It is rare that a drug becomes a household name and even rarer for one to become a superstar, but with its ability to grab headlines, Ozempic is the Taylor Swift of pharmaceuticals. So just what lies behind its star power? Even as the drug and its derivatives take off, researchers are racing to find out how it works.
鈥淲e鈥檙e seeing so many incredible benefits,鈥� says at the University of Illinois. 鈥淚t鈥檚 early days, but it鈥檚 looking like these drugs aren鈥檛 just going to change medicine but our whole economy.鈥�
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Most medicines only treat one or two conditions, meaning that 鈥渃ure-alls鈥� promising to tackle any and all ailments are usually viewed with scepticism and suspicion. Ozempic seems to buck that trend. Last year, Wegovy 鈥� a version of Ozempic approved for weight loss 鈥� was shown to by almost 20 per cent. The emergence of 鈥淥zempic pregnancies鈥� hinted at . People started noticing positive effects on depression and anxiety. In May, and death in people with diabetes during a three-year trial. In July, another version of and slow cognitive decline in people with Alzheimer鈥檚 disease.
Why this drug is helping so many conditions is still mysterious, but researchers are beginning to unravel the mechanisms underlying its extraordinary abilities. From its effects on reward circuits in the brain to its impact on inflammation, understanding these pathways should reveal the full spectrum of health issues it could address 鈥� and where we might fall foul of unintended consequences.
The Ozempic story begins in the 1980s, with the discovery of glucagon-like peptide-1 (GLP-1). This naturally occurring hormone helps lower blood glucose levels, which can get dangerously high in people with diabetes, so the thinking was that a drug that mimics GLP-1 could help treat the condition.
Drug company Novo Nordisk鈥檚 first such medicine, liraglutide (sold as Victoza), was approved by the US Food and Drug Administration in 2010. It reduced blood glucose but had to be injected daily. The real breakthrough came in 2017, when Novo Nordisk introduced a longer-lasting GLP-1 drug 鈥� semaglutide 鈥� which it marketed as Ozempic. Initially approved as a weekly injection for type 2 diabetes, it produced notable weight loss, leading to the creation in 2021 of Wegovy, a higher dose version approved as a treatment for obesity. This helped people typically lose around 15 per cent of their weight after one year of taking the drug. Despite its high cost 鈥� a month 鈥� it has been wildly successful, with around 25,000 people in the US.
It鈥檚 early days, but it鈥檚 looking like these drugs aren鈥檛 just going to change medicine but our whole economy
GLP-1 is released by the intestine, pancreas and brain after we eat, so it is perhaps no surprise that semaglutide modifies our eating behaviour. The hormone signals the pancreas to release insulin, which lowers blood sugar. It slows the passage of food through the stomach, which keeps you feeling fuller for longer, and acts on brain areas responsible for motivation and reward processing, all of which curb your appetite. Research also suggests that it may , encouraging a balance of bacteria that promotes a healthier metabolism.
Weight loss from taking semaglutide also explains some of the other health benefits we are seeing, such as boosts in fertility. 鈥淭here isn鈥檛 an organ in the body that isn鈥檛 improved by losing a little weight if you have a high body mass index,鈥� says at the University of Michigan in Ann Arbor.
Not just weight loss
But it isn鈥檛 the whole story. Take the discovery that semaglutide improves heart health, for instance. A study of more than 17,000 people with cardiovascular disease showed that the drug . A lower weight reduces cholesterol, which blocks arteries among other things, yet slimming down isn鈥檛 the dominant factor. 鈥淧eople are seeing benefits to their cardiac health independent of the amount of weight they have lost by taking the drug,鈥� says Seeley.
This is where another effect of semaglutide comes into play: it acts as an anti-inflammatory. It does this through , including modulating how cells signal to the immune system, decreasing the release of pro-inflammatory chemical messengers called cytokines and switching off genes responsible for the immune response. Chronic inflammation, which can compromise the immune system and cause arteries to harden, is increasingly being linked to a huge number of conditions, making it an ideal target for treating more than just heart disease.
In fact, semaglutide and similar drugs called GLP-1 agonists have been shown to improve many conditions that involve inflammation, such as , non-alcoholic fatty liver disease, . They are also showing promise for , as well as infections that create 鈥渋nflammatory storms鈥�, like . 鈥淲hat we have is this Goldilocks effect,鈥� says Seeley. 鈥淕LP-1 agonists reduce inflammation, but not so much that you put people at risk of infection and cancers 鈥� it鈥檚 vital we find out more about why.鈥�
Given the importance of inflammation in so many conditions, you might wonder why we are only just discovering the anti-inflammatory potential of GLP-1 agonists. Seeley says it just wasn鈥檛 on people鈥檚 radar. 鈥淩emember, these drugs were never designed to be anti-inflammatories, immunologists weren鈥檛 doing the early research,鈥� he says. 鈥淭hey were discovered by endocrinologists for glucose control. There鈥檚 a lot of serendipity at work.鈥�
Another factor is that compared with insulin, which has somewhat of a sledgehammer effect in the body 鈥� lowering glucose dramatically 鈥� GLP-1 agonists have a much more nuanced effect, which, had their wider benefits not become apparent in those taking them for diabetes or weight loss, immunologists might have found too subtle to spot.
Along with their anti-inflammatory properties, GLP-1 agonists also 鈥� two attributes that might help with Alzheimer鈥檚. Could the drugs offer a treatment? Perhaps. When at Imperial College London and his colleagues treated people with Alzheimer鈥檚 using liraglutide, they found it reduced brain shrinkage by 50 per cent and reduced the rate of cognitive decline by 18 per cent compared with a placebo after one year of treatment. The work was presented at the in Philadelphia, Pennsylvania, in July. In October, there was more good news: a in the US with diabetes but no prior Alzheimer鈥檚 diagnosis showed that semaglutide was associated with a 70 per cent lower risk of being diagnosed with the disease compared with insulin.
It isn鈥檛 clear what pathways the drug is targeting, but it is likely to be more than one, says Edison. 鈥淚n my view, there are a lot of independent processes involved in the pathology of Alzheimer鈥檚, so a drug that has a multipronged attack is well suited to treating the disease.鈥� A spokesperson for Novo Nordisk says it is evaluating an oral version of semaglutide for the treatment of early Alzheimer鈥檚 disease in a trial of around 1800 people.
Altering the brain
Neuroscientists are waking up to the huge potential for weight-loss drugs to alter the brain in other ways too. Many people taking Wegovy have reported reduced cravings not only for food, but also for alcohol, cigarettes, shopping and even nail-biting. If true, this phenomenon could have major implications for treating addictions. In October, a study of more than half a million people with a history of opioid use disorder showed that those who took Ozempic or similar GLP-1 drugs had than those who didn鈥檛 take these medications.
Some researchers believe that by targeting areas of the brain responsible for reward signals from food and reducing the motivation to eat, GLP-1 agonists also lessen the reward people get from addictive substances and the motivation to take them. Trials are now running to see if these medicines can help people quit , and .
But there may be a downside. A study presented in October at the Society for Neuroscience conference in Chicago showed that mice given semaglutide were less motivated to exercise 鈥� with the implication being that dampening reward circuits might make positive behaviours like exercise less rewarding too.
Seeley, however, considers this an oversimplification. 鈥淭he idea that you can clump all these rewarding behaviours together in the brain so that when you reduce reward from one you reduce reward from them all, just doesn鈥檛 make sense. The brain is more nuanced than that.鈥�
Indeed, GLP-1 receptors are scattered all over the brain, which could explain some of the effects we are seeing on people鈥檚 mental states. Early this year, an analysis of more than 4 million people linked GLP-1 agonists with lower rates of anxiety or depression. This may be partly thanks to the loss of weight 鈥� there is a well-established link between obesity and mood disorders.
Rachel Goldberg, a private psychotherapist in Los Angeles, says she tends to observe her clients feeling more positive and joyful after taking these weight-loss drugs. 鈥淚 believe this is often because, without the 鈥榝ood noise鈥� that many struggle with, they have more mental space to enjoy other aspects of life,鈥� she says.
There鈥檚 some level at which, as a physician, you don鈥檛 care how it鈥檚 working as long as it is working and it鈥檚 safe
鈥淔eeling more in control of food choices or behaviours can relieve stress, improving some people鈥檚 emotional balance,鈥� says , a physician in Florida. But studies indicate that something more complex is going on. A of liraglutide in 19 people with major depressive disorder or bipolar disorder suggested it improved mood, attention span and cognitive function, irrespective of whether they lost weight.
The drug increased the volume of brain areas involved in planning, organisation and emotional processing, which may be why it helps people regulate their mood. 鈥淕LP-1 receptors may impact mood-regulating neurotransmitters like dopamine and serotonin, which play key roles in emotional responses,鈥� says Tambini. The GLP-1 hormone also appears to affect how easily glucose is transported into the energy-hungry brain and the rate at which it consumes glucose, which may be why it boosts the brain鈥檚 ability to operate.
Such questions about glucose levels take us back to where we started, when GLP-1 and its impact on glucose was first discovered. Now that we can add everything from reward mechanisms to anti-inflammation to the list of its functions, understanding how all of these effects interact and overlap is going to take time 鈥� even if many people don鈥檛 want to wait.
Questions remain
鈥淭here鈥檚 some level at which, as a physician, you don鈥檛 care how it鈥檚 working as long as it is working and it鈥檚 safe,鈥� says Seeley. 鈥淯nderstanding the mechanisms behind all these things is going to take a while to figure out.鈥�
Beyond scientific curiosity, a deep dive into the mechanisms of this wonder drug could also help us tackle big unanswered questions. For one, semaglutide isn鈥檛 without side effects, such as constipation, muscle wasting and a newly discovered problem labelled Ozempic face, where facial ageing appears accelerated compared with that in people who lose weight without the drug. This seems to originate from a loss of fatty tissue and the altered growth of stem cells derived from this tissue, which are involved in the production of certain hormones and metabolites. Together these compromise the structural integrity of the skin, says Dayan. This is primarily a cosmetic issue, he says, but more research is needed to understand the exact consequences that skin changes might have on wider health.
Another big question is one being voiced by many people excited by semaglutide鈥檚 widespread effects: could everyone benefit from it in some way? 鈥淚 find myself thinking 鈥榮hould I be taking this in a microdose?鈥欌�� says Dayan.
It isn鈥檛 the first time we have thought this about a drug. Some live up to their promise: aspirin was but then showed beneficial effects in reducing pain and preventing cardiovascular disease. Today there is growing evidence that, in low doses, it also helps to . But it doesn鈥檛 always work out like this. 鈥淲hen statins were discovered, we went through the same thing. People were saying 鈥榠t鈥檚 so good should we just put this in the water?鈥� But it turned out it didn鈥檛 do everything we hoped,鈥� says Seeley.
We are now at the point of maximum enthusiasm, asking whether semaglutide can help cure cancer, treat Alzheimer鈥檚, reverse arthritis and more. 鈥淲e are in the 鈥榤aybe it will cure everything鈥� stage with this drug,鈥� says Seeley. 鈥淪ome of these ideas are going to fall by the wayside when we do good trials, some will work out, but there鈥檚 a lot of work to be done before we understand what these drugs are truly capable of.鈥�
