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
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.”
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.
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.
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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Mice Study Suggests Tirzepatide Enhances Metabolism by Activating Brown Fat in Addition to Reducing Weight
Key Takeaways:
- A preclinical mouse study indicates that tirzepatide may improve metabolism not only by reducing appetite, but also by activating brown adipose tissue.
- The research suggests that this activation increases energy expenditure and supports improvements in blood glucose and lipid levels.
- Findings remain preliminary and require confirmation in human studies before clinical conclusions can be drawn.
A closer look at tirzepatide’s metabolic effects
Tirzepatide has transformed the treatment landscape for people living with obesity and for those with poorly controlled type 2 diabetes mellitus. Despite its established clinical benefits, the precise molecular and cellular mechanisms underpinning its effects are not yet fully understood.
A recent study conducted in mice provides new insight into how the drug may influence metabolism beyond its well-recognised impact on body weight. The findings suggest that tirzepatide directly activates brown adipose tissue, a specialised form of fat involved in energy expenditure. According to the researchers, this discovery helps clarify how the drug works and may inform the development of more comprehensive treatments for obesity and related metabolic diseases.
The study was led by Marion Peyrou, Ramón y Cajal researcher at the Faculty of Biology and the Institute of Biomedicine of the University of Barcelona, the Sant Joan de Déu Research Institute and the CIBER in Physiopathology of Obesity and Nutrition.
A dual-action therapy
Tirzepatide, marketed under the name Mounjaro, is approved for weight management in adults living with obesity or with overweight accompanied by comorbidities. It is also indicated for the treatment of inadequately controlled type 2 diabetes.
Unlike earlier anti-obesity medicines, tirzepatide acts simultaneously on two hormonal receptors – glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). This dual mechanism leads to substantial reductions in body weight, primarily through decreased food intake driven by appetite suppression.
However, appetite reduction alone may not explain the full spectrum of its metabolic effects.
Investigating effects on adipose tissue
To better understand how tirzepatide exerts its actions, researchers conducted a detailed analysis of its effects on different fat depots in an experimental mouse model. Such in-depth tissue analysis is not feasible in humans.
In the study, mice were rendered obese through a high-fat diet and then treated with tirzepatide. Their outcomes were compared with a control group of mice that consumed the same quantity of food but did not receive the drug. This design allowed the researchers to distinguish between effects caused directly by the drug and those resulting solely from reduced caloric intake.
The analysis revealed that tirzepatide activates brown adipose tissue. Unlike white adipose tissue, which primarily stores excess energy and accumulates in obesity, brown adipose tissue specialises in burning calories to generate heat.
“This activation is associated with an increased capacity to burn metabolic energy and with the production of batokines by brown adipose tissue, molecules that are beneficial for metabolism,” says Marion Peyrou.
Metabolic benefits beyond appetite suppression
The activation of brown adipose tissue is particularly significant because it indicates that tirzepatide may exert metabolic benefits independent of weight loss due to appetite reduction.
“This drug not only reduces body weight, but also has beneficial effects on metabolism. Active brown adipose tissue ‘burns’ glucose and fat within the body, which would contribute to its positive effect not only in reducing body weight, but also in lowering blood glucose and fat levels, and improving metabolism,” the researcher points out.
By enhancing the body’s ability to utilise both glucose and lipids, activation of brown fat may contribute to improved glycaemic control and lipid profiles in addition to weight reduction.
Implications for obesity treatment strategies
For several years, activation of brown adipose tissue has been viewed as a promising strategy for tackling obesity and metabolic disorders. However, previous pharmacological attempts to stimulate brown fat have frequently been limited by adverse effects, particularly cardiovascular complications.
“Tirzepatide, although it activates brown adipose tissue, does not have these negative effects; on the contrary, it shows cardiovascular benefits. If our findings are confirmed in humans, it would reinforce the importance of developing therapeutic strategies that not only reduce food intake but also increase energy expenditure and brown fat activation,” explains the researcher.
These findings support the broader principle that obesity treatments may be more effective when they target multiple physiological pathways simultaneously. Addressing both energy intake and energy expenditure could offer a more comprehensive approach to weight management and metabolic health.
“This could help improve weight control and reduce associated disorders, such as type 2 diabetes and other metabolic disorders,” she adds.
Towards more personalised prescribing
A deeper understanding of tirzepatide’s mechanisms may also influence how such medicines are prescribed in future.
“Identifying which patient profiles could benefit most, for example those with more compromised energy expenditure, would open the door to more personalized medicine, based not only on appetite or weight control, but also on overall metabolic status,” she emphasizes.
Such an approach could support more tailored treatment strategies for people living with obesity and metabolic disease, taking into account differences in metabolic function rather than focusing solely on body weight.
The need for caution and further research
Despite the promising findings, the researchers emphasise that the results are based on animal data and cannot yet be directly translated into clinical practice.
“As this is a study conducted on mice, we must be cautious, as there may be significant differences between species in terms of metabolism regulation, adipose tissue distribution and response to drugs. Therefore, we need more clinical evidence on the action of these drugs on fat in humans,” concludes Peyrou.
Further human studies will be required to confirm whether the activation of brown adipose tissue observed in mice also occurs in people receiving tirzepatide and whether it meaningfully contributes to its metabolic benefits.
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GPs Offered £3,000 Incentive to Increase Prescribing of NHS Weight Loss Injections
Key Takeaways:
- GP practices in England will be eligible for a £3,000 annual payment for prescribing the maximum number of eligible patients the weight loss drug Mounjaro.
- Access to NHS weight loss injections remains tightly restricted, with eligibility based on BMI and specific health conditions.
- Professional bodies stress that prescribing decisions are driven by clinical judgement, not financial incentives, and warn that workload pressures may increase.
New financial incentives added to GP contract
GP practices across England are set to receive annual incentive payments of £3,000 for prescribing weight loss medication to the maximum number of patients who meet NHS eligibility criteria.
The payments will be incorporated into the national GP contract from April. In addition, practices will be able to receive approximately £1,000 per year for referring patients to weight loss support programmes.
Ministers have said the objective is to ensure that people who could benefit from structured weight management and pharmacological support are able to access it within primary care.
However, specialists in obesity care have cautioned that the overall impact of the scheme may be modest. They note that eligibility for NHS weight loss injections remains tightly restricted and that the incentive does not expand access to a broader population.
Focus on Mounjaro within primary care
The new incentive applies solely to Mounjaro, a next-generation injectable treatment for weight management.
Mounjaro became available on the NHS in 2025. Despite this, prescribing rates in general practice have reportedly been lower than expected, with some variation in uptake across different areas.
Another injectable weight loss medication, Wegovy, is also available through the NHS. However, it is not prescribed by GPs and is instead provided through specialist NHS weight management services.
More than one million people are estimated to be using weight loss injections in the UK. The majority, around nine in ten, are paying privately rather than receiving the medication through the NHS.
Government position: access based on need
The Health Secretary, Wes Streeting, described the medicines as potentially transformative for people living with obesity.
He said: “Weight loss drugs can be a real game changer for those who need them. I’m determined that access should be based on need, not ability to pay.
“Outside the NHS, we’ve seen those who can spare the cash buying privately, and the proliferation of rogue prescribers peddling dangerous unlicensed drugs that are putting patients at risk.
“Investing in general practice will help bring this modern medicine to the many, not just the few, and help shift the focus of the NHS from treatment to prevention.“
The government argues that embedding prescribing targets within the GP contract is consistent with longstanding practice. Incentive payments have previously been used to improve dementia diagnosis rates, increase vaccination uptake, and encourage the prescription of statins to reduce cardiovascular risk.
This marks the first time that weight loss injections have been formally included in the GP contract framework, with the £3,000 payment linked to prescribing the maximum number of eligible patients Mounjaro.
Strict eligibility criteria remain in place
Although the incentive has been introduced, NHS access to Mounjaro remains limited.
During the current financial year, GPs have only been permitted to prescribe the medication to people with severe obesity defined as a body mass index over 40, alongside certain weight-related health conditions.
From next year, eligibility is expected to expand to include people with a BMI over 35. By 2028, it is anticipated that 220,000 patients will be receiving Mounjaro through the NHS. Lower BMI thresholds apply for some ethnic groups.
Despite these planned expansions, the roll-out to date has been described as uneven, with variation between practices and regions.
Support from obesity advocates – with caveats
Katharine Jenner, Director of the Obesity Health Alliance, welcomed the move but emphasised its limitations.
She said: “This doesn’t mean weight loss drugs will suddenly be available to everyone who wants them.
“NHS access will remain very limited and focused on those with the greatest clinical need, and these treatments are most effective when combined with sustained support.“
She also stressed the importance of prevention alongside treatment:
“If we’re serious about moving from sickness to prevention, expanded treatment must go alongside stronger action to improve the food environment and prevent obesity in the first place.“
Her comments reflect a broader concern within public health that medication alone cannot address the structural drivers of obesity.
Concerns about equity and workload
Dr Katie Bramall, representing the British Medical Association, questioned whether the scheme would meaningfully reduce inequalities in access.
She said: “While the headlines promise much, in reality there will be no change to NHS England’s eligibility criteria for patients to access injectable weight-loss medication on the NHS.
“These proposals will do nothing over the next year to address the divide between those able to pay and those left waiting unable to afford private self-funded treatments“
Similarly, Professor Victoria Tzortziou Brown of the Royal College of GPs emphasised that prescribing decisions are rooted in clinical appropriateness rather than financial drivers.
She said: “GPs do not withhold treatment or prescribe based on financial incentives. Decisions are guided by clinical judgement and what is safest and most appropriate for individual patients.
“Widening the roll-out of these medications in general practice could end up increasing workload in a way that may not be sustainable and risk raising unrealistic expectations among patients who may not be eligible or for whom these medicines are not suitable.“
Her comments highlight the tension between expanding pharmacological options in primary care and managing existing workforce pressures.
A cautious step in a tightly controlled rollout
The introduction of incentive payments signals the government’s intention to embed weight loss pharmacotherapy more firmly within general practice. However, strict eligibility criteria remain in place and access is expected to expand gradually over several years.
While the policy aims to increase NHS provision and reduce reliance on private prescribing, professional bodies and advocacy groups have made clear that the immediate effect will be limited. For now, access continues to be targeted at people with the greatest clinical need, with broader prevention strategies still viewed as essential to addressing obesity at population level.
CCH insight:
It is surprising that GPs need incentivising to prescribe GLP-1 medications like Mounjaro – there is undoubtedly a huge need and demand for these drugs. The reluctance to prescribe them is most likely due to the weight bias that still pervades our society and our health system, the view that people shouldn’t need medication to manage their weight. Referring to these drugs as ‘weight loss jabs’ is not helpful – they are anti-obesity medications. Rather than offer a £3k bonus, GPs should be offered training in understanding obesity as a chronic, relapsing disease, and how GLP-1 medications not only support weight loss but can also improve long-term metabolic and cardiovascular health, and in the long run will save billions of pounds by reducing diabetes and heart disease.
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New Evidence Suggests GLP-1 Drugs May Improve Survival in Severe Psychiatric Disorders
Key Takeaways:
- People living with serious mental illnesses experience substantial excess cardiometabolic risk and premature mortality, driven largely by cardiovascular disease rather than psychiatric symptoms alone.
- GLP-1 receptor agonists may help narrow this mortality gap by targeting obesity, diabetes, cardiovascular disease, and renal disease rather than replacing established psychiatric treatments.
- While promising, the use of GLP-1 receptor agonists in people with serious mental illness requires careful attention to safety, access, cost, and equitable allocation.
A recent editorial published in Expert Opinion on Pharmacotherapy explored the emerging role of glucagon-like peptide-1 receptor agonists in improving survival and long-term health outcomes for people living with serious mental illnesses. The authors emphasised that these medicines are unlikely to replace established psychiatric therapies. Instead, their greatest potential lies in addressing the cardiometabolic drivers of excess morbidity and mortality that disproportionately affect this population.
The editorial situates GLP-1 receptor agonists within a broader public health context, arguing that interventions capable of extending healthspan and reducing cardiovascular mortality are urgently needed for people with serious mental illness.
Development and expanding indications of GLP-1 receptor agonists
The first GLP-1 receptor agonist, exenatide, received approval from the United States Food and Drug Administration in 2005 for the treatment of type 2 diabetes. Since that time, multiple GLP-1 mono-agonists have been approved, alongside tirzepatide, the first dual agonist targeting both the GLP-1 and glucose-dependent insulinotropic polypeptide receptors. Additional dual and triple agonists acting on GLP-1, GIP, and glucagon receptors are now in late-stage clinical development.
While initially developed for glycaemic control in type 2 diabetes, GLP-1 receptor agonists now have indications that extend well beyond glucose lowering and weight management in people living with overweight or obesity. Approved uses include treatment of metabolic dysfunction-associated steatohepatitis in people with moderate or advanced fibrosis, management of obstructive sleep apnoea in adults with obesity, reduction of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease, and slowing the progression of chronic kidney disease while reducing cardiovascular mortality in people living with both chronic kidney disease and type 2 diabetes.
Oral formulations are also expanding. Oral semaglutide is already available, and synthetic small-molecule oral GLP-1 receptor agonists are expected to receive approval in 2026. These formulations may help address barriers related to injectable delivery, manufacturing complexity, supply chains, and access. There is now broad consensus that GLP-1 receptor agonists have transformed the management of metabolic disease and are associated with reductions in renal disease progression, cardiovascular events, and mortality among people with metabolic disorders.
Cardiometabolic burden in serious mental illness
Conditions such as schizophrenia, major depressive disorder, bipolar disorder, and related serious mental illnesses are severe, prevalent, and often lifelong. They are major contributors to disability, reduced healthspan, and diminished social and economic participation, particularly among younger adults.
People living with serious mental illness experience markedly premature and excess mortality. Estimates of years of life lost typically range from five to twenty-five years, with cardiovascular disease accounting for the majority of this gap. Earlier onset of cardiometabolic conditions, higher prevalence of obesity and diabetes, and cumulative exposure to cardiometabolic risk factors all contribute to this disparity.
Each condition currently treated with GLP-1 receptor agonists contributes differently to cardiometabolic risk in this population. In parallel, several agents in mid- and late-stage development target chronic diseases such as peripheral artery disease and atherosclerotic heart disease, conditions that disproportionately affect people living with serious mental illness.
Limitations of current psychiatric treatments on mortality
Although antipsychotics, antidepressants, mood stabilisers, and anticonvulsants are clinically effective for managing psychiatric symptoms, their impact on healthspan and cardiovascular mortality has been limited. Demonstrated reductions in mortality have been confined to selected classes and agents, including second-generation long-acting antipsychotics, lithium, and clozapine.
Lithium, despite strong evidence of efficacy in bipolar disorder and potential mortality benefits, remains under-prescribed. This limits its overall public health impact and underscores the need for complementary strategies that directly address physical health outcomes alongside psychiatric symptom control.
Current and emerging clinical applications in psychiatric populations
GLP-1 receptor agonists are already recommended for managing weight gain associated with psychotropic medications when discontinuation or switching of psychiatric treatment is not feasible. This indication is particularly relevant given the high prevalence of medication-associated weight gain in people living with serious mental illness.
Preliminary evidence also suggests a potential protective effect against lithium-induced nephrotoxicity, a complication for which no approved therapy currently exists. In addition, several GLP-1 receptor agonists are being developed or repurposed for the treatment of alcohol, tobacco, and opioid use disorders.
Beyond metabolic outcomes, preclinical studies, small controlled trials, and observational research suggest that GLP-1 receptor agonists may exert beneficial effects on mood disorders and on specific psychopathology domains that significantly impair quality of life, including cognitive dysfunction and anhedonia. While these findings remain early, they point to possible neuropsychiatric benefits that warrant further investigation.
Safety considerations in people living with serious mental illness
Several safety considerations are particularly relevant in this population. Gastrointestinal side effects, including constipation, may interact with pre-existing gastrointestinal motility disturbances caused by psychotropic medications.
Clinicians should also consider the elevated risks of pancreatitis and sarcopenia, both of which disproportionately affect people living with serious mental illness. Renal function requires particular attention, as GLP-1 receptor agonists that are primarily renally eliminated, such as lixisenatide and exenatide, are contraindicated in severe renal disease, which is more prevalent in this group.
Early pharmacovigilance reports raised concerns about a possible association between GLP-1 receptor agonists and suicidality. However, larger subsequent studies have not demonstrated a causal relationship. Continued monitoring remains advisable, particularly in populations already at increased risk of suicidal ideation and behaviour.
Implications for healthspan and mortality reduction
People living with serious mental illness account for a disproportionate share of years of life lost and disability-adjusted life years worldwide. Despite decades of progress in psychopharmacology, the mortality gap between this population and the general population has not meaningfully narrowed.
Therapeutic strategies that directly reduce mortality and extend healthspan are therefore urgently required. In this context, GLP-1 receptor agonists represent one of the most promising pharmacological classes currently available. Their potential impact will depend on addressing persistent challenges related to cost, reimbursement policy, equitable access, and ongoing supply constraints.
Prioritising people living with serious mental illness within fair allocation frameworks could help reduce excess and premature mortality in this vulnerable population in the near term, while longer-term evidence continues to emerge.
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Wegovy Oral Obesity Treatment Launches in US Pharmacies Following FDA Approval
Key Takeaways:
- The oral form of Wegovy has launched in pharmacies, with the starting dose available now and higher doses expected shortly.
- Clinical trial data show weight loss outcomes comparable to the injectable version when taken as prescribed alongside dietary and activity changes.
- Pricing varies significantly depending on dose and insurance coverage, with list prices matching the injectable formulation.
Oral Wegovy becomes available nationwide
The oral form of Wegovy launched on Monday, with the starting dose now available in pharmacies across the country. Higher doses are expected to arrive by the end of the week, according to reports accompanying the launch.
The pill was approved by the Food and Drug Administration on 22 December for the treatment of obesity. It is also approved to reduce the risk of heart attack and stroke in people who are living with obesity or who are overweight.
Building on the success of the injectable formulation
The launch of the pill follows the blockbuster success of Novo Nordisk’s injectable Wegovy, which has been available since 2021. Demand for the injection was so high that it remained in short supply until February 2025.
Novo Nordisk has positioned the oral formulation as an alternative for people who prefer not to use injections, while maintaining similar clinical effectiveness.
Evidence from clinical trials
Clinical trial data suggest that the oral version of Wegovy delivers weight loss results comparable to the injectable form. In a study published in the New England Journal of Medicine, participants taking a 25 milligram Wegovy pill experienced an average weight reduction of 13.6% over 64 weeks. By comparison, participants receiving a placebo lost an average of 2.2% of their body weight.
Novo Nordisk estimates that people who remain on treatment, reduce their calorie intake and engage in regular physical activity could achieve an average weight reduction of 16.6%.
How the pill is taken and side effects
Unlike the injectable formulation, the Wegovy pill must be taken on an empty stomach. People are advised to wait at least 30 minutes before eating or drinking anything else to ensure the medicine is properly absorbed.
The most commonly reported side effects are similar to those seen with the injection and include nausea, diarrhoea and vomiting.
Pricing and insurance coverage
When Novo Nordisk announced a drug pricing agreement with the Trump administration in November, the company stated that it would offer the obesity pill for $149 per month to people not using health insurance. This price applies only to the starting dose purchased directly by consumers. Higher doses will be priced at $299 per month under the same arrangement.
The list price, which is used to determine insurance coverage, is set at $1,349 per month. This matches the list price of the injectable Wegovy.
Insurance coverage for obesity medications became more restrictive in 2025, according to an analysis from GoodRx, a website that helps people find discounts on prescription medicines. Novo Nordisk has said that people with insurance coverage may be able to access the Wegovy pill for as little as $25 per month.
How Wegovy compares with other oral GLP-1 medicines
Although the Wegovy pill is the first oral obesity treatment of its kind to receive FDA approval, Novo Nordisk already markets an oral GLP-1 medicine for Type 2 diabetes called Rybelsus. Rybelsus contains the same active ingredient, semaglutide, but is prescribed at different doses and is not approved for obesity.
Competition in the oral obesity drug market may soon increase. Eli Lilly, the manufacturer of the Zepbound injection, applied to the FDA in late 2025 for approval of its own obesity pill. The agency granted the company a priority review voucher, with a regulatory decision expected as early as this year.
CCH insight:
Hopefully oral Wegovy will be available in the UK soon, and at a more affordable cost than the injectable version. And this will hopefully enable increased access to the drug on the NHS. The current, very limited availability of GLP-1 therapy on the NHS is costing the UK tax-payer, because the cost of treating the complications and consequences of obesity is much greater than the cost of treating obesity – GLP-1s not only lead to weight loss, they reduce the risk of diabetes, heart disease, kidney disease and possibly many other conditions.
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Manchester Launches Landmark Five-Year Mounjaro Trial to Assess Real-World Outcomes
Key Takeaways:
- A five-year real-world trial in Greater Manchester will evaluate the long-term health, employment, and quality-of-life effects of the anti-obesity medication tirzepatide.
- Up to 3,000 people will participate, with recruitment taking place through GP practices to reflect everyday clinical conditions.
- The study is part of a £279 million partnership between Eli Lilly and the UK government aimed at addressing obesity and improving population health.
Introduction: A major real-world test of tirzepatide
A five-year clinical study has begun in Greater Manchester to examine the real-world effectiveness of the anti-obesity medication tirzepatide, marketed in the United Kingdom as Mounjaro. The trial aims to understand how the treatment affects long-term health outcomes when delivered through primary care. The first participants have now been enrolled after visiting their GP, marking the formal start of the project.
Scope and scale of the trial
Up to 3,000 people are expected to take part in what is described as a first-of-its-kind real-world study. The trial forms part of a broader £279 million initiative jointly developed by US pharmaceutical company Eli Lilly and the UK government. The aim is to evaluate new ways of addressing major public health challenges, including obesity and related long-term conditions.
Professor Martin Rutter, professor of cardiometabolic medicine at the University of Manchester, emphasised the focus on early intervention. He explained that the research will assess “how effective early intervention is in tackling obesity”, and will examine a wide range of clinical and social outcomes.
What is tirzepatide?
Tirzepatide is an injectable medication that works by mimicking a hormone that helps people feel fuller for longer, thereby suppressing appetite. While marketed as Mounjaro in the UK, it is sold under the brand name Zepbound in the United States.
Clinical trials have previously shown that people receiving Mounjaro experienced up to 20 percent weight loss after 72 weeks of treatment. The Greater Manchester study will build on this evidence by measuring how the medication performs in routine practice rather than controlled trial conditions.
Real-world outcomes beyond weight
A distinctive feature of the trial is its focus on long-term and practical indicators of wellbeing. Researchers will assess health metrics but will also study broader outcomes such as employment status, sick-day absences, and quality of life. These measures are particularly relevant given the significant economic and social impact of obesity.
According to Health Secretary Wes Streeting, illnesses linked to obesity currently cost the NHS £11 billion annually. In Greater Manchester alone, approximately 600,000 adults live with obesity, said Mark Fisher, chief executive officer of the NHS Greater Manchester Integrated Care Board.
A 2023 report by Health Innovation Manchester also estimated that obesity costs the region more than £3 billion each year when NHS treatment, social care, and the impact on quality of life are taken into account.
Role of primary care in the study
The trial is major in part because it is being delivered through GP practices, providing insights into how tirzepatide performs when prescribed in everyday settings. Dr Imran Ghafoor, GP Partner at Peterloo Medical Centre in Middleton, highlighted the importance of local trust and accessibility. He stated that patients see their GP practice as a “familiar and accessible space”, adding that the research will help “test solutions tailored to real lives”.
A diverse participant group
Professor Rutter, who also serves as the trial’s chief investigator, noted that the study intends to evaluate the medication’s health effects “in a diverse group of individuals”. This emphasis on diversity aims to ensure that the findings reflect the varied experiences of people living with obesity across the region.
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Use of GLP-1 Drugs Soars Among People Undergoing Bariatric Surgery, Study Finds
Key Takeaways:
- The use of GLP-1 receptor agonists such as semaglutide and tirzepatide among bariatric surgery patients increased sixteenfold between 2020 and 2024.
- Both people with and without Type 2 diabetes are increasingly using these drugs, showing a shift toward combination approaches in obesity management.
- Researchers emphasise the importance of multidisciplinary care and call for evidence-based guidelines to optimise the use of GLP-1 drugs alongside surgery.
A rapid evolution in obesity care
New research has revealed a dramatic increase in the use of weight loss medications among people undergoing metabolic and bariatric surgery, signalling a major shift in the treatment of obesity and Type 2 diabetes.
The study will be presented at the American College of Surgeons (ACS) Clinical Congress 2025, held in Chicago from 4–7 October.
“There is no one-size-fits-all approach to treating obesity, metabolic syndrome, or diabetes and its related conditions,” said Dr Patrick J. Sweigert, senior author of the study and bariatric and foregut surgeon at The Ohio State University Wexner Medical Center in Columbus, Ohio. “We are entering a new world of multidisciplinary care pathways and a new frontier of weight management that is important for patients and surgeons to think about.”
About the study
The research team conducted a large cross-sectional study examining the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) – specifically semaglutide (marketed as Wegovy and Ozempic) and tirzepatide (marketed as Zepbound and Mounjaro) – among people undergoing metabolic and bariatric surgery.
Using data from the Epic Cosmos database, which aggregates over 300 million patient records from healthcare institutions across the United States, Dr Sweigert and colleagues analysed nearly 365,000 individuals who underwent primary metabolic and bariatric surgery between 2018 and 2024.
The study assessed prescription patterns for semaglutide and tirzepatide, two of the most widely prescribed GLP-1RAs, to understand how their use has evolved before surgery.
Key findings
Preliminary findings showed a striking rise in GLP-1 prescriptions in the year preceding surgery – from 1.8% in early 2020 to 29.4% by the end of 2024, representing a sixteenfold increase.
Importantly, the surge was seen among people both with and without Type 2 diabetes, demonstrating the expanding role of GLP-1 drugs in obesity treatment beyond diabetes management.
Among those without Type 2 diabetes, use of GLP-1 drugs before surgery increased elevenfold – from 2.1% in early 2022 to 23.2% by late 2024. For those with Type 2 diabetes, preoperative use quadrupled – from 11.3% to 45.2% over the same period.
The median age of participants was 43 years, with a median preoperative body mass index (BMI) of 46. Women accounted for 80% of the cohort, and 33% had a diagnosis of Type 2 diabetes.
Changing perceptions and treatment pathways
Lead author Dr Stefanie C. Rohde, a general surgery resident at The Ohio State University Wexner Medical Center, explained that the findings represent an evolution in how people view their treatment options for obesity.
“While patients previously believed they had to choose between GLP-1 receptor agonists and surgery, we are now seeing that people are using both,” said Dr Rohde. “We know that patients can use GLP-1s after bariatric surgery to amplify their weight loss. But all of this is still very new in terms of how to manage patients effectively.”
She added that real-world data such as that provided by the Epic Cosmos network could play a critical role in establishing evidence-based clinical guidelines for how and when to integrate GLP-1 therapies – whether before surgery, in combination with it, or during postoperative follow-up.
Limitations and next steps
The researchers acknowledged several limitations. As with many analyses of large health databases, there may be inaccuracies in medical record data. The study was also unable to confirm whether individuals filled or took their prescribed medications, which could affect the reliability of prescription data.
Despite these caveats, the authors believe the study offers valuable insights into emerging trends in combined pharmacological and surgical approaches to obesity care.
Study co-author Mahmoud Abdel-Rasoul, MS, MPH, contributed to the data analysis and interpretation.
Looking ahead
The rapid rise in GLP-1 use among bariatric surgery candidates reflects a broader transformation in obesity treatment – one increasingly characterised by personalised, multidisciplinary, and data-informed care.
As Dr Sweigert noted, “We are entering a new world of multidisciplinary care pathways.” The challenge now lies in defining the most effective, safe, and sustainable ways to integrate these groundbreaking medications into established surgical treatment frameworks.
CCH insight:
These findings from the ACS, showing GLP-1 drug use prior to bariatric surgery, follow on from another study showing that many patients use GLP-1 drugs after surgery, in order to prevent weight regain. This will hopefully help to shift the thinking around obesity treatment. There is still a common perception that patients with obesity have the option of medication or bariatric surgery, and that it is a ‘one-and-done’ treatment. However, we know that obesity is a complex, chronic, relapsing disease which requires a long-term, multi-disciplinary approach. So we need medications, we need surgery and we need behavioural support and other interventions, used together in various combinations, at different times, to provide the life-long care that obesity patients require.
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