Losing weight is hard. Very hard. Indeed, research suggests that only around 20 per cent of people who intentionally lose a significant amount of weight through dieting manage to keep it off for at least a year.
However, the emergence of glucagon-like peptide-1 (GLP-1) receptor agonist drugs has made this battle easier. By dramatically reducing people’s hunger drive, these drugs have made substantial weight loss achievable for the estimated 40 million adult users in the US.
Few medicines have transformed public health this quickly. Within just a few years of GLP-1 drugs becoming mainstream, the US adult obesity rate has begun to fall for the first time since records began.
But evidence is rapidly emerging that the effects go far beyond appetite suppression and weight loss. As researchers have studied millions of people taking GLP-1 drugs, they’ve uncovered a growing list of unexpected effects – some remarkably promising, others potentially concerning.
Here are five of the biggest surprises.
1. They may help curb addiction
It might not just be our cravings for food that GLP-1s can help treat – they could blunt addiction across the board.
A major study of 600,000 US veterans, published in The BMJ, found that GLP-1 use was associated with a lower risk of substance use disorders involving alcohol, nicotine, cannabis, cocaine and opioids.
The researchers also looked at 524,817 participants who did not have a substance use disorder at the start of the study. Those taking GLP-1 medications were 14 per cent less likely to develop one than people taking other diabetes and weight-loss medications.
And among the participants who already had a substance use disorder, GLP-1 use was associated with 12 fewer serious addiction-related events per 1,000 users.
The authors suggest that GLP-1 treatment can “blunt that craving that pulls people toward whatever they’re addicted to”.
However, Naveed Sattar, professor of cardiometabolic medicine at the University of Glasgow, cautions that this kind of observational data isn’t the same as proving GLP-1s cause a drop in addiction.
“Other than for alcohol, we don’t yet have the data. We need big trials to validate the benefits in alcohol addiction and trials, too, to investigate the benefits for binge-eating and depression,” he says.
2. They can prevent heart attacks and strokes
Although much of the cardiovascular benefit of GLP-1s stems from weight loss, mounting evidence suggests the drugs also have direct protective effects in people who have already experienced a heart attack or stroke.
For instance, in one trial of over 17,000 patients, those given semaglutide were 20 per cent less likely to have a further heart attack, stroke or cardiovascular death than those given a placebo. Tellingly, this benefit appeared before patients had lost a meaningful amount of weight.
A follow-up analysis found the cardioprotective effect was independent of how much weight patients actually lost, suggesting GLP-1s act directly on the heart and blood vessels rather than simply working through weight loss.
Exactly how the drug does this, however, is less certain. One theory is that the drugs have anti-inflammatory effects, calming immune cells in the bloodstream and lowering markers of inflammation.
Chronic inflammation can cause plaques to build up on blood vessels, creating a blockage that can cause a heart attack or stroke. By reducing this inflammation, the drugs help keep blood vessels clear and relax artery walls. And there are clinical trials to back these claims.
“We know that they affect blood pressure, which is a key risk factor in cardiovascular disease,” says Sattar.
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3. They could help hold off dementia
Early studies suggest that dementia and other brain diseases stand to benefit from GLP-1s.
These include a recent major review of 30 studies that found the drugs reduced the build-up of amyloid-beta and tau – two proteins that can damage and kill brain cells in Alzheimer’s – in animals.
Human evidence is earlier-stage but promising in places. One trial of GLP-1 drug liraglutide in 204 people with mild to moderate Alzheimer’s found patients on the drug had a slower decline on cognitive tests and 50 per cent less brain volume loss than those on a placebo.
However, the wider clinical evidence is mixed. Extensive clinical trials published in The Lancet found that semaglutide taken in the form of pills did not slow memory or functional decline in patients with early Alzheimer’s disease over two years.
The overall picture suggests GLP-1 drugs do affect the brain in some way. Exactly what they’re doing, however (and how they’re doing it) remains unclear.
As University of Cambridge neuroendocrinologist Prof Giles Yeo previously told us, drug companies have “no freaking clue” what GLP-1s are doing in our brains.
4. They (might) make people exercise less
You might expect people who lose weight to become more active. Yet research analysing smartwatch data suggests the opposite may happen for some GLP-1 users, who appear to exercise less after starting the drugs.
On average, participants walked around 560 fewer steps a day after beginning treatment, with their daily step count falling from 5,047 to 4,487. Time spent doing moderate-to-vigorous exercise also dropped, from 28 minutes to 22 minutes a day.
However, obesity expert Dr Marie Spreckley at the University of Cambridge thinks the results should be treated with some caution.
“Because this was an observational analysis, it cannot establish that the medication itself caused the reduction in activity,” she says. She notes, too, that some people experience nausea, gastrointestinal symptoms or fatigue, which could temporarily reduce their activity levels.
“The findings reinforce something we already know: medication works best as part of comprehensive obesity care,” she says. “Maintaining physical activity during weight loss is important not only for cardiovascular health, but also for preserving muscle strength, physical function and independence.”
5. They affect our bones
GLP-1 drugs also appear to affect our bones, something that initially surprised researchers. Whether they’re ultimately good or bad for the skeleton, however, remains uncertain.
Some studies suggest GLP-1 drugs may strengthen bones by acting on the cells that maintain bone tissue, slowing bone breakdown while stimulating the formation of new bone.
Separately, early evidence (mostly from animal studies) suggests the drugs could offer a potential treatment for osteoarthritis.
However, somewhat confusingly, other studies suggest the treatments can lower bone density.
Research from the University of Colorado linked GLP-1s to an increased fracture risk in obese patients without diabetes, particularly in those with a body mass index (BMI) over 40 and aged over 68.
That doesn’t necessarily mean the drugs are directly weakening bones, though. Rapid weight loss is known to reduce bone mineral density, and losing muscle at the same time can make people less stable on their feet. Together, those changes could leave some people more vulnerable to falls and broken bones.
“[This research] has understandably raised questions about the potential long-term effects of GLP-1 receptor agonists on skeletal health,” Spreckley says.
But, she notes, weight loss itself can improve osteoarthritis symptoms in people living with obesity by reducing strain on joints.
“I think the key message is that the goal should be healthy weight loss rather than simply maximum weight loss,” she says.
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