Transcript

MIC CAVAZZINI: Welcome to Pomegranate Health, a podcast about the culture of medicine. I’m Mic Cavazzini, for the Royal Australasian College of Physicians. Whatever specialty you’re in, I’m sure you’ve heard the hype around semaglutide. In the media it’s usually referred to by the brand names Ozempic or Wegovy and it’s held up as some kind of weight loss miracle cure.

Over the last year, the drug raked in estimated sales of 12.5 billion US dollars for its manufacturer, Novo Nordisk. This didn’t just make it the most valuable listed company in Europe, but it boosted Denmark’s GDP by almost 2 percent. Demand for semaglutide is so high, that it’s been hard to supply the patients with type 2 diabetes for whom it was first indicated, and Australia’s Therapeutic Goods Administration has been warning prescribers not to start new patients on it.

We’ll talk about this supply bottleneck later, but let’s start with the basics. Type 2 diabetes is characterised by resistance to insulin and dysfunction of the pancreatic β–cells which secrete it. This means that spikes in blood glucose are not brought under control, contributing to cardiovascular disease and renal failure. Eighty to ninety percent of patients with the disease are obese, and in fact insulin resistance often comes about from the organellar dysfunction and oxidative stress associated with obesity. While exercise and dietary modification are the preferred interventions, adherence is hard to maintain.

Enter semaglutide, an analogue of glucagon-like peptide 1. GLP-1 is known as an incretin hormone, meaning that it’s released into the gut in response to a meal. It stimulates activity of pancreatic β-cells and also reduces secretion of glucagon would otherwise signal the liver to release more glucose for circulation. As well as these direct effects on glycaemic control, we’ll hear later how GLP-1 can modulate appetite in a couple of different ways. The effects of endogenous GLP-1 only last a few minutes since it’s quickly degraded, but semaglutide survives for days and can be administered once a week by subcutaneous injection. 

Semaglutide was first registered by the US Federal Drugs Administration in December 2017, and the by the TGA in August 2019, but it’s not the first GLP-1 receptor agonist to hit the shelves. That was AstraZeneca’s exenatide about a decade earlier, before Novo Nordisk came out with one called liraglutide. Eli Lilly joined the party in 2015 with dulaglutide, but it’s about to really shake things up with a potent dual receptor agonist called tirzepatide.

In a recent systematic review for the Internal Medicine Journal, Australian physicians sought to clarify how semaglutide holds up against the other drugs in this class. One of the principal investigators was gastroenterologist Professor Chris Rayner. I called him in Adelaide alongside endocrinologist Professor Gary Wittert.

CHRIS RAYNER: So I'm Chris Rayner. I work at the Adelaide Medical School, University of Adelaide, as a clinical academic, but I'm also a gastroenterologist and active in that side of my clinical practise.

GARY WITTERT: Gary Wittert. I'm an endocrinologist and Professor of medicine at the University of Adelaide. I'm based at the South Australian Institute of Health and Medical Research and practise clinically at the Royal Adelaide Hospital.

MIC CAVAZZINI: Chris let’s use that systematic review in the IMJ as a starting point, from trainee physician Brandon Stretton and a bunch of your other colleagues. It wasn’t a metaanalysis so much as a look at head to head comparisons between semaglutide and the various other GLP-1 receptor agonists in adult patients with type 2 diabetes. Dr Stretton identified five papers published between 2016 and 2021, all sponsored by Novo Nordisk or Eli Lilly. They reported that 1mg of semaglutide delivered weekly for 40 weeks causes drops in glycated haemoglobin of 1.5 to 1.8 percent. The next closest competitor in this class was dulaglutide with reductions of up to 1.4 percent. How impressive is the antihyperglycaemic effect of semaglutide compared to the existing standard of care?

CHRIS RAYNER: Well the antihyperglycaemic effect is quite impressive, I would say. The big advantage of this group of over other injectables, particularly long-acting insulin, are that their lowering of blood glucose is glucose-dependent. They only stimulate insulin secretion when the blood glucose is elevated so they're much less prone to resulting in hypoglycaemia. Certainly, until we had tirzepatide, which we’ll speak more about, semaglutide was the most effective of the other GLP-1 receptor agonists so far. It's longer acting than some of the original ones so there's more persistent exposure to drug, which is good for fasting glucose lowering in particular.

MIC CAVAZZINI: But semaglutide was trumped by tirzepatide which reduced HbA1c by 2.1 percent at the 5mg dose, and by 2.4 percent at the 15mg dose. Tirzepatide, or Mounjaro, is Eli Lilly’s latest contribution. It doesn’t just bind the GLP-1 receptor but also that of another incretin hormone called glucose-dependent insulinotropic polypeptide. Does GIP receptor agonism recruit additional pathways or does it just amplify the same ones recruited by GLP-1?  

GARY WITTERT: It should be noted that the superiority of tirzepatide has to a certain extent got to do with its superiority for weight loss. So you're getting far more weight loss and the reduction in adipose tissue mass is going to, under any circumstances, increase beta-cell function.

CHRIS RAYNER: But it's fair to say that the scientific community is divided as to what the GIP receptor has to add to GLP-1 receptor stimulation in tirzepatide. So there's a lot of complex pharmacology around receptors. And for instance, the way tirzepatide interacts means that the GLP-1 receptor is not internalized so well, so it's more available. So it makes it a super GLP-1 compound compared to semaglutide, for instance. Whereas its effect on the GIP receptor tends to allow that receptor to be internalized—it may even act as a functional GIP antagonist.

If you look at data from murine studies, there's data showing that GIP might be good for weight loss, and GIP antagonism may be good for weight loss. So it's an extremely complicated area. It's interesting to note that there are polymorphisms for the GIP receptor and people who have got these that have a less a function of the receptor do tend to have a leaner phenotype. So, that's interesting. And it's a fascinating comment, perhaps that you've got a drug that's now come to market and we don't really understand the mechanisms completely.

MIC CAVAZZINI:                Interesting, so that there are layers of effect here. You’ve just mentioned weight loss—that was actually a surprise bonus identified in the early trials. In the particular studies included in your review, Chris, diabetes patients lost 6 to 7 percent of their preintervention weight with semaglutide. This was about twice as effective as the other single-acting agents but not as good as tirzepatide which had an 8 to 13 percent effect on weight, depending on dose. By contrast, classic interventions for hyperglyaemia like insulin and sulphonylurea medications often lead to weight gain. So, is this dual impact of the incretin receptor agonists enough to consider it a paradigm shift in diabetes management?

CHRIS RAYNER: I think it should be regarded as a paradigm shift, but I think the other thing that's worth noting is the additional benefits of this class of therapy as far as cardiovascular protection and renal protection goes. It does share that in common with the SGLT 2 inhibitors, which are currently more available and less expensive. But there are subtleties between which of those drugs to choose between in different situations. But certainly cardiovascular protection and renal protection are two big draw cards of the GLP-1 class.

GARY WITTERT: Do you think that the effects on cardiovascular and renal are the consequence of weight loss or some GLP-1 independent effect? Do you have a view on that?

CHRIS RAYNER: I'm not at the top of my head sure of animal models to differentiate weight loss from other effects.

GARY WITTERT: Why I raise that is the data on bariatric surgery for improving renal function and decreasing proteinurea, as well as for cardiovascular protection is excellent. And I don't think one can invoke sustained GLP-1-based effects to the same magnitude.

MIC CAVAZZINI:                Gary, hold that thought because I think I want to end there with the comparison to bariatric surgery. So we talked about the weight loss. Other the secondary outcomes—changes in waist circumference and systolic blood pressure—also followed a similar pattern with these drugs. But before we hand the trophy to tirzepatide we do need to consider side effects.

So with semaglutide you get nausea in about 20 percent of patients and vomiting in half as many, diarrhoea in 12 to 15 percent but constipation another handful. Fewer than 1 percent experienced hypoglycaemia, gall bladder disorders or pancreatitis in these studies. For tirzepatide the numbers were pretty similar at the lower doses and a fraction higher at 15mg. And discontinuation rates due to adverse events for both drugs was under ten percent. Is there anything remarkable about that safety profile?

CHRIS RAYNER: I think that it's been very much underplayed in the clinical trials. Certainly, it's acknowledged that the rates of GI adverse effects are high, and they're mainly mild to moderate, and they tend to be greatest in about the first month of therapy, eased by slowed up-titration of the dose. But if you look at the fine detail, there's still some persisting GI symptoms, even after 12 months use. And in a clinical trial, there's a lot of support to cajole patients into staying in the trial. So something like a seven or eight percent dropout due to GI adverse effects looks very good, but I suspect you wouldn't be able to maintain that sort of rate in a real world setting. In fact, I think if you look at community pharmacy dispensing data for GLP-1 receptor agonists, at about 12 months only about half the people are still taking the prescribed drug.

GARY WITTERT: You mean, as in semaglutide?

CHRIS RAYNER: Yes, a range of—I can't remember where the semaglutide was in this analysis, because it goes back a few years.

GARY WITTERT: Yeah I think semaglutide is differently tolerated and the difference is weight loss. In clinical practice, is that I've not seen any patients, or very few patients come back and say, “I don't want to take semaglutide”. And that stands in marked contrast to liraglutide and dulaglutide where there were a significant proportion of patients who said they didn't want to take that. With Byatta or exenatide it was even higher, very few of my patients wanted to take it. You know, we've done trials with topiramate, which in its earliest formulation was extremely toxic in terms of adverse events. And people were losing a lot of weight, and didn't want to withdraw from the trial because of the weight loss. So I think that if the weight loss is significant people will tolerate the nausea, which is quite a remarkable observation

MIC CAVAZZINI:                So discontinuation is one potential negative in the column of these GLP-1 agonists. So tirzepatide hasn’t yet been launched in Australia, but as it stands, even semaglutide is not the first line option for type 2 diabetes in the eyes of the advisory committee of the Pharmaceutical Benefits Scheme. To qualify for the PBS subsidy a diabetes patient also has to be receiving metformin or sulfonylurea and have a contraindication or intolerance to the combination of that pair. Patients must also have had an HbA1c above 7 percent despite treatment with those meds. And then there are some complicated rules about accepted HbA1c thresholds once gliptin, glitazone or SGLT2 inhibitors have been started. Are all these hurdles put up by the PBS simply about the cost of the drug to Medicare and to the taxpayer?

GARY WITTERT: Well, that may be some of the rationale. I can't speak for the TGA, but from a point of view of logic, I don't think sulfonylureas make any sense at all, not in the current environment. I mean, they cause hypoglycemia, potentially. They lead to weight gain, despite their efficacy, and some of that efficacy is lost with time. They're potentially cardiotoxic in comparison to other drugs. So I think the starting point of metformin makes perfectly good sense. You know, metformin is extremely cheap—you know, $9 a month if you bought on a private script, maximum 12, I think. So metformin make sense. Of course, there's some people who won't tolerate metformin, but I suspect they're also the people who won't tolerate semaglutide.

DPP-4 inhibitor is weight neutral, but effective. And of course, SGLT-2 inhibitors are extremely effective if they’re used appropriately as an add on to metformin with also cardiac and renal benefits. And in fact, may well be more cost effective. However, if someone is significantly affected by obesity with multiple end organ effects, then there's no question that the weight loss of semaglutide makes enormous sense.

MIC CAVAZZINI:                That's a that's an interesting point. So how big an effect you need, how far above the threshold, are they?

CHRIS RAYNER: And then there'll be other subtleties that you'll take into account in the algorithm. Like, cardiovascular risk in particular.

MIC CAVAZZINI:                Going by the PBS website, it seems that the government gets Ozempic into the country at $133 for three weeks of therapy, though with a PBS subsidy the patient only pays $30. Meanwhile Eli Lilly’s application to have their tirezaptide formulation, Mounjaro, listed on the PBS for the same narrow range of diabetes indications was rejected entirely. Again, is it a good guess that Eli Lilley they wanted too much money for it and our Health Minister called their bluff?

GARY WITTERT: No question about it. It was never going to wash that if Lilly wanted four or five hundred dollars or whatever it is, for Mounjaro, that they were going to get it on the PBS. So I don't know what Lily were thinking, other than the fact that that so many people may be desperate to get it that they may be prepared to pay those outrageous fees.

MIC CAVAZZINI:                If money were no object would, would you want to have tirzepatide listed?

GARY WITTERT: Well, I think you have to have money in the equation. We have limited healthcare budgets. Resources are precious. And if we've got an effective drug, that's a quarter of the price, that's what we should be using. And it's very effective. Does the extra weight loss make a huge difference clinically? I don't think we know that. I don't think we have head-to-head outcome studies. Yes, it might be nice. Is it super important? No data.

MIC CAVAZZINI: Given the remarkable weight loss in trials in patients with diabetes, Novo Nordisk started testing GLP-1 receptor agonists in people who were obese or with other comorbidities related to excess weight. In one paper published in 2021 it was reported that semaglutide at 2.4mg weekly for 68 weeks, led to an almost 15 percent decline in body weight. A trial of tirzepatide in the same sort of cohort achieved up to 20 percent weight loss. So we’re talking two or three times the effect size we described from the diabetes studies. Both trials were double blind, placebo controlled, and published in the New England Journal of Medicine.

“But wait, there’s more.” Eli Lilly has just published the findings of a Phase II trial of a triple receptor agonist called retrarutide. This also hits the glucagon receptor on top of those for GLP-1 and GIP. Participants assigned to a 12mg weekly dose lost on average 24 percent of body weight after 48 weeks. This is getting close to the realm achieved with bariatric surgery, but it does come with a fair few side effects that need further investigation.

Either way you look at it, though, it compares very favourably what’s normally achieved by people through dieting and lifestyle change, and we know how frustrated dieters get from the difficulty of keeping weight off. Probably the largest cohort that’s been tracked longitudinally has been the US National Weight Loss Registry. In 2005 researchers reported that 20 percent of overweight individuals were successful at losing at least 10 percent of initial body weight and keeping that off for at least a year. Other reviews usually put the success rate at half of that, but either way, this leaves a lot of people struggling with unwanted or unhealthy kilos.

One popular theory is that we all have a metabolic set point; a narrow weight range which our body and brain strive to stay within. So even if you reduce your caloric intake, your metabolism just slows down so that fewer calories are burnt and absorbed, meaning that weight loss isn’t as dramatic as hoped for. This would have been life saving for prehistoric humans struggling through lean winters and droughts, but not so appreciated by those of us leading an indulgent first world lifestyle.

The metabolic set point doesn’t just influence your GI tract but also your brain, with some of the very same hormones acting centrally to drive your appetite. The contribution of incretins to this is suggested by the widespread expression of their receptors. One of Chris Rayner’s research interests is how GLP-1 suppresses gastric motility and therefore how quickly nutrients pass through the stomach and gut.

CHRIS RAYNER: The interesting thing is that people view the main mechanism of stimulation of insulin secretion, in fact, that's only one mechanism. It will do that when your blood glucose is elevated. But because it's slowing emptying, actually, the demand for insulin is less because you're slowing the release of carbohydrate into the small intestine for absorption, so there are multiple mechanisms of action here.

These hormones are released to a greater degree from the distal and proximal gut. And one of the reasons why we've got them is to help prevent nutrients racing too quickly through the gut. So nutrients that are exposed to the distal gut will provoke a great response with not only GLP-1 but also other hormones like PYY, which subsequently feeds back to slow gastric emptying and retard small intestinal transit. So you’re really trying to spare nutrients for digestion and absorption rather than let them pass on absorbed through the gut. That's the physiological function of these hormones.

MIC CAVAZZINI:                Maybe paint the picture a little bit more. Are there GLP-1 receptors right on the smooth muscles of the gut? Or is acting through intermediaries like ghrelin or leptin or whatever?

CHRIS RAYNER: Yeah, so a lot of the action of GLP-1 is paracrine. So it's acting locally in the gut and stimulating vagal nerve endings, and it's via those nerve impulses that we get effects on motility. But also to a large degree, that's a major part of this satiation side of the hormones. There are also central components to hormone action as far as the appetite effects go. So we talk about satiation as feeling that you've had enough during a meal. And a gut hormone classically signals like that. But then you've got satiety, which really talks about the length of time before you want to start eating again. And you wouldn't expect to gut hormone pure and simple to have much effect on satiety, and yet, this does seem to be an effect of GLP-1 receptor agonists. We're only just beginning to understand the neural circuitry. Most of these studies done on rodents and there are substantial differences in physiology in the incretins between rodents and humans. So this is why there's a lot of confusion about mechanisms.

MIC CAVAZZINI:                I've just got one line note here; a 2017 study where subjects were offered ad libidum food, and energy consumption was reduced by 35 percent, over 12 weeks. And there’s evidence of GLP-1 receptors in the brainstem, hypothalamus, and afferents of the vagus nerve, too. And I was struck with sympathy by this comment reported in the New Yorker from a member of a support group for overweight people, “no wonder that skinny people think heavy people have no willpower. Their brains actually do tell them to stop eating. I had no idea.”

GARY WITTERT:                Well, I have a patient with Prade-Willi syndrome, or many patients with Prade-Willi syndrome, a disorder where their brain doesn't register any degree of satiety or satiation. They're hungry constantly, and doesn't matter how much they eat that sensation remains. And one of the young men I look after had a Roux-en-y gastric bypass, and said to me afterwards, “For the first time, I know what it's like to feel slightly full.” Slightly full. And so you know, these are very interesting mechanisms, with many, many pathways that impact on them.

And one of those pathways which uses GLP-1 as a mediator works on the hedonic aspects of feeding, so the pleasure of food. One of the things that people who go on this drug tell us is that they're much less likely to pick highly palatable, processed carbohydrate foods. And in fact, there is some suggestion that these drugs will modify addiction, for example, to alcohol. So this is a very interesting pathway, and is also important to the action of the drug.

CHRIS RAYNER: It's also one of the things that people with successful outcomes from bariatric surgery report isn’t it Gary?

GARY WITTERT:                Exactly correct. And you can abrogate that effect by blocking the hormones with somatostatin. And they suddenly say that those appetites sensations and drive for carbohydrate food comes back. So you know, the physiology of obesity and maintenance of fat mass, is very, very striking and I don't think we should ever consider that people with obesity have a lack of willpower. None of them want to be like that.

MIC CAVAZZINI:                One of my reviewers shared some literature with me showing improvement in patients with confirmed metabolic dysfunction-associated steatohepatitis. Doesn’t roll off the tongue as easily as non-alcoholic fatty liver disease. After 72 weeks the disease was resolved in 60 percent of patients taking semaglutide every week at just 0.4mg. Can you spell out the mechanisms a bit more bluntly. Is it simply that reduced caloric intake causes more reliance on burning of fat to provide energy? Or is there also a more direct effects? You know, downregulation of lipogenesis, that kind of thing?

GARY WITTERT:                GLP-1 has effects on the accumulation of intrahepatic fat. So there's certainly a component to the physiology that involves effects on intermediary metabolism. But you know, clearly, the low dose indicates that the efficacy is separate from pure weight loss.

CHRIS RAYNER: Certainly, with metabolic associated fatty liver disease, if you can get to the early stages, that's when you stand the greatest chance of avoiding progression. And we've got to remember that this is now the most common cause of cirrhosis and liver deaths in the advanced world. What we're less clear about is that it's going to have an impact on established fibrosis. We haven't got a lot of liver biopsy studies yet to tell us about this. But there's some interesting combinations with other compounds that might have more of an antifibrotic effect.

MIC CAVAZZINI:                So in the 2021 Novo Nordisk study in obese and overweight patients, semaglutide also resulted in significant improvements in blood pressure, lipids levels, C-reactive protein and HbA1c. And patients also reported improvement in reported quality of life and physical functioning. And there were similar findings from a double blind trial published in the New England Journal just in September in overweight patients who had heart failure with preserved ejection fraction. Will this have cardiologists reaching for their script book as well as endocrinologists?

GARY WITTERT:                Absolutely, I mean, cardiologists reach for their script book, in the case of SGLT-2 inhibitors now. And they're both on the PBS. Certainly for renal disease, it's on the PBS, you don't need to have diabetes and so on. But whether again, this is an effect of a reduction in weight, which I think is very much the case, rather than anything specific about GLP-1 that is a question. I rather think it's substantially weight, although there are GLP-1 receptors in cardiac tissue. So you know, the jury's out a little bit.  

MIC CAVAZZINI: There was a stronger criticism of this trial in patients with heart failure in Medscape’s This Week in Cardiology podcast. Cardiologist John Mandrola MD argued that any obese person will report feeling better when they lose a significant amount of weight, regardless what comorbidities they have. And the functional outcomes were hardly astounding; participants taking semaglutide increased the distance they could walk in 6 minutes from a median of 320 metres to 340. Given that the study enrolled just 529 people and didn’t track any relevant clinical outcomes such as rate of heart failure-associated hospitalisation, Dr Mandrola described it as "marketing masquerading as science".

But just one day before our podcast went live, his wishes may have been answered with an advance publication in the New England Journal of Medicine. This was a multi-centre RCT that recruited over seventeen and a half thousand participants who were overweight with some preexisting cardiovascular disease but not diabetes. For example, 68 percent had had prior myocardial infarction, and there was also a significant proportion with risk factors like dyslipidaemia. The participants were mostly men with an average age of 61 years.

The intervention group received 2.4 mg semaglutide weekly, and both they and the placebo group were all enrolled in a lifestyle programme as well. The primary cardiovascular end point was a composite of deaths from cardiovascular causes, nonfatal heart attack or nonfatal stroke. There was a clear separation in the cumulative incidence curves from the moment participants were randomised. At the mean follow up of three years and four months, the primary endpoint occurred in 6.5 percent of people administering semaglutide compared to 8 percent of people in the placebo group.

While this was significant, slight improvements in the confirmatory end points did not quite meet the significance threshold. Those included death from cardiovascular causes and heart failure-associated outcomes. Participants taking semaglutide lost “only” 9 percent of their preintervention weight at the two year mark but there were huge declines in CRP and triglycerides, along with a small increase in beneficial HDL cholesterol.  Professor Wittert is still inclined to attribute these benefits principally to weight loss, but the findings do lend confidence to there being cardiovascular benefits of GLP-1 agonist therapy in high risk, nondiabetic patients.
 
So how are indications for weight loss being handled by regulators and prescribers? Novo Nordisk relaunched semaglutide under the name Wegovy in 2021, with doses up to 2.4mg per shot. But the indications for use are very narrow. Patients must have a body mass index over 30, which is the obese range, or over 27 in the presence of at least one weight-related comorbidity. While the TGA site doesn’t spell any of these out, the FDA gives a couple of suggestions, notably hypertension or dyslipidemia. As we’ve heard, steatohepatitis would be another good candidate. I asked Gary Wittert how liberal you’d be with other comorbidities such as sleep apnoea.

GARY WITTERT:                It's difficult because to treat sleep apnoea, you have to lose around 20 percent or more of body weight to resolve it. Now, improving sleep apnoea doesn't mean you can give up your CPAP, you may still need your CPAP. And then there's the question of different phenotypes of sleep apnoea. So yes, I know, that ResMed shares have gone down 36 percent, that’s profoundly premature. So I want to be absolutely clear that any notion that this should abrogate proper patient assessment, identification of comorbidities, and targeted treatment for those comorbidities, in the hope that someone spending vast sums of money every month, will solve the problem—we don't know that.

And I think you have to look at how to classify someone in terms of current state of health. So, if you have a look at a staging scale, and there's some very nice staging scales, where you can look at psychological and physical risk, and the magnitude of obesity and—you know, are you in the green, the yellow or the red of an Edmonton staging scale, for example—that's extremely helpful to work out a threshold for where this should be applied. Vague guidance, I think is going to create some distortion of the market and is also going to raise some issues in terms of health equity about who can afford it, who will get it and so on. I think there are lots of questions that have to be answered.

MIC CAVAZZINI:                That’s a great answer. Wegovy hasn’t actually been launched in Australia, because Novo Nordisk’s request for a PBS listing was rejected not once but twice even for this narrow cohort of obese and overweight patients. One of my reviewers, I guess playing devil’s advocate to the argument you’ve just made, asked why there’s this distinction being made compared to diabetes patients who do benefit from a PBS subsidy. Is it just about clinical efficacy versus available options, as you’ve discussed? Or do you think there is some moral judgement creeping into those decisions as well?

GARY WITTERT:                It would be nice to think there's no moral judgment, but there is. We all have implicit biases. But I think implicit biases make it either less likely that you're going to prescribe; or lazy, because you don't want to deal with lifestyle change.

MIC CAVAZZINI:                Well is there a cohort, however narrow, for whom you think a PBS listing is appropriate?

GARY WITTERT:                Yeah I mean, starting at the top, someone who is profoundly physically, emotionally, psychologically and functionally incapacitated by severe obesity, no question. So let's start there. And then as you start coming down the layers, with significant cardiac disease and cardiac failure, severe renal disease awaiting a transplant; you know, someone with intractable, benign intracranial hypertension, where you've got, you know, limited options to deal with it, despite, maybe putting in shunts or using diazoxide; so, you can come down with a hierarchy of need. And I think that's why staging systems are useful.

MIC CAVAZZINI:                Perhaps the scale of the problem is also part of the PBAC’s reasoning, considering, that 31 percent of Australians are obese and 36 percent are overweight. Fatty liver disease is six times more prevalent than type 2 diabetes. Maybe they just don’t think that Medicare can afford all these drugs. But there are also costs of not intervening. That same reviewer of mine said wondered if treating people early for serious weight problems would pay for itself in fewer admissions for liver failure, cardiovascular interventions, even knee replacements.

GARY WITTERT:                There's no evidence for that. I mean, there are models of cost efficacy done by ICER in the United States, which shows that at least based on the price in the USA, prescribing semaglutide for people without diabetes increases healthcare costs, it doesn't decrease healthcare costs. And I think we need to bear that in mind. And also, let me be clear, if my diet consists of Vili’s pies and Coke, and I eat less Vili’s pies and Coke, and I lose weight, am I going to cost the healthcare system less? We don't know that. I certainly won't be healthier. And I don't think my longer term health outcomes will be better despite losing weight.

MIC CAVAZZINI:                A couple of my reviewers were worried that this easy fix could be permissive of continuing an unhealthy lifestyle.

GARY WITTERT:                Yeah, exactly. Eating less of a sub optimal diet and failing to get exercise and proper sleep and manage your stress may not lead to a better health outcome even if you lose weight. By contrast, if I can be persuaded to adopt a better diet and exercise a little bit each day, with some resistance and some aerobic, without even necessarily being hungry, and I get my sleep apnoea treated, I will definitely have better outcomes, no question about it and I won't necessarily have lost weight. So you know, I think these are the debates that we ought to be having.

MIC CAVAZZINI:                You talked about persuasion there, persuading your patients to get on board with lifestyle change. Does having this quick fix there on the shelf make that messaging harder?

GARY WITTERT:                I don't think it does. I mean, I use the analogy, “Would you put ethanol blend in your Bentley? And would having a smaller tank allow you to put ethanol blend in your Bentley?” Well, not really. And people get that. And I think when you actually have a frank discussion with people about the toxicity of inappropriate diets and processed foods, they get it. So, you know, people want to be healthier, they want the drug to help. And that said, of course, for some people, there is a cosmetic issue. But I think we need to separate that out and be very clear about what's appropriate and inappropriate prescribing, but, you know, it's got to be packaged with proper health advice and proper monitoring.

MIC CAVAZZINI:                I asked before about where incretin analogues sit with regards to the standard of care for diabetes, but what about obesity? So bariatric surgery is one intervention with well-proven effectiveness- there’s a much higher success rate than there is for dieting- and it has well understood-complications. It also works out no more expensive than a year or two of medication therapy. Where do you stand on the options available for…

GARY WITTERT:                Well, they're very limited, because bariatric surgery for the most part is not available in public hospitals. Despite the fact that for many people it's a life-saving operation. And allows people with very severe grade three and four obesity to return to a socially and economically productive life. It keeps them out of hospital in the future. But most public hospitals are not offering a service. And in private, there are all sorts of strange procedures being done of questionable benefit, other than for those who stand to profit out of it.

So, you know, I think we need to think very carefully for people with severe obesity problems, you know, grade three or four fantastic operation, if it's the right operation changes their outlook on life. And for people with diabetes, if it's done early enough in the disease it can lead to sustained remission, where no medication is required whatsoever.

But even the best of bariatric surgery, people are treated as a lifelong chronic disease, and they need optimal nutrition, they need physical activity, they need people to look after their bones and all of those kinds of things. I think on a on a health economics on a health equity perspective, there needs to be broader availability of Roux-en-y gastric bypass and accessibility to those people on an absolutely equitable basis.

CHRIS RAYNER: Gary, there must be quite a subset of patients who are so comorbid with their extreme obesity, that they're not good surgical candidates?

GARY WITTERT:                Oh no, the bigger you are the more comorbid you are, the better the candidate you are, because medically you can get these people fit for surgery very quickly. You know, you treat the comorbidities, you get them onto a very low calorie diet. And you know, within a few months, you can have them on the table with the operation. Remember that you can get weight off people, you just can't keep it off.

CHRIS RAYNER: Do you think that something like Ozempic has got a place?

GARY WITTERT:                Absolutely. Yeah, very much so. So I think it's got a place to prep people for surgery. And it's also got a place for those people who have had surgery and are struggling with weight regain, which does sometimes happen.

MIC CAVAZZINI: There are, of course, many other benefits of lifestyle change that need to be weighed up in the calculus of how widely to spruik medications for weight loss. Good food and exercise benefit mental health, immune function, even susceptibility to cancer. But in the real world, there are psychological and socioeconomic barriers to wider take-up of lifestyle change; the marketing and the low cost of junk foods; the stigma that overweight people feel in a trendy gym; urban design that discourages walking or cycling. The allure of a pharmaceutical quick fix is sometimes just too hard to ignore.

Starting in mid-2022, semaglutide had a meteoritic rise in the public awareness thanks to some cunning marketing, celebrity gossip, and of course, Elon Musk. When asked on the platform formerly known as Twitter about his “ripped and healthy” physique, Musk credited Wegovy. Dozens of celebrities became the subjects of fevered speculation as to whether their weight loss had been a little too miraculous. And unsurprisingly, hundreds of thousands of otherwise healthy people with a bit of undesired weight began asking their doctors for semaglutide too, or getting scammed into buying fake product online.

The massive spike in demand worldwide has choked supply for diabetes patients. It’s actually not the manufacture of the compound itself that has hit a wall but of the injection devices and cartridges. And because the whole supply chain has been diverted, there’s now also a shortage of insulin products using the same delivery system. Novo Nordisk can hardly be surprised by all this hype around their drug. Consumer-facing tv commercials in the US have a catchy jingle and trumpet weight loss as one of the explicit benefits of the Ozempic “Tri-Zone” along with improved glycaemic control and lowered CV risk. Only at the bottom of the advert does the fine print advise that: "Ozempic is not a weight loss drug."

In Australia, where direct-to-consumer advertising of pharmaceuticals is prohibited, the TGA has taken the unusual step of reminding us of the million dollar penalties and potential jail time. They’ve insisted that even social media influencers could be prosecuted for spruiking off-label applications of Ozempic.  We said earlier that the full public price for Ozempic in this country is $133 for a three week supply. But people with off-label scripts have been paying three to six hundred dollars for it privately at the pharmacy. And in the USA, Wegovy has been sold at the equivalent of 1500 Australian dollars. You can see why Eli Lilly intends to go ahead with the launch of tirzepatide by the end of the year even without a PBS listing.

Writing for the New Yorker, US journalist Jia Tolentino described how easy it was for her to get a script from a telehealth clinic, without even needing to lie about her weight. “Only in America”, I thought, until I bumped into a woman recently who was getting Ozempic from her regular pharmacy at the low low price of $30. She was in her mid-forties, a little burly, but quite strong and fit from an outdoorsy job. She told me she didn’t have diabetes, the required indication for a PBS-script, and that she’d simply told her GP that she’d like to lose 15 kilos because the weight was making her a bit depressed. I asked Gary Wittert whether laissez faire prescribing was contributing to the short supply of semaglutide in Australia, or whether it was mostly the struggle of getting it into the country in the first place.

GARY WITTERT:                Off-label prescribing, yeah, there's 50,000 scripts a month being written or dispensed for people who do not fit the PBS criteria in Australia. So it's entirely attributable to that. And it’s being used by bodybuilders to cut. Why wouldn’t you?

MIC CAVAZZINI:                Well, it beats running around the block in a garbage bag. Australian stocks of Ozempic did receive a boost in February, but then in June, Novo Nordisk warned that deliveries would still limited into 2024. The PBS advisory committee has recommended that the medications “be restricted to patients who are contraindicated, intolerant or inadequately responsive to SGLT-2 inhibitors,” so semaglutide should only be a backup option. And as recently as September the TGA advised prescribers not to start new diabetes patients on the medication. How consequential has this been for your patients?

GARY WITTERT:                It’s been extremely consequential. I’ll give you an example, I look after a man in his forties, he's got schizophrenia. He's extremely incapacitated by schizophrenia, the drugs have made him extremely large. And because he’s so large, he won't go out of the house. And he doesn't want to go into the house because he's paranoid. But his diabetes is perfectly controlled on the semaglutide. He still needs a CPAP—it's not that fantastic that it reduces his weight to the extent, but it allows him to be more normal. And now he's off it, he gains another ten kilograms, and his blood sugar goes up, and his triglycerides go up, and so on. So these are sort of people where you don't want cycling of weight. You do want sustained supply, and it's the kind of person who's maximally disadvantaged by the absence of this medication.

MIC CAVAZZINI:                You touched on this too. In March, the Pharmaceutical Benefits Advisory Committee irked GPs by suggesting that they would need special authorisation to prescribe. Should they even be initiating patients on semaglutide or should that left to endocrinologists, who work through the options empirically?

GARY WITTERT:                 I think there's too many people with type two diabetes and the workload for endocrinologists would be excessive. But you know, that should not abrogate GPs from behaving more responsibly—managing the patients according to what I think should be an acceptable defined and pre-specified framework,. And I can tell you that patients who have been started on this, who shouldn't have been, are many. Now, that's before we get to the clinics that are allowing prescriptions over the telephone, who are sending the scripts to their own pharmacies. And I wonder whether those pharmacies have a privileged supply that they're able to get and what premium patients are being charged.

MIC CAVAZZINI:                Well that New Yorker journalist wrote that even were there was limited supply of the Novo Nordisk product, she was able to get it supplied by a compounding pharmacy using semaglutide salts.

GARY WITTERT:                Oh there's another scandal, compounding pharmacies are making it known to GPs and patients that they can supply it. They're very careful about asking for the script to say semaglutide not Ozempic. But we don't know what the patients actually get, and the patients don't know what they actually get. You know, I think this is a very serious issue of bottom feeders entering the market and trying to capitalise on the distress of people unable to get their medication.

MIC CAVAZZINI:                I did find an Australian website that was advertising this service too. Novo Nordisk have an oral formulation due in Australia next year called Rybelsus. I’m sure that’s intended solely to increase convenience for patients with the clinical indications we’ve talked about, but the media didn’t get the memo. News.com.au report it as a weight loss drug first and then a treatment for diabetes. And there’s a book you can buy online called “The Complete Guide on How to Use Rybelsus Medication to Lose Weight and Destroy Obesity.” And it’s a gift that keeps on giving for Nordisk. In an extension to one of the longer trials published in 2022, non-diabetic people who stopped taking semaglutide regained two thirds of the weight they had lost within a year. So it doesn’t cure anything. But do you see it as a potential bridge to a healthier lifestyle? Maybe allowing people to lose a bit of self-consciousness as well as weight, and therefore gain motivation to exercise in public?

GARY WITTERT:                No, because it'll just gain the desire for more drug. You know, the reality is, people will be motivated to a healthy lifestyle, if they can see the benefits of the healthy lifestyle. Feeling better from lifestyle change is so motivating. And I want to separate that from weight loss because I'm not talking about weight loss, I'm talking about feeling better at any weight. I look after, a lot of men and a lot of them have got diabetes and obesity and metabolic syndrome and erectile dysfunction. And their sexual function improves with weight loss. And that's highly motivating when they improve their diet and their overall pattern of living and they get rid of the vast amount of alcohol and they get the depression treated. And then they feel better and then you can deal with the rest of the metabolic issues with some medication on top.

MIC CAVAZZINI:                And finally, this popularisation, we don’t really know what other side effects from perpetual use of GLP-1 agonists could be. In October an audit of US health claims was published in JAMA reporting that semaglutide use was associated with a fourfold increase in the rate of pancreatitis compared to bupriopion-naltrexone treatment, and a threefold increase in the rate of gastroparesis. Chris is this the other side of the coin of the gastric motility model you were presenting earlier?

CHRIS RAYNER:                 Well, it is I mean, definitely the gut motility issues are important. This has come to light because people coming for endoscopy, who apparently have fasted overnight, still have a gastric residue, which puts them at risk of aspiration. If you haven't emptied your stomach and you've got residual gastric contents, when you're anaesthetised and can't protect your airway, you can get reflux of content, and have aspiration of that fluid into the lungs, which is a potentially life-threatening complication.

So this has been a focus for both gastroenterologists and anaesthetists as to try to form some guidelines as to what to do. And I must say that we're really hampered by an extreme lack of evidence to base some of these guidelines. We don't know a lot about gastric emptying because both Novo and Lilly have resisted attempts to measure this with the best techniques. They’ve favoured the paracetamol absorption test as a way of measuring gastric emptying, which is a very crude method, it associates with the liquid phase of a meal. It doesn't give us good information about gastric emptying.

There is some evidence that you develop tachyphylaxis as for the slowing of gastric emptying when you get continuous exposure to GLP-1, so it's certainly true that the effects on gastric emptying decrease over time, but they're not abolished. And that's what's been ignored, I think, by the industry, and it's potentially now coming back to bite them.

GARY WITTERT:                One of the interesting points about the pancreatitis is in that JAMA article most of those cases came from patients taking liraglutide not semaglutide. So think about this for a minute. People with diabetes and high blood sugars and elevated triglycerides are at risk of pancreatitis. But semaglutide is far better at reducing white triglycerides and blood sugar. And you know, it may be that the lower rate of this disorder, despite its more potent effect on the pancreas, is simply because they have lower blood sugars and better metabolic control. Certainly, I don't know of any colleagues who've seen an occurrence of pancreatitis, despite large numbers of prescriptions. And indeed, many people are now prescribing it quite comfortably despite the guidelines for people with prior pancreatitis without any trouble at all.

MIC CAVAZZINI:                That's pretty convincing. In terms of long-term outcomes, I’ve come across one placebo-controlled trial of semaglutide that went for two years. That was a non-inferiority trial in over 1600 patients with not just diabetes but also established cardiovascular or chronic kidney disease. That intervention was associated with significantly reduced rates nonfatal MI and nonfatal stroke over the two years, though there was no significant difference in the rate of cardiovascular death. Still, this is an important distinction from weight loss drugs of previous generations that typically increased CV risk?

GARY WITTERT:                Yes, some of them did increase CV risk. Sibutramine is really is the only drug that's been studied in that context and sibutramine activates the autonomic nervous system or sympathetic drive. Now, you know, cardiologists, for decades have been beta-blocking people after myocardial infarction. And, you know, here, they went out and did a trial where they said, “Oh, we're going to be fine, because you know, you'll lose weight, therefore, your sympathetic activation doesn't matter”. That's absurd. The people who make phentermine were clever enough not to do such a trial, and it's flown under the radar.

So there’s no such data on the cardiovascular effects of the other drugs, but also, none of the other drugs are as effective at reducing weight. We have a drug now that is very effective at reducing weight, but in order to maintain the benefit you have to take semgaglutide lifelong, and we don't know what the lifelong consequence of this is, we don't even know seven to ten years. There are absolutely predictable adverse effects in the terms of loss of lean body mass, and loss of bone mass, and we don't know what the long term effects of those are in terms of frailty, for example.

You know it's perfectly feasible to substantially improve health, without losing weight, by improving the nutrient profile of your diet, correcting sleep disorders and obtaining some physical activity. Abrogating behaviour change and working with patients to have a more positive lifestyle and then use this as an excuse not to do so, seems to me we're on a very slippery slope here.

CHRIS RAYNER:                 These drugs will not be a panacea. You know, they're very much viewed that way in the public's mind. It's not that often that a blockbuster drug emerges that's a household name. But almost certainly, that means its expectations are overinflated and overstated. There'll be many people who can't tolerate these medications, just don't want to stay on them because they feel bad. And of course, we've got the affordability and the availability issues.

It's also worth saying that it's unlikely that semaglutide will remain this expensive in the long-term future. It's got competitors coming in, there are going to be multiple medications which are highly competitive to semaglutide. And so there'll be a price lowering for that reason. So it's definitely not the one all time solution here.

MIC CAVAZZINI: Many thanks to Chris Rayner and Gary Wittert for contributing to this episode of Pomegranate Health. The views expressed are their own and may not represent those of the Royal Australasian College of Physicians. I’ve included their declarations of interest at our webpage racp.edu.au/podcast.

At the same page, you’ll find a transcript of this episode, complete with links to all the academic references we’ve cited. And you can carry on the conversation at the Comments section there, or on the RACP Online Community. To make this easier, there’s a phone app called “RACP- the ROC” available for Apple or Android. The website also lists the College members who provided me with feedback in the development and editing of this podcast. I really appreciate all the time and dedication. In the new year I’ll be recruiting some fresh contributors to this motley editorial group. You can send an expressions of interest, or any other suggestions, to the address podcast@racp.edu.au.

As always, I recommend you check out the many other video lectures and eLearning modules developed for you. Just do a browser search for RACP Online Learning, or follow the links from the College home page. This podcast was produced on the lands of the Gadigal people of the Yura nation. I pay respect to their storytellers and healers who came before me. I’m Mic Cavazzini, thanks for listening.