Injectable drugs for weight management

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Hello and welcome to the Australian Prescriber Podcast. I'm Jo Cheah, a hospital pharmacist in Melbourne, and your host for this episode. In this episode, I have the pleasure of interviewing Dr Terri-Lynne South, GP and Medical Director at Lifestyle Metabolic in Brisbane. Today, we will be discussing injectable drugs for weight management, which is the title of Terri-Lynne's and Dr Natasha Yates's article in Australian Prescriber. Welcome, Terri-Lynne. Thanks for joining me.

Thank you for having me.

So to begin, what are the currently available drug classes of injectable drugs for weight management?

The drug classes are known as GLP-1 [glucagon-like peptide-1] medications, but that actually in Australia at the moment, refers to 3 different drugs, and they are liraglutide, or liraglutide, which is a daily GLP-1 injectable medication. Semaglutide or semaglutide, which is a weekly GLP-1 injectable medication. And tirzepatide, which is not just a GLP-type medication, it is a twincretin. It has a second mechanism of action, which is through the GIP [gastric inhibitory polypeptide] pathway.

And how do they work?

So these drugs are basically replicating a naturally occurring hormone that is released from our intestines that has a role in appetite regulation. The natural GLP and GIP proteins, hormones, are really only lasting minutes in the native state and these medications are replicas of that. Their mechanism of action are similar, but their duration of action of stimulating their receptors are lasting days and up to weeks with the weekly injectables.

There are a lot of receptors of the GLP and GIP throughout the body. And these medications, although we're talking about obesity management, they actually have positive effects in a number of different organs; working in the brain with regards to appetite regulation and possibly food selection, but also in the heart, kidneys and liver, which is where we're starting to see some of these additional TGA [Therapeutic Goods Administration] guidelines for conditions that we would say are associated with obesity.

That brings me to my next question about the indications for these drugs. So, I guess the drugs can be used for other indications other than just weight loss.

That's right. So the daily injectable liraglutide is only TGA-approved for obesity management, but semaglutide is on-label for obesity management at that higher dose of 2.4 mg. The trade name for that is Wegovy. But at the lower dose of the one mg semaglutide, it's on-label or TGA approved for the management of type 2 diabetes. And I think it's an interesting clinical point for our listeners to understand, that the one mg semaglutide is the dose that is best utilised for blood glucose control, the indication for type 2 diabetes. But patients will often need a much higher dose of 2.4 mg semaglutide for the management of obesity.

And semaglutide is also TGA-approved for secondary prevention of cardiovascular disease in patients who have a higher BMI [body mass index]. And then with tirzepatide, which is that twincretin, GLP-1 and GIP, it is on-label for the treatment of obesity as well as type 2 diabetes and also treatment of moderate to severe sleep apnoea associated with a higher BMI.

And what are the main differences between the drugs? So when would you recommend one over the other?

To be honest, a lot of it will come down to the individual patient. And so if they do have some of those TGA-approved, what I'd call obesity-plus-metabolic conditions, then I will use the evidence to say, this patient already has established cardiovascular disease. I would choose Wegovy because of the TGA indication. Or if they do have sleep apnoea, I'd be choosing Mounjaro-tirzepatide because of the TGA indications there. Otherwise, with regards to obesity management, I think they're both very good medications.

And our audience should understand that liraglutide is one of the first generation GLP-1 medications, a daily injection. There is a generic version of liraglutide now available in Australia, and it's almost half the price of the branded Saxenda recommended retail price. I might use the daily liraglutide around people who are actually planning a pregnancy because of the shorter half-life. And so there is less time for washout between last dose of liraglutide and trying to conceive.

So it definitely is horses for courses and prescribers really need to understand the individual patient, what their health goals are, their priorities, as well as what their particular risks may be in regards to choosing one medication over another.

Absolutely. And if we're talking about weight management as a whole, at what point in your treatment regimen would you consider starting an injectable drug? Would you have tried other treatments prior to this?

Yeah, it does depend on the individual patient. Almost all of the patients that I see who wish to talk to me about obesity management have actually tried something in the past. It would be very rare for me to be bringing the concerns about weight management to a patient who hadn't thought it was an issue or hadn't tried [anything]. I think, again, our audience needs to understand that all of the evidence around using GLP-1 injectable medications are on a baseline of what we would call lifestyle and behaviour management.

It's mentioned in your article that the effect of the drugs can wear off once they're ceased. So do you have a recommended duration of treatment? And, in practice, how long are you actually seeing patients continue these medications for?

If we can agree that obesity is a chronic clinical condition, then this is something that needs to be managed long-term. But my concern about these medications is that a lot of patients think that it's a quick fix, that it's going to sort of get them started and then they're not necessarily going to continue it. But what the evidence would show is that abrupt cessation of these medication leads to rapid [weight] regain as well as a return [reversal] of any improvements in those metabolic health markers.

The medications have only been real world experience in Australia for the last couple of years. So we are still looking with regards to the data of what does weight loss maintenance look like. We do have some evidence from the original STEP trials that weight loss is maintained out to 3 to 4 years with both the GLP and the combination twincretin. There is some softer evidence that suggests that the more people can do from a lifestyle point of view, the better in regards to weight loss maintenance.

It would be interesting to monitor the data over the years as the durations of these drugs continue for some patients.

Absolutely.

So in which patient groups or what patient factors do you expect to see the greatest benefit of injectable drugs for weight management?

The greatest benefit are going to be in patients who have the biggest burden of the disease called obesity. So those typically are patients with a much higher BMI, but also with the most comorbidities, particularly around things like type 2 diabetes, cardiovascular disease, sleep apnoea, and osteoarthritis.

We talk about percentage weight loss. So I always work out what percentage weight loss patients are talking about with regards to their health goals. So in my head, I know that at least a 5% total body weight loss reduction improves high blood glucose. I'd want at least a 10% total body weight reduction in regards to blood pressure management, and maybe up to 15% with regards to sleep apnoea and possibly up to 20% if we were trying to do early type 2 diabetes remission diagnosis.

You had mentioned in the article that in some patients, for whatever reason, there are a few reasons listed in your article, they may not actually gain any benefit or have effect from the drugs.

There's very much an individual response to the medications, particularly if we're talking about weight loss. In some of the original trials, some people actually put on weight with these medications. So I think it's really important for patients to understand that if their goal is actually weight loss for their obesity management, not everybody responds well. The average is just an average and there is a huge variability on both sides of that.

And what are some expected and serious adverse effects that we should be monitoring for?

When I talk to my patients about what is known, I break it down into common, uncommon and rare. Not only do I say common, but it should actually be manageable, and these are typically your gastrointestinal side effects; things like nausea, reflux, burping. And we need to be very mindful from a hydration point of view because becoming dehydrated can lead to headaches. Uncommon would be things like gallstones. Any sort of significant weight loss can increase the risk of gallstones. And rare would be things like pancreatitis, which there is still some conflicting evidence of how much of a risk that is.

And there have been recent news articles about the risk of serious mental health or behavioural side effects that people have reported on these drugs. Can you comment on that as well?

Yeah. So with a recent TGA broadcast about the potential risk of worsening suicidal ideation, I think it's interesting to understand that one, it's been flagged as a potential risk, and so I can't even give my patients a background incident of that. I can't actually tell them whether it's common, uncommon, or rare. There has been some conflicting research around the effects of mental health, some research suggesting there's a positive association and some are negative.

What that says to me is there's very likely to be a subgroup that is at increased risk of worsening mental health, particularly in a recent WHO analysis, World Health Organisation, it was suggested that that subgroup may be patients who are already taking an antidepressant or anti-anxiety medication. But the reason I think the TGA has taken such a significant step is because, if we have a patient who is experiencing worsening suicidal ideation on one of these medications, that worsening suicidal ideation is a potentially life-threatening condition, and that's why the potential risks to be broadcast to prescribers, as well as the public, is so important.

Yes, very important to be monitoring and reporting any side effects as they arise.

That's actually another really good point that you're mentioning, Jo. These medications are still new to Australia, so they're still under what we call the Black Triangle monitoring scheme. And so we are still seeking real world reports of potential adverse reactions to be submitted and highlighted to the Adverse Drug Reactions [Advisory] Committee through the TGA. And so that's why I think we still need to be very cautious in that we don't know what we don't know, and we are looking for potential early safety signals now that more patients are using these medications.

I'd be interested in hearing your thoughts about off-label use of these drugs. Obviously there are people who don't necessarily fit the patient groups that these drugs are indicated for and they're using these drugs. I'd be interested to hear your thoughts on that.

Yeah, there are 2 groups of patients that I think we should pull out to discuss specifically with regards to off-label use. It's basically the drug semaglutide and whether it's the one mg semaglutide called Ozempic, versus the 2.4 semaglutide called Wegovy. This is very confusing for patients because semaglutide, whether you call it Ozempic or Wegovy, is exactly the same thing and people use the trade name Ozempic to apply to all of these medications.

And so what patients need to understand is that yes, Ozempic is on-label for type 2 diabetes. It's actually not on-label for obesity management, but there's a huge price discrepancy between the one mg semaglutide called Ozempic, versus the one mg semaglutide called Wegovy. And it is almost double the price once it's got the brand name Wegovy. And so this is where there can be a lot of confusion about expectations of cost, but also about expectations with regards to weight loss.

So again, the one mg semaglutide is not expected to be an obesity management medication. You can have people who are strong responders and they can have some good results on that dose. But in general, I'll have people who've come to me and said, �Oh, Terri, Ozempic didn't work for me.� And first of all I'll say, �Well, what do you mean it didn't work?� And they might say to me, �Oh, I only lost 6% on Ozempic.� And I'd be saying, �Well, actually that's what you would expect on a one mg dose of semaglutide.� If we're talking about obesity management and expecting more weight loss, that dose is actually a 2.4 mg dose.

And the other off-label group that I have real concerns about is, typically it's women who are being motivated to seek weight loss from a body image point of view, a self-esteem point of view. And I feel as though this is only going to worsen some of the risks associated with that, including disordered eating and eating disorders that are worsening in regards to that societal pursuit of a thin ideal. And I do have concerns of how that's going to play out now that there is greater access to these medications.

And do you have any advice for prescribers who might be approached by a patient requesting the drugs and clearly they're wanting to use it for off-label use?

Well, I think the prescribers really need to understand their medico-legal risk. And I do think that trying to understand where the patient is coming from can really open up a discussion about some of the myths that the patient might have. So, I'll give you some examples from my clinical experiences. I find that my patients are still very wedded to this idea of a healthy weight range or this idea that BMI is the be-all-and-end-all with regards to an assessment of health status. So, I like to go beyond that. I really like that The Lancet came out with some useful definitions of what is clinical obesity, and it's not just based on BMI, it's based on assessment of actual abnormal excess adipose tissue actually causing dysfunction.

And so for some of my patients, because I have the luxury of being able to assess beyond weight and BMI alone, whether that is a bioelectrical impedance assay or a DEXA body composition assay, even just taking a waste measurement can really start to change that conversation that a person's risk and health assessment is more than just their BMI. And we can start to actually talk to patients about what else might be driving this and actually bring up some of those ideas around body image and where their motivations are coming from. Or possibly even doing some disordered eating screening and suggest that going on this medication might make some of these things, that they weren't aware about, worse, including loss of muscle and the problem of weight regain. Again, these are not quick fix medications. We know that there is often weight regain [when the medications are stopped].

And I think that we really do have an ethical need to first do no harm and to understand that we may be doing our patients a metabolic disadvantage by not talking to them about the real concern of what we call weight variability. So, losing weight, regain, losing weight, regain, that may actually worsen a person's future metabolic health than actually having maintained an above-average BMI, but actually working on healthy habits.

So, my concern is more of this drive that the only way to treat obesity is weight loss. It's not; it's about health gains. And I would actually have some of my patients on these medications independent of weight loss because I know that they are still helping some of those other metabolic health parameters, particularly in regards to triglyceride lowering, reducing their inflammatory markers such as CRP [C-reactive protein] and including fatty liver disease. So, for me, obesity management is not just about weight loss.

I guess another consideration is the drug supplies. So if these drugs are being prescribed potentially inappropriately, then the drugs that are available on the market could be used up and the patients who actually are indicated for it might not have access to it, which did occur last year, we had issues with supply of these drugs.

Yeah, that's exactly right.

And are there any absolute contraindicated patients that you would not prescribe these drugs in?

Surprisingly, there are a few absolute contraindications, but the absolute contraindications are around a very rare and specific type of thyroid cancer, which is medullary thyroid cancer, both a personal history or a family history, but there are a lot of cautions around prescribing in particular patients that have already a history of reflux or gallstones, patients who might have had previous pancreatitis, patients who already have a risk or experience gastroparesis. We need to have those concerns around pregnancy, breastfeeding, and particularly about patients who might already have some diabetic retinopathy and a worsening of that with initiation of these medications.

And I think we'd already touched on, but I do think we need to be very mindful of, the risk of worsening mental health, disordered eating, eating disorders, but also another one to watch is the risk of sarcopenia. So particularly for our patients who've had a lot of weight cycling, they may have a higher BMI, but they may actually be low in muscle, otherwise known as sarcopenia. There's a particular subgroup of obesity called sarcopenic obesity. We're more likely to see that in patients who had that weight cycling or our older adults. And this is where that lack or relative decrease in muscle mass of itself is actually a health predictor. And the last thing we would want to do as [with] someone who's already behind the 8-ball with muscle mass, is to lose more because of the pursuit of a number going down on the scale.

So, I keep talking to my patients about obesity management is not just weight loss, it's health gains, but if there is some pursuit of weight loss, the type of weight that needs to be lost is fat tissue, preferably that visceral adipose tissue, which is the most risky from a metabolic health point of view, the stuff around the middle and the waist. And the last thing we want to do is to be losing muscle, knowing that most Australians from midlife, particularly women post-menopausal, are significantly reducing muscle mass as part of that ageing process.

And finally, what are the recommended behavioural and lifestyle modifications for weight management that you would recommend in conjunction with these medicines?

I think these medications do a lot better if there is formal dietary and behavioural advice. The experts from a dietary advice point of view are accredited practising dietitians. They can help patients reduce some of the early side effects, which tend to be gastrointestinal, but also some of the longer-term side effects, which includes that reduction in muscle mass, but also in regards to the risk of nutrient deficiencies. These can be both what we call macronutrients, including protein, fibre and fluid, but also those micronutrients people know as the vitamins and minerals. So nutritional quality is extremely important. People with a higher BMI often have micronutrient deficiencies, and then if they start a GLP-1 medication, where they are significantly reducing the amount of food they eat, amount of calories, then there is more pressure to be able to get that nutritional quality in a reduced amount of foods.

So, I think that's actually really quite hard to do. Some of those patients may need some supplementation if they can't meet their needs through food. I think food-first approach is extremely important, but there could be a role for supplementation. As well as, depending on how health literate the individual patient is, express advice with regards to reducing what we call low quality, low nutrient dense food. For example, alcohol, sugar sweetened beverage, and what we call discretionary foods, which back in my day was called junk foods, but they're called discretionary foods now, but basically that's the foods that are high calorie, but not getting any of those important things like fibre, protein or micronutrients.

The other part of the lifestyle intervention is in regards to physical activity, exercise. All patients should be encouraged to move towards meeting the Australian guidelines in regards to physical activity. So that's at least 150 minutes of moderate to vigorous activity a week, plus 2 sessions of what we would call muscle resistance exercise. Now, a lot of Australians are not anywhere near that. So I think, again, it's important to think where our patients are when they start this conversation with their prescriber and help them move along that next step.

I often find that patients living in a larger body can be inhibited from doing a lot of physical activity and exercise, but anything is better than nothing in regards to getting the best benefit from these medications in regards to weight loss management and preservation of the muscle mass, in addition to the known positive effects that exercise has in regards to sleep and mental health, which is also some of those pillars of lifestyle intervention. And as well, we're wanting some behaviour change that hopefully some of these healthier habits are maintained, even if the medication is not maintained for whatever reason.

Thank you for going through all of that. Obviously, yes, as we've mentioned, throughout the article, the injectable medicines aren't a quick fix and definitely requires a broad approach and utilising our multidisciplinary colleagues as well. Thank you so much, Terri-Lynne. I really appreciated your time on the podcast today.

Thank you for having me. It was my pleasure.

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The full article is available on the Australian Prescriber website. The views of the hosts and guests on the podcast are their own and may not represent Australian Prescriber or Therapeutic Guidelines. Terri-Lynne South has received honoraria from Nestle, Eli Lily, iNOVA, Boehringer and Novo Nordisk for sponsored presentations and advisory roles. I'm Jo Cheah, and thanks again for joining us on the Australian Prescriber Podcast.