Beyond GLP-1s: Rethinking Obesity Treatment for the Long Term

GLP-1 drugs are changing how we treat obesity – and stirring global debate about what comes next. While early data shows impressive weight loss and wider health benefits, these treatments also raise questions about long-term use, access and what should count as a sustainable solution to a global health crisis.

Professor Simon Griffin, program lead of the Prevention of Diabetes and Related Metabolic Disorders in High Risk Groups program at the University of Cambridge, has spent decades studying diabetes and obesity prevention. He’s clear-eyed about the potential of GLP-1s – and their limits.

“After a longstanding litany of failure (mainly due to serious adverse effects) of weight management drugs, the GLP-1s appear to be highly effective and safe, which is something of a game changer,” said Griffin.

The impact of GLP-1s

GLP‑1 receptor agonists, such as semaglutide and tirzepatide, have reshaped obesity treatment. These drugs mimic a natural gut hormone to reduce appetite, slow digestion and improve blood sugar levels. Trials show people lose ~15–20% of their body weight, far more than with older medications or lifestyle changes alone.

“Most people do not choose to be obese, and some can now benefit from an effective treatment,” said Griffin.

These drugs have also shown the potential to help beyond weight loss, such as cardiovascular or metabolic benefits. The SELECT cardiovascular outcomes trial, involving over 17,600 participants at high cardiovascular risk, found that semaglutide cut major cardiac events by 20% over nearly 3 years. Earlier diabetes-focused trials, such as the LEADER clinical trial examining liraglutide, confirmed similar cardiovascular and metabolic improvements.

“Obesity is a risk factor for multiple non-communicable diseases from type 2 diabetes, cardiovascular disease and some cancers, through to mental health problems and, as you will recall from the COVID-19 pandemic, also for adverse outcomes of communicable disease,” said Griffin.

“GLP-1s are therefore likely to reduce the risk of a wide and increasing range of obesity-related conditions. GLP-1 receptors are found in multiple tissues in the body, so benefits are likely to extend beyond what we currently consider to be obesity-related conditions,” he added.

Despite the huge impact these drugs have had, caution is needed. There is a lack of clear data on long-term safety beyond a few years, and common side effects – such as nausea, vomiting, constipation and gallbladder issues – are well known. Rare outcomes like pancreatitis or more serious events may also surface.

“Placebo-controlled trials to date appear to be relatively reassuring in terms of the adverse effects of these drugs over and above the adverse effects of any intervention leading to weight loss (for example loss of lean mass) but their widespread use has been relatively short-lived, so it is likely that some adverse effects will emerge over time,” Griffin added.

Crucially, studies have shown that once an individual stops treatment, the weight tends to return, and quickly.

In the STEP 1 extension, participants regained  around two-thirds of the weight lost within a year of stopping semaglutide, returning to a ~5.6% net loss over two years.

GLP-1 drugs and the equity gap in obesity care

GLP-1 drugs are becoming widely used in the UK, although mostly by those who can afford them.

“At the end of 2024, 500,000 people were taking semaglutide or tirzepatide in the UK, of which 95% were buying the medications privately at a cost of around £150 a month,” said Griffin.

“GLP-1s are a classic example of the inverse care law,” he added.

Obesity hits the poorest hardest, yet GLP-1 treatment reaches wealthier people first. Obesity rates are rising fastest in low‑ and middle‑income countries, where health budgets are already stretched.

In the UK, the NHS plans to treat 220,000 people over 3 years. At the same time, half a million are self-sourcing these drugs privately, raising safety concerns since online vendors often lack regulation.

“In a resource-constrained health care system, the huge cost of these drugs will inevitably mean that there are fewer resources to devote to other conditions,” Griffin said.

The promise of lower prices as drugs go off‑patent and competition increases may help. But Griffin believes the real answer lies in population-wide prevention.

“In an ideal world, the need for such drugs would be reduced by population-based preventive strategies that reverse the upward shift in the population distribution of body mass index/body fat percentage.”

Unlike individual treatments, policy-level interventions need less personal effort and tend to reduce rather than increase health inequalities. They can also address shared drivers like food systems and climate, delivering multiple benefits to the health of individuals and the planet.

Beyond GLP-1s: Digital, behavioral and policy solutions

Digital tools and behavior insights can help us move beyond drug-focused obesity care.

“I am biased by my our group’s research interest, but I would say that scalable, digital approaches to support weight loss maintenance, which draw on Acceptance and Commitment Therapy (ACT) and can follow behavioral, drug and bariatric surgery weight loss interventions, show promise,” said Griffin.

“Greater understanding of appetitive traits and how people respond differently to environmental cues should inform the development of more personalized behavioral approaches to weight management,” Griffin added.

These digital interventions, apps, wearables or web platforms using ACT, help people keep weight off after initial losses. ACT encourages acceptance of cravings while committing to values-based actions. In one evaluation, digital platforms added to GLP‑1 therapy boosted weight loss by ~60% at 3 months.

Tackling unhealthy food environments through regulation, taxation and incentives is also important, methods that do not rely on individuals to act.

“There is progress in understanding and evaluating our dysfunctional food systems and the wider underlying collective determinants of obesity. However, translating this knowledge into effective, implementable strategies/policies is an uphill struggle for several reasons,” said Griffin. “These include the very powerful, wealthy, influential and frequently supra-national organizations with vested interests in maintaining the current obesogenic environment, and the nature of the evidence underpinning population-based approaches, which tends to be less persuasive than the randomized controlled trials demonstrating effectiveness of drugs.”

“Despite the huge economic cost of obesity, policymakers appear reluctant to use fiscal or regulatory approaches to address its wider determinants,” he added.

Individual and collective level strategies work best in combination, while drugs such as GLP-1s can kickstart change, ACT-based digital tools and a less obesogenic environment can help sustain benefits.

Treating obesity as a chronic condition

“Obesity is a chronic problem like hypertension and type 2 diabetes, neither of which one would treat for a year, then stop treatment and assume that the condition had resolved,” said Griffin.

That’s why short-term fixes – even highly effective ones like GLP-1 drugs – won’t solve it alone.

“By 2050, half of all adult humans will be overweight or living with obesity, so expensive medications like GLP-1s cannot be the sole strategy for tackling the obesity crisis, which is a societal as well as a medical problem,” Griffin added.

Treating billions of people with weekly injections for life is not realistic. It’s also not the most effective use of limited health budgets.

Pharmacology is also evolving. Griffin notes that “Ozempic^TM and Mounjaro^TM represent the first of many incretin-based drugs for weight management.”

MC4R agonists like setmelanotide are now approved for rare genetic obesity, cutting weight by ~7–10% and improving metabolism despite some skin‑pigment effects.

“Advances in ‘omics’ technologies should increase the rapidity of novel drug development,” Griffin added.

Although these will help, the challenge isn’t just biological – it’s structural, social and economic.

“The GLP-1 drugs are not a panacea. The drugs will form an important element of obesity treatment once their limited availability increases, alongside behavioral weight management (which is effective), bariatric surgery and so on,” said Griffin.

The future of obesity care won’t be a single fix. It will be a model that treats obesity like the chronic, relapsing disease it is, while also changing the conditions that made it widespread in the first place.

“We should exercise some caution as the ‘wrap-around care’ required to go along with the drugs, is not yet widely available, the cost of drug treatment of all those who are potentially eligible is unaffordable and medicalising half of all adult humans to deal with a societal problem is inefficient and illogical,” Griffin concluded.