Drugs for the management of obesity

And not only is there an increase in hunger after weight loss, there's also a reduction in energy expenditure by 300 calories. So, this is why I believe that we need some help with hunger suppression after weight loss. And most people need it also during weight loss.

[Music] Welcome to the Australian Prescriber podcast. Australian Prescriber. Independent, peer reviewed, and free.

Being overweight is common in our society. Obesity is less common, and it's hard to ignore the burden of disease it drives, but in amongst the struggles our patients have with it, it's frequently misunderstood. So hard to ignore the increasing attention given to medicines for long-term obesity management. What role do they have to play in whom, and how can we navigate this space? I'm David Liew, your host for today, and a clinical pharmacologist and rheumatologist. With me is Professor Joseph Proietto, an internationally renowned obesity researching clinician, and also from Austin Health in Melbourne, who has written an article entitled Medicines for Long-term Obesity Management. Professor Proietto, welcome to the program.

Thank you for inviting me, David.

So before we get into the medicines themselves, perhaps you can give us a little bit of a background as to how people become obese, and what drives obesity.

What drives obesity is genes. And these can be either the classical genetic mutations, or it can be epigenetics. There've already been three or four mechanisms for epigenetic obesity, and there will be more, I think. Now, the reason why it's genetic, there's very good evidence for that. Both from identical twin studies, adoption studies and, in addition to that, we have not one, but two negative feedback systems to prevent obesity. So while lifestyle can cause mild two or three kilo weight gain, to develop obesity, you need to have a gene. Now, these negative feedback systems, very briefly, are leptin, which is a very powerful hormone that inhibits hunger, and it's made by fat cells. So as we accumulate fat, we make more and more of the hormone that tells us to stop eating.

The second mechanism was only discovered about five years ago, and it appears that our bones weigh us. There's evidence that osteocytes can detect increased pressure, and then can send a signal to the brain to say, "Eat less."

The other bit of evidence that weight is genetic comes from the fact that the body vigorously defends weight. We have eight hormones that are released after a meal, and they all take hunger away. The only hunger hormone we have that has physiological relevance is ghrelin, which comes from the stomach. That goes down after a meal. The ghrelin level, the hunger hormone, rises after we lose weight, and all of the other hormones, the ones that take hunger away after a meal, and also leptin, drop dramatically after weight loss. All this happens with just 5% weight loss, and it doesn't get much more severe with further weight loss.

And then we discovered, in 2011, in a paper that we published in The New England Journal of Medicine, that these hormone changes are long-lasting. We found that leptin was lower and ghrelin was higher three years after weight loss in people that were still maintaining some weight. And then there was evidence from the US that at least leptin is still lower six years after weight loss. And not only is there an increase in hunger after weight loss, there's also a reduction in energy expenditure by 300 calories. And interestingly, the body doesn't fiddle with metabolism. The change in energy expenditure is not a drop in metabolism. It's a drop in fidgeting – spontaneous activity. And because spontaneous activity is throughout the day and night, it adds up significantly. And so after weight loss, there's a drop of 300 calories. So this is why I believe that we need some help with hunger suppression after weight loss. And most people need it also during weight loss. Even if you do, you try to do a ketogenic diet.

So to circle back on that, this is part of the reason why, even when I don't eat well, I put on a few kilograms, but I don't quite move into the obese category, but certainly there are people who eat better than me, but will potentially move that way.

Correct.

And so really with these medicines, we are talking about those patients who are fighting both on the genetic side of things, as well as the environment. And they're trying to deal with both of those. You run a busy weight loss clinic as part of a public health service, as an academic clinic. What's your approach? And when do you use these medicines?

Well, we started out in the clinic using a ketogenic diet, because ketones are very good at suppressing hunger, and they do it two ways. They act directly on the brain to suppress hunger through the mechanism by which glucose suppresses hunger. You say, "But glucose doesn't suppress hunger. People eat sugar and don't feel less hungry." That's because the maximum effect of glucose is at physiological level, 5 mmol. People who have diabetes and are on insulin will tell you that if their sugar drops to around 2, they get very hungry. So ketones act on the brain through that mechanism. And in addition to that, we discovered that they stopped most of the hormones from changing. So ghrelin can't rise if you are ketotic. We found that CCK can't drop if you are ketotic.

So in the clinic, we set out trying to use ketosis. Now to achieve ketosis, you must not have any carbohydrates, because the body has a strong preference to burn sugar before fat, and fat before protein. So if you avoid carbohydrates, for the first two days you get hungry. But after, on the third day, when the body has run out of all the glycogen that we store in our muscles, then it starts to burn fat. And when the liver burns fat, it produces ketones. And so what do you do for the first two or three days? You can have extra protein. If you have extra protein, like a roast chicken, then you will not delay the ketosis. And then when you eventually reach ketosis, then you'll find that you're comfortable and not hungry.

Our problem arises in people who, for various lifestyle factors, can't stay away from carbohydrates. And then we can use medications to suppress hunger, or who have so much weight to lose that they need to stay off carbohydrates for too long. And then we need medications. But we just about need medications in all patients after they've lost weight. That's really very important. And because the hormone changes are so long-lasting, and the energy expenditure changes as well, then we need to choose agents that we can use long term.

Right. Just to figure out where the population sits, we're not talking about using these in all people who want to lose weight. We're looking at a very specific segment of patients who are obese, but we are also looking at patients who have not responded to those first-line, conventional therapies, the ketogenic diets, and I guess all of this is in addition to lifestyle measures that have already been tried in the first place.

Oh yes, yes. Lifestyle measures are necessary. And there are several studies that show that, if you combine a good diet or an energy-reduced diet with medications, you get a lot more weight loss than you do if you just choose the medication alone.

And I think it's also written very clearly in this article that all of these medications, they're really only in the context of working on those lifestyle measures as well. Right?

Correct.

Let's just talk a little bit about what these medicines can do in practice. What are they there to try and achieve, and how do they go about achieving that?

All right. Well, first we should talk about what medications we have here in Australia, and of those few that we do have, there's only one that doesn't suppress hunger: orlistat, and orlistat can be purchased over-the-counter without a prescription. It's a lipase inhibitor. And so, if the patient eats fat, they get steatorrhoea, diarrhoea etc. So they avoid fat, and by avoiding fat, you lose some weight. The other medications, we have some old ones like phentermine. More recently, we've had liraglutide, which suppresses hunger by acting on the brain, but also slows gastric emptying and makes you feel fuller for longer. We have bupropion and naltrexone, which are a combination. It activates the melanocortin-4 system in the brain and suppresses hunger that way.

And then we have two agents that have not been approved by the TGA for weight, but are available in Australia for other indications. And I'm talking about semaglutide and topiramate. So these medications can also be used because, you see, there's a huge variation in sensitivity to these hormones, both in side effects and efficacy. And so, it's good to have a range to select from. You take liraglutide, for example. It can cause nausea. That's why you have to start at a low dose. If you start at a low dose, you'll find that some people don't get any nausea at all and some people get nausea that they can't cope with. And if you then go up very, very slowly, you find that you can get to a higher dose because you get below the radar, so to speak. Because there are these side effects that can be a problem, you need to have other agents that you can try that this particular patient may be sensitive to, without any side effects. And this is why you need to do a bit of trial and error to see what is more suitable for this particular patient.

So it sounds like none of these are set-and-forget type medicines, that this is very much the domain of people who are aware of the intricacies of these therapies, and titrating this to effect.

Yes, you need to use agents that are effective, and also you need to think of the side effects. And the other thing you need to think about is cost. Because these agents have to be used long term, you have to factor in cost. And some people can't afford to spend a lot of money on drugs. And in the article, I have the cost, each month, for most of these medications at their top dose.

So maybe let's just start with the most accessible, I guess, of all of those, which I think is probably orlistat, because it's over-the-counter, but that doesn't suppress hunger. Does it?

No.

It's a different mechanism. It's an intestinal lipase inhibitor. So it's really about fat, isn't it?

Yes.

Yeah. And so, what kind of effect do we see with that in practice? How do people tolerate that? Is it an effective agent? I mean, obviously that's in the context of all the other interventions that need to go along simultaneously with using it.

Well, it does work. The XENDOS study showed that it does help, especially if you advise your patient to avoid fat, because if you don't, they get a terrible, terrible steatorrhoea. So if you warn your patient to avoid fat, they will change their diet to be low fat. Of course, the problem with that is, if you have a low-fat diet for any length of time, you're going to get gallstones, because you don't trigger your gallbladder to empty, which requires fat in the gut, right?

Yeah, absolutely.

Yeah.

And then, I guess there's been a lot of excitement recently, probably driven from use in diabetes for the GLP-1 agonists, for liraglutide and then semaglutide as well, as you mentioned some of this off label, but what would you say about that excitement? And where should we temper our excitement with the reality?

Semaglutide has great advantages, because it's a weekly injection, which is very convenient for patients. It does suppress hunger, and it does make you feel fuller after a meal. And because it's one of our own hormones, if you happen to be one of those lucky individuals that are sensitive to this hormone, then you can help maintain the weight with a relatively low dose, which then helps with cost as well, because the hormone will last longer if you don't have to use such a high dose in the maintenance phase.

Is there anything that we should be concerned about in terms of potential adverse events? Is pancreatitis a consideration?

There was one study with liraglutide at 3 mg, where they had six cases of pancreatitis. You see, GLP-1 has an evolutionary pedigree as a growth factor for the gut. This is really very interesting. There's a lizard in the North American desert, called the Gila monster. And it's not a monster at all. The lizard is only about a metre long, and it only eats twice a year. And after it's finished eating, because it doesn't eat for a while, the gut atrophies a bit. And the next time it eats, six months later, it has an atrophied gut. And as it chews the mouse that it's caught, or whatever it eats, it releases a cocktail of factors from its saliva that then cause the gut to grow very quickly.

And it was in the saliva of the Gila monster that American scientists discovered that one of these factors was exenatide, which later became Byetta and Bydureon. Therefore exenatide, which we secrete into our bloodstream, the Gila monster produces it in its saliva. And so, it has this factor, acts as a growth factor for the gut. So you'd have to be careful not to give it to people who have known bowel cancer, for example, because while the hormone doesn't cause cancer, if there's a cancer there, it can make it grow faster, theoretically.

Absolutely.

And the pancreas, of course, is embryologically an offshoot of the gut, so it can affect the pancreas as well.

So in practice, how closely do you have to monitor these patients who are on medicines, either during that weight loss period, or trying to maintain weight loss?

Well, you need to check, first of all, what side effects the patient is getting, and whether you need to adjust the dose because of those. You need to assess efficacy, and that's easily done by seeing if the hormone is helping the patient maintain the weight loss, for example.

Absolutely. So in the future, where do you think that this is going? I get the sense that, there are some patients who, despite the lifestyle, non-pharmacological measures, despite ketogenic diets, and then subsequently these medicines, still have substantial problems with obesity.

Well, in the future, you talk about the future, I've advised these various pharmaceutical companies that, if nature chooses to secrete eight hormones to suppress our hunger, why eight? Why not just one? Well, it turns out, for some reason, that all of the hormones that suppress hunger, when they're injected into individuals, cause nausea. And yet, we release eight of them simultaneously, and don't feel sick after a meal usually. Right? So we need to ask why. So it is possible that, if we use each of these at a lower dose together, we may minimise the nausea, and maximise the effect. So I've suggested to these companies that they should mix at least three hormones. I think a combination of GLP-1 from the gut, amylin from the pancreas, and leptin from fat would be a good combination to try, to see if it works, and to see if it's more effective than just one agent at a higher dose. I don't think it's a good idea to go to a what I call a sledgehammer dose.

I think it's never a good idea to go to a sledgehammer dose for that very, very good reason. Where does it stand in terms of the end game for these medicines? Because once we've started them, we've been able to maintain some weight loss. Do we know how long it takes in terms of these medicines being able to reset hormones, to be able to maintain that hard-earned weight loss?

No, no. The medicines don't reset the hormones, the medicines suppress the hunger directly, and we need to maintain them lifelong, because if the hormones are still different six years after weight loss, I can guarantee you that they'll be there indefinitely.

Well, it certainly sounds like there's a lot more to be understood in terms of how to best use these. And I think we need a lot more clinics like yours, and a lot more expertise like yourself, to be able to enact them. Thank you so much for joining us today, Professor Proietto.

Pleasure. Pleasure.

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Professor Proietto has been on the medical advisory boards for liraglutide, semaglutide and bupropion/naltrexone. He's also been involved in educational sessions for Nova Nordisk, and iNova. I am a member of the Drug Utilisation Subcommittee of the Pharmaceutical Benefits Advisory Committee. The views of the guests and the hosts on the podcast are their own and may not represent Australian Prescriber or NPS MedicineWise. I'm David Liew. And thanks very much for joining us, once again, on the Australian Prescriber Podcast.