How do weight loss jabs work?

How do weight loss injections actually work? John Wilding is a professor of medicine at the University of Liverpool and has published widely on these agents…

John - Clinically I trained as a doctor working in diabetes and endocrinology, which is to do with glands and hormones and so on. And during my training I saw lots of people living with Type 2 diabetes, which is a condition which is largely caused by obesity. And then I spent some time working in a laboratory trying to understand what it is that makes people eat more or eat less and why some people develop obesity and some people don't. And one of the things that I did in that laboratory was seeing whether different chemicals in the body, different hormones, affected body weight. And one of the things we discovered was that with this hormone that we already knew was involved in controlling sugar metabolism also is an important signal after we've eaten to tell the brain that we're full. So that got me really interested in this as an area that might help people with obesity as well as diabetes.

Chris - What hormone was that?

John - This was a hormone called Glucagon-like peptide-1, or GLP-1 for short, which is actually the basis now for treatments for both Type 2 diabetes and treatment of people with overweight and obesity.

Chris - Where does it come from in the body? Where does it go? In the body and what does it do?

John - GLP-1 is actually made in the small intestine, so it's made in the gut and it's produced when we eat. So when we eat, the GLP-1 levels go up. And it goes around in the bloodstream and it goes to two main places where it has its actions. One is the pancreas where it tells the pancreas to make a hormone insulin which controls the blood sugar after we've eaten. And the other thing it does is it goes to the brain where it tells the brain, 'Hey ho, you've had some food. It's time to slow down and eat a bit less now, otherwise you're going to start feeling too full.'

Chris - So these drugs which mimic that action, they're basically telling the body, 'stop eating you've had your fill.' It's as though you've had a big meal and you haven't.

John - That's exactly right. And of course it's one of many hormones from the gut that do the same thing. It's one of the important ones. But we know that there are at least half a dozen other chemicals from the gut that are performing that function.

Chris - And when we use these agents, are they actually effective or in the same way that if you flog a system very hard by giving it fake signals, eventually it becomes deaf to them and ignores them. So does that happen with these drugs or, when you use them, does the body remain sensitive to them and so they do drive a fullness sensation and therefore a reduction in calorie intake?

John - Yes, so these medicines are based on the natural hormone GLP-1, but they've been chemically modified because if we give the natural hormone, which we actually did in some of those early experiments, it only stays in the body for about three minutes because it has been produced continuously by the intestine. So these drugs make that long acting and the first drugs maybe you had to give by injection twice a day, the later ones once a day, and now we've got drugs that we can give once a week. So these drugs last a lot longer in their effects than the natural hormone. And they're also much more powerful. We do know from long studies going on for at least four years now in people with diabetes and in people with obesity, that these drugs continue to work with both actions, both to continue to stimulate insulin secretion and to continue to signal to the brain that feeling of fullness even after you've been taking them four years.

Chris - If you've got something that is promoting the release of insulin though, and you are not eating enough because you've suppressed your appetite because your brain is now being told you are full, do you not end up with lower blood sugar? And is that not a bad thing?

John - No, that's one of the very interesting things about this hormone because the way this hormone works in the pancreas is that it only stimulates insulin secretion when the blood sugar is high. When the blood sugar drops to below normal levels, it stops working. So there's a built-in safety mechanism there, which wasn't there with some of the older drugs that we used to treat diabetes with.

Chris - And how good are they? When we start a course of this stuff, how effective is it at suppressing calorie intake first and foremost, and how does that translate into weight loss and over what sort of time course?

John - So there have been some short term studies that have been done that have looked at people who've taken the drug for a few days to build up the levels in the body and then looked at how hungry they feel in a short term laboratory setting. And people tend to eat about two thirds of their normal meal size. So that's quite a big reduction in their energy intake in these acute situations. It's probably not quite as strong as that in the real world. There are lots of other temptations and so on around, but what we do know is that with the more recent drugs, particularly ones like semaglutide and Tirzepatide that are given once a week, we see people lose weight over a period of about six months to a year. And then usually the weight reaches a steady state after that. But that weight loss is around 15 to 20% of the original body weight. So if you start off at a hundred kilos on average, you might expect to get to between somewhere around 80 and 85 kilos after taking this medicine for a year. The reason why it reaches a plateau, of course, is that as you get smaller, your body needs less energy and that means that that lower food intake eventually matches your new lower energy requirements. So eventually you stop losing weight, which is a good thing because otherwise we disappear into nothing.

Chris - <laugh> indeed. But on that note, one of the things that we try to emphasise is remaining fit and active because the more lean tissue, the more muscle you have, that's where the energy's being burned. You want to shed the fat. So when you take something like one of these drugs, does it lead to preservation of the lean tissue and loss of the fat, or do you end up sacrificing both?

John - We've actually looked at this in some of the studies that we've done, particularly with semaglutide. And what we find is that if you lose 15 kilos, you might on average lose about two thirds of that and the rest is lean tissue. That includes water and muscle and everything else in the body. We can't separate exactly muscle. That happens if you lost 15 kilos by going on a diet or if you lost even more than that by having bariatric surgery. Whatever way you lose the weight, that is about the proportion that happens. So you don't lose any more probably, and you probably don't lose any less when you're taking the drug, than if you lost weight with other means.