Novo Nordisk Launches Late-Stage Trial to Find the Lowest Effective Dose of Oral Wegovy
Key Takeaways:
- Novo Nordisk has begun OASIS-5, a 60-week late-stage trial testing lower maintenance doses of the oral Wegovy pill.
- The trial will enrol 450 adults with a BMI of 30 or above, or 27 with a weight-related health condition.
- Interest in lower dosing reflects real-world practice, where cost and side effects already drive some people to take reduced doses.
A trial built around dose flexibility
Danish drugmaker Novo Nordisk has started testing smaller doses of its Wegovy pill in a new late-stage study designed to identify the lowest dose that still supports weight loss, according to a listing on a US clinical trials database.
The study, known as OASIS-5, began on 12 August and is scheduled to run until 2028. It will examine lower strengths of the daily maintenance dose – the dose used to sustain weight loss once it has been achieved, rather than the escalating doses used at the start of treatment. At present, the approved long-term dose of the Wegovy pill is 25 milligrams.
“Having a broader range of maintenance doses could provide greater flexibility in treatment and optimising the patient experience,” Novo said in an emailed statement to Reuters.
Novo has not specified which new dose strengths are being tested. The Wegovy pill is also approved in doses of 1.5 mg, 4 mg and 9 mg.
What OASIS-5 will measure
The 60-week trial will recruit 450 adult participants who have previously struggled to lose weight, with a Body Mass Index of 30 or above, or 27 in combination with a weight-related health issue.
The primary objective is to establish whether lower doses of oral semaglutide – the active ingredient in Wegovy – produce greater weight loss than placebo over the 60-week period. Secondary objectives include changes in waist circumference, other health benefits and the side effect profile at these reduced strengths.
The study will exclude people living with diabetes, those who have experienced recent major weight changes, and anyone currently being treated with GLP-1 medications.
Seeking health benefits beyond weight loss
The trial arrives against a backdrop of dosing behaviour that is already happening outside clinical protocols. Some people taking GLP-1 medicines, including Wegovy and Lilly’s Zepbound injections, are microdosing or otherwise taking lower-than-approved doses. The practice has become popular largely because of the high cost of the medicines and the side effects associated with them.
“People are using low dosages of these products… they just decide on their own,” Novo CEO Mike Doustdar told Reuters in an interview last week, noting that patients often seek health benefits beyond weight loss.
That observation points to a broader question facing prescribers: what people hope to gain from GLP-1 therapy is not always confined to the number on the scales. Understanding the pharmacology behind dose escalation and maintenance, and being able to discuss the trade-offs between efficacy, tolerability and cost, is increasingly central to safe prescribing. It is a theme covered directly in the College of Contemporary Health’s CPD short course GLP-1RAs in Practice: Prescribing, which examines dose titration, monitoring and shared decision-making in day-to-day clinical settings.
Competitive pressure in a growing market
Novo is under pressure after losing ground to US rival Eli Lilly in an obesity drug market projected to exceed $100 billion by 2030. Investors are watching the Wegovy pill closely; it generated second-quarter sales of 3.22 billion Danish kroner ($499.89 million).
Doustdar expects market segmentation to prevent a winner-take-all contest with Lilly – a view consistent with a future in which different doses, formulations and treatment goals serve different groups of people rather than a single product dominating.
Lilly did not immediately respond to a Reuters request for comment on whether it plans to test smaller doses of its oral drug Foundayo, which has lowest approved doses of 0.8 mg and 2.5 mg.
What this could mean for practice
If OASIS-5 demonstrates that lower maintenance doses deliver meaningful weight loss, it would give clinicians a wider set of options for people who cannot tolerate higher strengths, who are managing the cost of long-term therapy, or who have reached a weight they wish to maintain rather than continue reducing. It would also bring an existing real-world practice within the evidence base, replacing self-directed dose reduction with an approved, monitored alternative.
Results are not expected until 2028, so any change to prescribing practice remains some way off. In the meantime, conversations about dosing, expectations and adherence will continue to sit with the healthcare professionals supporting people through treatment.
CCH insight
Dose selection, titration and tolerability are among the most common practical challenges in GLP-1 prescribing. The College of Contemporary Health’s CPD short course GLP-1RAs in Practice: Prescribing covers dose escalation and maintenance, managing side effects, patient selection and monitoring – equipping healthcare professionals to make confident, evidence-based decisions as the treatment landscape evolves.
Explore GLP-1RAs in Practice: Prescribing →
Source: Reuters
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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.
Navigating these considerations well – patient selection, contraindications, side-effect management and monitoring – is the focus of professional training such as the College of Contemporary Health’s GLP-1RAs in Practice: Prescribing, a CPD-accredited online short course.
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.
CCH insight
This emerging evidence points to real promise for a group facing a stark mortality gap – but realising it safely depends on clinicians who are confident using GLP-1 medications well, particularly in patients with complex comorbidities. CCH’s GLP-1RAs in Practice: Prescribing CPD short course (2 CPD hours, fully online, CPD-accredited) equips prescribers to get every part of the consultation right, from patient selection and contraindications through to titration, side-effect management and monitoring.
Explore GLP-1RAs in Practice: Prescribing →
Higher Dose of Semaglutide Delivers Greater Weight Loss and Metabolic Improvements
Key Takeaways:
- Tripling the standard dose of semaglutide led to significantly greater weight loss and improved metabolic outcomes, without an increase in serious adverse effects.
- Participants on the higher dose achieved clinically meaningful reductions in body weight, waist circumference, and HbA1C levels, with nearly one-third losing 25% or more of their starting weight.
- Side effects were mostly mild and transient, suggesting that the higher dose may be a safe option for people requiring more intensive obesity treatment.
Landmark findings from the STEP UP trials
Tripling the standard dose of semaglutide – a widely prescribed glucagon-like peptide-1 receptor agonist (GLP-1RA) – resulted in markedly greater weight loss and cardiometabolic benefits, according to results from two large multicentre clinical trials led by UT Southwestern Medical Center. The studies, published in The Lancet Diabetes & Endocrinology, indicate that patients may be able to safely take a higher semaglutide dose than currently approved if they need to lose additional weight.
“Semaglutide and other drugs in its class have been life-changing for people living with obesity around the world. Our new findings suggest that increasing the dose can lead to even greater benefits and may be appropriate for some patients,” said study leader Dr Ildiko Lingvay, Professor of Internal Medicine in the Division of Endocrinology and in the Peter O’Donnell Jr. School of Public Health at UT Southwestern.
Context: The global obesity challenge
Obesity affects nearly one billion people worldwide, according to the World Health Organization, and is a major driver of conditions such as Type 2 diabetes, cardiovascular disease, certain cancers, and liver disease. GLP-1RAs, first authorised in the early 2000s, have transformed the management of Type 2 diabetes and, more recently, chronic weight management and cardiovascular risk reduction.
Semaglutide received approval from the US Food and Drug Administration (FDA) in 2017 for people with Type 2 diabetes and has since been approved at a 2.4 mg weekly dose for weight management in both the United States and European Union. While this dose can produce significant weight loss, many patients do not achieve their treatment goals.
The STEP UP trials: Design and participants
To explore whether higher doses could deliver additional benefits, researchers conducted two phase 3b clinical trials – STEP UP Diabetes and STEP UP Obesity – to compare the effects of a weekly 7.2 mg dose of semaglutide with the standard 2.4 mg dose and placebo.
In the STEP UP Diabetes trial, 512 adults with both obesity and Type 2 diabetes were randomly assigned to three groups:
- 307 participants received 7.2 mg semaglutide weekly.
- 103 participants received 2.4 mg semaglutide weekly.
- 102 participants received placebo.
Participants were followed for 72 weeks at 68 trial sites across eight countries in Europe, southern Africa, and North America, including UT Southwestern. All participants received counselling every four weeks to encourage reduced-calorie diets and increased physical activity.
Results: Substantial weight loss and metabolic gains
Weight loss outcomes
As seen in earlier studies, the standard 2.4 mg dose produced a mean weight loss of 10.4% of starting weight, compared with 3.9% in the placebo group. However, participants taking the higher 7.2 mg dose achieved an even greater mean weight loss of 13.2%.
In addition, those receiving 7.2 mg were significantly more likely to:
- Reach a 20% reduction in waist circumference – a key measure of cardiometabolic health.
- Achieve superior improvements in HbA1C, an indicator of blood sugar control.
Outcomes in people without type 2 diabetes
The STEP UP Obesity trial, which focused on people with obesity but without Type 2 diabetes, showed even more striking results. Nearly one-third of participants on the higher dose lost 25% or more of their starting weight, compared with 15% of those on the standard dose and none on placebo.
Safety profile and side effects
The most frequently reported side effects were gastrointestinal symptoms, such as nausea, diarrhoea, and constipation. These affected approximately half of participants taking semaglutide and about a quarter of those on placebo. Most symptoms occurred during the dose-escalation period and tended to diminish over time.
The only side effect reported more frequently in the higher dose group was dysaesthesia (a change in touch sensation), experienced by approximately 20% of participants taking 7.2 mg, compared with 5% of those on the lower dose. Importantly, there was no increase in serious adverse events associated with the higher dose.
“These findings reinforce the promise of semaglutide and other GLP-1RAs, with benefits that appear to increase at higher doses without compromising patient safety,” Dr Lingvay concluded.
Funding and disclosures
Both STEP UP trials were funded by Novo Nordisk A/S, the manufacturer of semaglutide. Dr Lingvay reports receiving personal consulting fees from Novo Nordisk.
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