Are the new generation of anti-obesity therapies a ‘game-changer’?
By Prof Giles Yeo
I am a research scientist, based at the MRC Metabolic Diseases Unit, University of Cambridge, where my colleagues and I study the causes and consequences of obesity. Having been in the field for the best part of 25 years, it is not hyperbole to say that when it comes to the treatment of obesity, there has never been a more exciting time. The new so-called GLP1R agonists, which include Semaglutide (sold under the brand names Ozempic, Wegovy and Rybelsus) from Novo Nordisk, and Tirzepatide (sold under the brand name Mounjaro) from Eli Lilly, have demonstrated efficacies on weight-loss approaching that of bariatric surgery. Ozempic, in particular, made international headlines last year after going viral on TikTok, with the #MyOzempicJourney trend showcasing scarcely believable body transformations. Similarly, the #Ozempic hashtag has been viewed nearly 80 million times on the platform. So how do this new class of drugs work, and are they truly a game-changer?
What are they?
These drugs are the latest in the line of glucagon-like peptide 1 or GLP1 analogues. GLP1 is a gut hormone that was originally identified as an ‘incretin’, because it signals to the pancreas and is able to increase insulin secretion. Semaglutide and all its predecessors are, in effect, weaponised versions of GLP1, and because of their incretin action, were originally designed as treatments for Type II Diabetes. Their main super-power is that they survive far longer in the blood than native GLP1, which only has a half-life of two minutes. Earlier approved GLP1 analogues, including Exenatide from Astra Zeneca and Liraglutide from Novo Nordisk, required daily injections. In contrast, someone with Type II Diabetes need only inject Semaglutide once a week, thus enhancing insulin secretion and speeding the uptake of glucose from the blood into muscle and fat.
How do they work?
What does any of this have to do with weight loss? Well, this is related to another function of GLP1 as a gut hormone, and that is to regulate food intake.
Our brain needs to know two key pieces of information in order to control food intake. First, it needs to know how much fat we are carrying. Why? Because how much fat we are carrying, which is our long-term energy store, is a marker for how long we would survive in the wild without any food. The second piece of information our brain needs to know, is how much and what we are currently, or have just, eaten. These are short-term signals that come from our gut. Every time we take a mouthful of food, from the moment we begin chewing, till the moment it emerges out the other end, hormones are secreted at every step of the way. What is interesting is that the vast majority of these gut hormones, including GLP1, make us feel full when they signal to the brain.
So a side-effect of having a long acting GLP1 analogue like Semaglutide hanging about in our blood stream, is that it signals to the brain and makes us feel full. What happens when we feel full? We eat less. What happens when we eat less? We lose weight. In fact, clinical trials with Semaglutide have shown that over two years of once weekly injections, people lose, on average, 15% of their body-weight!
Are they safe?
OK, so they are effective, but are they safe? The results from the Semaglutide trials appear to indicate it is, certainly in the short to medium term. However, as with all drugs, there are side effects to consider. These have to do with yet another biological role of gut hormones, and that is to regulate the passage of food through our digestive system. Under certain circumstances for example, such as with food poisoning, it’s role is to expel food from our system. When our body senses that it has ingested a toxin, gut hormones are rapidly released. This sudden spike in gut hormones, including GLP1, leads to the unpleasant and explosive ejection, in the upwards direction, of the contents of our stomach. Thus, one of the side effects of Semaglutide is nausea. In other circumstances, perhaps food is pushed through the digestive system a little too quickly, and so a second reported side-effect happens to be diarrhea. To be clear, most people do not get these side effects, and this is seen in the high rates of completion of the clinical trials. That being said, it would be useful to somehow identify ‘hyper-responders’, and therefore those most likely to suffer from side-effects, either to personalize the dosing, or not to subject them to nausea and diarrhea in the first place!
Are they a game-changer?
So is this class of drugs a game-changer for the treatment of obesity? Yes I believe so. 15% of weight loss in two years is phenomenal, and there are competitors out there that have a similar mechanism of action, such as Tirzepatide from Eli Lilly, that are yet to be approved, but show even more weight loss.
A few things to reflect on though.
First, it was interesting that when Semaglutide was first approved for use in the UK, people kept asking me if it was ‘morally right’ to have a treatment for obesity? Inherent in this question is the assumption that obesity is a choice, which it is not. Some people are simply more drawn to food, and hence less likely to say ‘No’ to food, than others. Their hunger ‘thermostat’, if you like, is set a little higher. What these drugs do is to make you feel full faster, thus lowering the thermostat.
Second, should this drug be available, off the counter, for celebrities and others who can afford it? Given the effects on blood sugar levels, the issues with regards to dosing and side-effects, and the limited data on long-term safety, the medical consensus is that Semaglutide and other similar compounds should only be available on prescription, at least for now.
Third, and most importantly, as with any other treatment, the moment you come off the drug, the weight will come back on. If we take high blood pressure medication as an analogy, which is very effective, no one is countenancing stopping the treatment once your blood pressure has normalised. It would simply come back up again. The same is true for weight loss treatment. Obesity is perhaps best thought of as a chronic relapsing condition. People living with obesity need lifelong access to treatment and support, even if the intervention is a pharmaceutical like with Semaglutide.