Can GLP-1 drugs help tackle addiction?

New research has lent weight to the intriguing idea that GLP-1 agonists may have a role to play in helping people with substance use disorders (SUD) break their addiction.

A meta-analysis carried out by researchers at Washington University School of Medicine in St Louis (WashU) and published in the BMJ has suggested that GLP-1s – now widely prescribed for diabetes and weight loss – may target a common biological pathway underlying addiction.

Their retrospective study was carried out on data from more than 600,000 US veterans with type 2 diabetes (T2D), with those prescribed GLP-1 agonists compared to another group treated with SGLT2 inhibitors, another commonly used treatment for T2D.

They found that after three years of follow-up, the group taking GLP-1 agonists like Novo Nordisk's semaglutide and Eli Lilly's tirzepatide were 14% less likely to develop substance use disorders across all major addictive substances – including alcohol, opioids, cocaine, cannabis, and nicotine – compared to those taking SGLT2.

There was also a significantly reduced risk of severe harm, including overdose and death, in a cohort of veterans who already had SUD at the start of the study. SUD-related emergency department visits fell by around a third, hospital admissions and suicidal thinking or attempts were down by a quarter, and overdoses fell by 39%. Overall, the risk of death from SUD-related causes fell by 50%.

"In addiction medicine, a lot of treatments target just one thing – for example, a nicotine patch helps with smoking, but not alcohol – but there is no medication that works across addictive substances, let alone all of them," said senior author Ziyad Al-Aly, a WashU Medicine clinical epidemiologist.

"The revelation about GLP-1 medication is that it really works against all major substances, and it works uniformly, not because it acts against alcohol or opioids or nicotine specifically, but because it is likely acting against the craving itself," he added. "It blunts that craving that pulls people toward whatever they're addicted to."

Developers of GLP-1 agonists and independent investigation teams are taking the potential seriously, with numerous clinical trials prospectively testing these agents for SUDs. Lilly is testing tirzepatide follow-up brenipatide in phase 3 for alcohol use disorder (AUD) and phase 2 for people addicted to nicotine, for example, while an investigator-led phase 2 trial of semaglutide showed promising efficacy in AUD last year.

Others looking at SUD include Baseline Therapeutics, which started a phase 3 trial of its BT-001 candidate in AUD earlier this year, as well as Altimmune, which is expecting phase 2 results with its pemvidutide for alcohol dependency in the third quarter of this year. The US Department of Veterans Affairs is also planning a large-scale trial of semaglutide in AUD.

There are limitations with the new meta-analysis, including that it involved mainly older men – though a subgroup analysis suggested similar findings in the much smaller female cohort – and it remains possible that unmeasured factors, such as the severity of addiction and socioeconomic status or lifestyle, may have affected the results.

Study finds not all weight returns after stopping GLP-1s

Another meta-analysis, meanwhile, has found that when overweight patients stop taking GLP-1 agonists, they will generally see a rapid regain in weight, but plateau at a new, lower weight.

Published in The Lancet's eClinicalMedicine journal, the study by researchers at the University of Cambridge in the UK has attempted to determine the likely trajectory of weight regain after taking the hugely popular therapies, and found that people on average regain around 60% of their prior weight over 12 months.

It isn't clear, however, whether the weight regain constitutes both fat and muscle, or mainly fat. Previous studies have suggested that lean body mass – including muscle – can constitute up to 40% of total weight lost during treatment.

"If the regained weight is disproportionately fat, individuals may ultimately be worse off than before in their fat-to-lean mass ratio, which may have adverse consequences for their health," said Brajan Budini, one of the study's investigators.

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