptide-1 receptor agonists was independently associated with reduced mortality at one year. This association persisted both in the overall cohort and among people who underwent major lower-limb amputation, suggesting a consistent survival benefit linked to this class of medication.

Interpretation and implications for care

The findings confirm that one-year mortality after a diabetic foot ulcer remains unacceptably high and is closely linked to age, comorbidity burden, and disease severity. Importantly, the inclusion of community-identified ulcers highlights that people with diabetic foot disease are highly vulnerable even outside hospital settings.

The observed association between GLP-1 receptor agonist use and improved survival adds to growing evidence that these therapies may offer benefits beyond glycaemic control. Alongside pharmacological treatment, structured follow-up and early involvement of specialist services appear to play a critical role in improving outcomes.

Conclusions

This nationwide study shows that mortality following a first diabetic foot ulcer is substantial, particularly among people with advanced comorbidities and those requiring major amputation. Glucagon-like peptide-1 receptor agonists and coordinated, multidisciplinary care were associated with better survival and should be prioritised in high-risk populations.

Together, these findings underscore the urgent need to strengthen preventive strategies, optimise care pathways, and ensure timely access to specialist diabetes and foot care services for people living with diabetes who are at risk of ulceration.

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