Are GLP-1 RAs becoming lifelong medicines?

A recent systematic review published in the BMJ has reignited debate about what happens when patients stop taking glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and related GLP-1–based incretin therapies.

The analysis found that weight often returns quickly once treatment is discontinued – in some cases faster than with other weight-loss interventions.

And it’s not just weight that rebounds. Cardiometabolic risk markers, including blood pressure, blood glucose and blood lipids, were also found to revert towards pre-treatment levels.

As prescribing of these medicines continues to rise, the findings raise a broader question: should patients be starting these medicines in the first place?

AP spoke with experts to unpack the evidence.

Weight regain predictable, but not the real problem

Professor Clare Collins, Professor of Nutrition and Dietetics at the University of Newcastle, said the pattern of rapid weight regain following cessation was entirely unsurprising.

‘This is exactly what you would expect,’ she said.

For Prof Collins, the findings reinforce a core principle of chronic disease management: when an effective treatment is withdrawn, the condition it was controlling usually returns.

‘If someone stops taking antihypertensives, what happens? Their blood pressure goes back up,’ she said. 

‘While predictable, the deterioration back to baseline is why we need to be thinking much more carefully about what is needed for long-term maintenance.’

Prof clare collins

While weight regain attracts headlines, Prof Collins said the more clinically concerning signal is the deterioration in metabolic markers once treatment ceases.

‘While predictable, the deterioration back to baseline is why we need to be thinking much more carefully about what is needed for long-term maintenance.’

Not a sign of treatment failure

Associate Professor Trevor Steward, Director of the Melbourne School of Psychological Sciences’ Brain and Mental Health Hub, agrees that the rebound effect reflects how GLP-1 RA medicines work, rather than a failure of the drugs or patient behaviour.

Instead of creating permanent physiological change, GLP-1 RAs amplify hormonal signals that already exist in the body – particularly those involved in appetite regulation, digestion and satiety. The benefits seen during treatment depend on sustained exposure to these hormones.

‘That’s why we see this rapid rebound effect of people experiencing weight gain when they stop using them, because there’s no longer increased circulating levels of hormones impacting their different body systems,’ A/Prof Steward said.

However, the mechanisms behind the accelerated regain are not yet fully understood.

‘Some indications are that while these newer medications help people lose weight faster, they may cause a stronger slingshot effect,’ he said.

Prof Collins points to emerging evidence suggesting incretin therapies cross the blood–brain barrier, influencing reward pathways linked to appetite and environmental cues to eat.

‘For example, if you go to the supermarket for a loaf of bread and come back with donuts too – that’s what’s referred to as “food noise”,’ she said. ‘Some people say this [noise] really goes down when using these therapies.’

When treatment is withdrawn, the surrounding food environment can quickly reassert itself. This is where tapering, behavioural support and nutrition strategies become critical.

‘It may be that people are more receptive to maintenance support programs as they’re tapering or finding out what their maintenance medication dose is,’ she said. ‘If they’re aware of that point, they’ll recognise when the food noise starts again.’

Nutrition: the missing variable

Prof Collins recently led a systematic review which highlighted that changes in dietary intake and nutrition remain largely invisible in incretin trials.

‘Of all the phase three trials, only two actually measured and reported what people ate,’ she said.

Most trials provided standardised advice but did not collect data on dietary intake, leaving clinicians to infer how appetite suppression, nausea and early satiety shaped eating patterns over time.

‘They mostly worked with people to identify dietary changes that would remove about 2,000 kilojoules a day – enough to trigger weight loss,’ she said.

But reduced intake doesn’t automatically equate to improved diet quality or nutrient adequacy,  with micronutrient deficiencies and loss of lean mass emerging if nutrition isn’t actively monitored.

With frequent patient contact, Prof Collins believes pharmacists are uniquely placed to identify emerging problems, intervene early and support appropriate referral to dietitians for medical nutrition therapy.

‘[And] if pharmacy staff are trained, they can say, “Hang on a minute, you need to talk to the pharmacist”.’

The University of Newcastle also has a suite of resources pharmacists could direct patients to, including a healthy eating quiz and obesity management podcast, available here.

When visible deterioration or rapid weight loss appears, referral becomes essential. ‘Once you think, “this person is fading before our eyes”, that’s when you alert the GP and refer to a dietitian,’ Prof Collins said.

Supporting persistence with therapy also plays a role in outcomes.

‘The main benefit isn’t weight – it’s metabolic health,’ she said. ‘Helping people manage [adverse] effects supports continuation.’

As weight loss occurs, pharmacists should also be alert to the need to review other medicines.

‘If someone is dropping weight rapidly, blood sugars and blood pressure can fall,’ she said. ‘There are also rare but potentially severe complications – pancreatitis, gallstones, bowel obstruction and non-arteritic anterior ischaemic optic neuropathy,’ she said. ‘Staying well hydrated is critical – urine should look straw-coloured.’

Playing the long game

A/Prof Steward said there’s now sufficient evidence to normalise weight regain after cessation. And given the established risks associated with long-term obesity, he suggests continued therapy may represent a lower-risk option for some patients.

‘As we know, having a very high BMI for a long period of time confers its own levels of risks in terms of cardiovascular disease and other issues,’ he said. ‘So [many clinicians] think it’s worth staying on these [medicines] long term as opposed to the potential risk of weight [regain].’

For people with repeated cycles of weight loss and regain, A/Prof Steward said GLP-1 RAs are increasingly being understood as potentially lifelong treatments – similar to medicines used for other chronic conditions.

‘Clinicians want clearer evidence around tapering and maintenance – and right now, they’re operating in the dark.’

A/prof trevor steward

‘I recently had a conversation with someone who has lost over 50 kilograms three times in her life,’ he said. ‘After a sustained period of lifestyle change, the weight still comes back. She would rather stay on these medicines for life than put her body through that cycle again.’

As use expands, A/Prof Steward emphasised the importance of clarifying intent and expectations before treatment begins.

‘It’s really important to have that conversation with a pharmacist or GP about whether they want to make that commitment to potentially taking these long term,’ he said.

This also creates space to explore motivations for initiating therapy.

‘A lot of people are taking these medications for non-health related reasons, e.g. if they have a wedding coming up,’ A/Prof Steward said.

‘So it’s really worth emphasising that these medications are serious drugs that impact the entire body, and it’s not something that should be frivolously taken for the purpose of losing a few kg in a month – only to just have them come back.’

While Prof Collins doesn’t think the BMJ findings should deter prescribing, she said cost must be contextualised early – particularly as maintenance strategies continue to evolve. This may include lower costs associated with food and other medicines.

‘If you’re improving your weight-related health, how much would medical visits have cost if your health hadn’t improved?’ she said. ‘These medications are a long-term cost, like a car or a mobile phone. We also don’t yet know whether, for some people, they may be able to have periods where they don’t take it and then reinitiate at lower doses again.’

With potential PBS listings and new formulations on the horizon, A/Prof Steward said clinical messaging will need to evolve alongside the evidence.

‘Over half a million Australians are now taking these medicines,’ he said. ‘Clinicians want clearer evidence around tapering and maintenance – and right now, they’re operating in the dark.’

For more information, read the AP CPD article Weight loss management.