GLP-1 Tag

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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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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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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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.”

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.

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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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Combination of Hormone Therapy and Tirzepatide Linked to Greater Weight Loss After Menopause, Study Finds

Key Takeaways:

• Postmenopausal women using menopausal hormone therapy alongside tirzepatide lost around 35% more weight than those using tirzepatide alone in an observational study.
  
• The findings suggest a potential interaction between hormone therapy and GLP-1-based obesity medications, although causality cannot be confirmed.
  
• Researchers say the results warrant randomised clinical trials to explore mechanisms and broader cardiometabolic effects.
  
  
  

Weight management challenges after menopause

A new study led by researchers at Mayo Clinic suggests that combining menopausal hormone therapy with tirzepatide may be associated with substantially greater weight loss in postmenopausal women. The findings, published in The Lancet Obstetrics, Gynaecology, & Women’s Health, indicate that women receiving hormone therapy lost around 35% more weight while taking tirzepatide compared with those treated with tirzepatide alone.

Tirzepatide is approved by the US Food and Drug Administration for the treatment of overweight and obesity. The study’s authors say the results could expand treatment options for the many women who experience weight gain and related health risks following menopause.

Menopause is associated with accelerated age-related weight gain and a higher likelihood of developing overweight or obesity, both of which are major risk factors for cardiovascular disease, type 2 diabetes, and other long-term conditions. In addition to changes in body weight, the decline in oestrogen levels that occurs during menopause is also linked to physiological changes that may independently increase cardiovascular risk.

“This study provides important insights for developing more effective and personalized strategies for managing cardiometabolic risk in postmenopausal women,” says Regina Castaneda, MD, postdoctoral research fellow at Mayo Clinic and first author of the study.

Hormone therapy and obesity treatments

Menopausal hormone therapy is considered the most effective first-line treatment for common menopausal symptoms, such as hot flashes and night sweats, which affect up to 75% of postmenopausal women. Despite its widespread use, evidence on how hormone therapy may interact with pharmacological obesity treatments remains limited.

Previous research has suggested that postmenopausal women using hormone therapy may experience greater weight loss when treated with semaglutide, another GLP-1-based medication for obesity. However, until now, no studies had specifically examined whether hormone therapy might influence outcomes in people treated with tirzepatide.

To explore this question, Dr Castaneda and colleagues reviewed data from 120 participants with overweight or obesity who had received tirzepatide for weight management for at least 12 months. Outcomes among participants who were also using menopausal hormone therapy were compared with those of participants with similar characteristics who were not receiving hormone therapy.

Findings and limitations

According to the researchers, women using both treatments experienced markedly greater weight loss than those using tirzepatide alone.

“In this observational study, women who used menopausal hormone therapy lost about 35% more weight than women taking tirzepatide alone. Because this was not a randomized trial, we cannot say hormone therapy caused additional weight loss,” says Maria Daniela Hurtado Andrade, MD, PhD, endocrinologist at Mayo Clinic and senior author of the study.

She adds that other factors may partly explain the difference observed between the groups.

“It is possible that women using hormone therapy were already engaged in healthier behaviors, or that menopause symptom relief improved sleep and quality of life, making it easier to stay engaged with dietary and physical activity changes.”

The authors emphasise that, as an observational analysis, the study cannot establish a causal relationship between hormone therapy and enhanced weight loss. Nonetheless, they argue that the size of the observed difference is clinically meaningful.

Possible biological synergy

Dr Castaneda notes that the findings align with emerging preclinical evidence suggesting a biological interaction between oestrogen and GLP-1-based therapies.

“The magnitude of this difference warrants future studies that could help clarify how GLP-1-based obesity medications and menopausal hormone therapy may interact. Interestingly, preclinical data suggest a potential synergy, with estrogen appearing to enhance the appetite-suppressing effects of GLP-1,” she says.

Such a mechanism could help explain why women receiving hormone therapy appeared to derive additional benefit from tirzepatide in this study.

Next steps for research

The research team plans to build on these findings through more rigorous study designs.

“Next, we plan to test these observations in a randomized clinical trial and determine if benefits extend beyond weight loss – specifically, whether hormone therapy also enhances the effects of these medications on cardiometabolic measures,” says Dr Hurtado Andrade. “If confirmed, this work could speed the development and adoption of new, evidence-based strategies to reduce this risk for millions of postmenopausal women navigating this life stage.”

The study was funded by the Mayo Clinic Center for Women’s Health Research. The full publication includes a complete list of authors, disclosures, and funding sources.

CCH insight:

This is an interesting study, but as the authors state, no conclusions can be drawn from the findings. But it does raise many questions about the possible potential synergistic effects of oestrogen and GLP-1 therapy. Establishing whether cardiometabolic benefits of GLP-1 medications are amplified, as well as weight loss, should be a priority.

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Almost a Quarter of UK GPs Report Obesity in Children Aged Four and Under

Key Takeaways:

• Nearly one in four UK GPs report seeing children aged four and under where obesity is a clinical concern, with cases identified even in infancy.
• Most GPs find conversations about weight with children and parents difficult, citing fear of distress, stigma and complaints.
• The survey also raises concerns about inappropriate private access to GLP-1 weight loss medicines among adults who do not meet eligibility criteria.
  
  
  

Growing concern among family doctors

Almost a quarter of UK general practitioners report seeing children aged four or under who are living with obesity, according to a new survey of family doctors. The findings point to what respondents described as an “alarming” escalation of childhood obesity presenting at ever younger ages.

The research found that almost half of GPs, 49 per cent, have seen boys and girls up to the age of seven with obesity, including a small number of children younger than one year old. These early presentations raise concerns about long-term health consequences and the pressures faced by primary care clinicians in addressing weight sensitively and effectively.

Survey scope and headline findings

The survey, conducted by MDDUS, asked 540 family doctors about their experiences of managing obesity, the rapid growth in the use of weight loss medications, and the implications of widespread overweight and obesity for the NHS.

Almost one in four respondents, 23 per cent, said they had seen children aged zero to four where obesity was a clinical concern. Across childhood more broadly, 81 per cent of doctors reported seeing obesity in children between the age of 12 months and 11 years.

Dr John Holden, chief medical officer at MDDUS, said:
“These findings are an alarming confirmation of the growing crisis of childhood obesity across the country and the very real difficulties this creates in everyday GP consultations.”

Challenges of discussing weight with families

Despite the scale of the issue, most GPs reported significant difficulty in raising concerns about weight with children and their families. Four in five doctors, 80 per cent, said they find it somewhat or very challenging to talk to the parents of a child under 16 living with obesity about their weight and health. Only 10 per cent said they found such conversations easy.

Nearly two thirds of respondents, 65 per cent, also reported difficulty speaking directly with young people themselves about weight, with just 20 per cent describing those discussions as easy.

Doctors cited multiple reasons for this hesitation. Conversations with parents are often constrained by concerns that parents may become upset, reported by 72 per cent, angry, reported by 47 per cent, or may make a complaint, reported by 24 per cent. A further 74 per cent worried that such discussions could cause shame or stigma. Similar concerns were reported when speaking with children, including fears that conversations about weight could contribute to disordered eating behaviours.

The wider determinants of childhood obesity

Respondents highlighted that obesity is shaped by complex and interrelated factors, including poverty, limited access to nutritious food, and fewer safe or affordable opportunities for children to be physically active. These realities, the survey suggests, shape how GPs approach discussions about weight.

Dr Holden said GPs therefore approach these conversations “with care and empathy for families under pressure”. He added:
“When parents feel judged or blamed, conversations can quickly become emotionally charged and, as our members tell us, can lead to complaints from distressed or angry parents.”

Calls for stronger prevention measures

Katharine Jenner, executive director of the Obesity Health Alliance, said the findings underline a failure to protect children early in life.

She said that the high numbers of GPs seeing infants and very young children with obesity “is another sign we’re letting children down before they even start school. If we’re serious about prevention, it has to begin in the earliest years, otherwise the damage follow them through life.”

Jenner called for a stronger focus on prevention, including reformulation of food and drink products to improve their nutritional quality, tighter restrictions on the marketing of products high in fat, salt and sugar, and better support for families facing structural and financial barriers to healthy eating.

Concerns over private access to weight loss drugs

Alongside childhood obesity, the survey also explored GP experiences of adult patients using weight loss medications inappropriately. Doctors reported that some adults who should not be using GLP-1 weight loss drugs are obtaining them through deception from private pharmacies.

These include people with eating disorders, such as anorexia or bulimia, and people already taking other medications that could interact adversely with so-called “fat jabs” and pose risks to their health.

It is estimated that around 1.5 million people in Britain are using GLP-1 medicines for weight loss, the majority having obtained them privately rather than through the NHS, where eligibility criteria are strict.

One GP told the survey that GLP-1s are being “accessed privately pretty indiscriminately by many people whose body mass index is not in the obese category”. Another described a patient with a history of anorexia nervosa who had also obtained the drugs privately. Overall, 67 per cent of family doctors said they had seen patients using GLP-1s despite not meeting eligibility rules.

These findings raise questions about how rigorously private pharmacies are carrying out appropriate checks, including assessments of medical history and potential drug interactions, before supplying weight loss medications.

Implications for the NHS and future care

The vast majority of GPs surveyed said obesity is likely to be a defining public health challenge during their careers, with 92 per cent agreeing with that statement. An even higher proportion, 95 per cent, believe obesity will significantly affect the NHS’s ability to deliver care.

However, views on weight loss injections were more mixed. While 59 per cent of respondents believe such medications will ultimately save the NHS money, 22 per cent disagreed.

Government response

The Department of Health and Social Care did not comment directly on the survey findings. A spokesperson said:
“Every child deserves the best possible start in life, which is why this government is taking decisive action to tackle childhood obesity.

“We are restricting junk food advertising on television before 9pm and online, a move expected to remove up to 7.2bn calories per year from children’s diets; while giving local authorities new powers to stop fast food shops opening outside schools.

“Through our ten-year health plan, we’re shifting the focus from sickness to prevention to create a healthier nation.”

CCH insight:

This study highlights the considerable challenges that primary care practitioners face in addressing obesity in young children. It is a very sensitive issue, and there may also be cultural attitudes that see overweight children as beautiful or healthy. Unfortunately, healthcare professionals in the UK are not trained to deal with obesity and the unique challenges it presents. It requires a very sensitive approach, communicating with parents in a non-judgemental way, highlighting the role of the obesogenic environment and finding ways to support behaviour change at a family level. On the positive side, if this can be achieved, an entire family can benefit from these interventions, not just the child with excess weight.

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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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Study Highlights Benefits and Limits of Generative AI in Weight Management

Key Takeaways: 

• A short field experiment suggests that generative AI can support modest reductions in weight and body mass index through personalised dietary feedback.
  
• Private use of AI tools appears more effective than public sharing, with public analysis associated with higher dropout rates.
  
• People with lower levels of nutritional knowledge benefited most, indicating potential for AI to help reduce health inequalities, although it does not replicate the value of human community support.
  
  
  

Introduction

Nearly three-quarters of adults in the United States are living with overweight or obesity, and prevalence continues to rise globally. As a result, demand for high-cost interventions such as bariatric surgery and glucagon-like peptide-1 medications has increased, placing significant financial pressure on health care systems.

A new working paper suggests that generative artificial intelligence may offer a low-cost way to support people with weight loss by helping them make more informed dietary choices. However, the research also indicates that AI tools do not replicate the benefits of community-based programmes where people can share experiences and openly discuss the physical and psychological challenges associated with obesity.

The study was conducted by Catherine Tucker, Professor of Marketing at MIT Sloan School of Management, and Linyi Li of Singapore Management University. They followed 416 adult participants of varying ages over a three-week period in late 2024.

Study design and intervention

The researchers partnered with an Asia-based Fortune 500 company that runs an online weight loss boot camp combining guidance on healthy eating and physical activity. The programme included a group chat function using WeChat, enabling participants to interact, share experiences and support one another.

Participants were divided into three groups to assess the impact of a generative AI tool designed to analyse meals. The tool evaluated the nutritional content of food based on photographs and provided real-time, personalised suggestions such as adding more vegetables or choosing leaner protein sources.

The three groups were structured as follows:

• Group 1 – control group: Participants received general healthy-diet tips and access to the group chat but did not use the AI food-analysis tool.
  
• Group 2 – private analysis group: Participants sent photos of their meals privately to an administrator and received personalised AI-generated nutrition reports.
  
• Group 3 – public analysis group: Participants shared meal photos within the group chat, where both the images and the AI-generated nutrition reports were visible to all group members.
  
  
  

Finding 1 – Generative AI supported weight loss

Compared with the control group, both groups that used the AI food-analysis tool showed higher engagement with the programme, greater weight loss and larger reductions in body mass index.

On average, participants in Group 1 lost 0.966 kg over the three-week period. Those in Group 2 lost 1.426 kg, while participants in Group 3 lost 1.358 kg.

Although the absolute numbers were modest, Tucker emphasised their significance given the short duration of the intervention.

“Weight loss is such a big challenge. If it were easy for us all to lose weight, we’d just lose weight,” Tucker said. “The fact that a digital tool such as AI can have any effect is wonderful because interventions such as surgery or injectables are expensive. This is evidence of the cost efficacy of a very small intervention in terms of changing behavior.”

According to Tucker, the results highlight the value of generative AI in personalising individual experiences by offering tailored feedback, practical knowledge and guidance on day-to-day dietary decisions.

Finding 2 – Public analysis reduced participation

The way in which the AI tool was used had a clear impact on engagement. Participants with private access to the food-analysis tool were significantly more likely to remain in the programme for the full three weeks.

In contrast, Group 3, where meal photos and AI feedback were shared publicly, had the highest dropout rate. Tucker suggested that some participants may have felt discouraged by seeing highly engaged or high-performing peers, leading to disengagement.

“Dropout is the big enemy of weight loss,” Tucker said. “A likely explanation [for dropouts in Group 3] is that staying in the group introduced pressure [when] consistently reporting less-favorable statistics compared to others.”

The findings suggest that making AI-generated feedback public may alienate some individuals and reduce sustained participation. Community-based programmes such as Weight Watchers have historically succeeded by fostering mutual support during both successful and challenging periods.

As Tucker noted,

“There’s a set of people there to support you through good or bad weeks. I think what we are demonstrating is that if you make it too easy to post success stories, then you lose some of that [shared] vulnerability within the community.”

Finding 3 – Potential to reduce health inequalities

The researchers also found that the greatest benefits from the AI tool were seen among participants with lower levels of education and less prior nutritional knowledge. These individuals often struggle to interpret standard weight loss advice and appeared to gain particular value from detailed, personalised recommendations generated by the AI system.

The authors suggest that this capability could help reduce health inequalities by improving access to understandable, tailored dietary guidance for people who may otherwise be disadvantaged by traditional educational approaches.

Implications for the use of AI in health behaviour change

Although the study focused specifically on weight loss, the authors argue that the findings have broader relevance for how people interact with AI systems. Generative AI appears well suited to supporting individual behaviour change through personalisation, prompts and reminders. However, it does not replicate the social connection and emotional support provided by human communities.

For organisations and programme designers, the research suggests that AI should be used to enhance individual-level support rather than as a replacement for community-building or large-scale digital ecosystems.

Although the research was conducted in China, Tucker stated that the findings are likely to be applicable in other settings.

“I think what our research shows is that in the generative AI age, technology can certainly assist with information retrieval, reminders, prompts, all those good things, but we can’t really use it to replace that sense of community,” Tucker said.

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More Than One in Four Adults Worldwide May Be Eligible for GLP-1 Weight-Loss Medicines, Global Analysis Suggests

Key Takeaways: 

• More than 27 percent of adults globally may be eligible for GLP-1 receptor agonists for weight management, based on pooled data from 99 countries.
  
• Eligibility is highest among women, older adults, and people living in low- and middle-income countries, raising significant questions around access and health equity.
  
• Researchers emphasise that medicines alone are not sufficient, and sustained investment in prevention and non-pharmacological obesity care remains essential.
  
  
  

A growing global obesity challenge

The worldwide prevalence of obesity has more than doubled over the past three decades, accompanied by sharp rises in weight-related conditions such as type 2 diabetes, cardiovascular disease, and several cancers. This escalating public health challenge places increasing strain on healthcare systems and national economies across the globe.

Against this backdrop, a new international study suggests that glucagon-like peptide-1 receptor agonists, commonly referred to as GLP-1 medications, could play a substantial role in addressing obesity and its related complications at scale. The analysis was co-led by investigators from Mass General Brigham and aimed to estimate how many adults worldwide might benefit from these medicines.

Large-scale global data analysis

Researchers from Mass General Brigham collaborated with colleagues at Washington University School of Medicine in St. Louis and Emory University’s Rollins School of Public Health to pool household health survey data from 99 countries, collected between 2008 and 2021.

The final dataset included 810,635 adults aged 25 to 64 years, selected based on the availability of key clinical measures, including:

• Body mass index
• Blood pressure
• Diabetes biomarkers
• Diagnostic history of hypertension and diabetes
  

Eligibility for GLP-1 treatment was defined using established clinical thresholds. Adults were considered eligible if they had:

• A BMI greater than 30, or
• A BMI greater than 27 in the presence of hypertension, diabetes, or both
  
  
  

One in four adults eligible worldwide

Using these criteria, the researchers found that 27 percent of adults globally would be eligible for GLP-1 medications for weight management. Notably, around four-fifths of eligible individuals lived in low- and middle-income countries, highlighting a potential mismatch between need and access.

Eligibility varied substantially by region:

• Europe and North America showed the highest rates at 42.8 percent
• The Pacific Islands followed closely at 41.0 percent
  

Differences were also observed across demographic groups:

• Women were more likely to be eligible than men, at 28.5 percent versus lower rates among men
• Older adults showed markedly higher eligibility at 38.3 percent, compared with 17.9 percent among younger adults
  

The findings were published as a research letter in The Lancet Diabetes & Endocrinology.

Rethinking obesity through biology

Commenting on the findings, co-senior author Jennifer Manne-Goehler, MD, ScD, a physician at Brigham and Women’s Hospital and Mass General Brigham, highlighted the paradigm shift represented by GLP-1 therapies.

“There has never been such a potentially transformational and scalable tool for obesity, type 2 diabetes, and other health-related complications of obesity.”

She also reflected on the historical framing of obesity as a personal failing rather than a biologically driven disease.

“For so many decades, we told everyone the problem was you – you need to move more and eat less, then you will not struggle with this problem. GLP-1 receptor agonists have allowed us to really understand that biology is much more powerful than that, and ‘eat less, move more’ is just an oversimplified way to think about things.”

Global interest meets practical constraints

The potential of GLP-1 medicines has already been recognised by the World Health Organization, which is actively exploring ways to make these treatments more widely available as standard therapies. However, translating this promise into real-world impact depends on understanding the scale of need and addressing significant barriers to access.

Corresponding author Sang Gune K. Yoo, MD, who conducted the work while a research fellow in cardiology at Washington University School of Medicine, noted that the findings were consistent with global obesity trends.

“Given the steadily increasing prevalence of obesity, it is not surprising that our analysis found that more than one quarter of adults around the world may be eligible for this medication.”

He cautioned, however, that important questions remain unanswered.

“This medication has the potential to help many individuals, although further research is needed to better understand its long-term safety and sustainability. Access remains a major challenge as these medications are difficult to obtain in many settings. Most importantly, we must continue to invest in and develop effective non-pharmacological strategies for the prevention and treatment of obesity, an area where substantial gaps remain.”

Equity at the centre of global implementation

The study also underscores profound equity considerations. Eligibility was disproportionately high among women and people living in regions with limited healthcare resources.

Manne-Goehler highlighted the urgency of addressing these disparities.

“These socioeconomic and gender eligibility percentiles are especially staggering. As of last year, type 2 diabetes was the top cause of death for women in South Africa. There are parts of the world where women can really benefit from these medicines, and it is our job to see through their implementation.”

Co-lead author Felix Teufel, MD, from Emory University’s Rollins School of Public Health, framed access to GLP-1 therapies as a broader ethical issue.

“Global access to GLP-1s is a question of health equity. The goal is to ensure large-scale access for people who would benefit most – not just those easiest to reach.”

Beyond medicines alone

While the findings point to a potentially transformative role for GLP-1 medications in global obesity care, the authors stress that pharmacological approaches cannot replace comprehensive prevention and treatment strategies. Addressing obesity at scale will continue to require sustained investment in public health, supportive environments, and evidence-based, non-pharmacological interventions alongside new medical therapies.

CCH insight:

This study reminds us of the scale of the obesity pandemic. There are more than 1 billion people estimated to be living with obesity, according to the World Health Organisation – most of whom could in theory benefit from GLP-1 medications. The priority should be to provide access for those who are in greatest need, rather than those who can afford to pay for them. The development of oral GLP-1s is a big step, as this will increase access and bring prices down, but there is a very long way to go.

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