Podcast: the past, present, and future of GLP-1 medications with Professor John Wilding

GLP-1 medications have been around for a while for the management of type 2 diabetes, but it's only in recent years that we've seen them being used for weight loss.

Can you remind our listeners of the ones that are currently licensed for weight loss in the UK?

For quite a few years now, we've had the drug liraglutide with a higher dose than is used for diabetes.

Three milligram daily dose is the top dose that we can use of liraglutide for the treatment of obesity.

That has, however, fallen mostly out of use now, largely because it's been superseded by semaglutide.

which is also a GLP-1 analogue, again approved some time ago for the treatment of diabetes, but since 2022 for the treatment of obesity.

Somaglutide is a drug that's been given by a once weekly dose up to 2.4 milligrams until recently, where there's a new dose that's just come out, which takes the dose up to 7.2 milligrams as the maximum dose.

We also have slightly more recently the medication tezepatide, which is a GLP-1 and GIP dual agonist.

This has been approved both for the treatment of type 2 diabetes and obesity and can be used in doses up to 15 milligrams.

Again, this is a once a week preparation.

And much more recently, we've had two oral medications approved.

First one being an oral version of semaglutide, up to 25 milligrams for the treatment of obesity.

We've had the MHRA, the approval of Orphoglipron, which is a small molecule GLP-1 analogue, also again for the treatment of obesity.

We're going to be chatting about the oral weight loss medications later.

Again, I'm sure our listeners will know this, but how is it that GLP-1 agonists or GLP-1 medications, if you're including Tazepatide, how is it that they're helping patients to lose weight?

So if we go back to the original basic science of this, and I was involved in some of this work back in the 1990s, what we knew at that time was that there were hormones from the gut that included both GLP-1 and GIP that are released after a meal and actually act as the main stimulus to insulin secretion after a meal.

And that led to expiration of these naturally occurring peptides as potential treatments for type 2 diabetes because they stimulate insulin secretion.

And they do that in a way that is dependent upon the prevailing glucose levels.

So they don't tend to cause hypoglycemia.

At the same time, people were also interested in some of the signaling molecules from the gut that led to people feeling fuller after meals.

And I was involved in some of that research back again in the mid 1990s, where we were able to show in experimental models that GLP-1 was actually part of that natural satiety system.

In other words, it switches off the food intake so that we feel fuller after a meal.

And what we noticed when we started using these medicines for the treatment of diabetes, some of the earlier drugs including one called exenatide and then later liraglutide, was that these drugs did actually cause some weight loss consistent with what we knew about the fact that these drugs not only are acting on the pancreas but also are acting on the brain to make us feel full after meals.

The observation that these medicines caused weight loss in people with diabetes was then used by researchers in the pharmaceutical industry to develop higher doses of these medications that could be used as effective treatments for obesity.

And the drug liraglutide, which was the first of these, on average produced somewhere between about 8% and 10% of weight loss, which is pretty good, much better than most things for treatments for obesity that had come before it, and certainly better than just diet and exercise alone in most cases.