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Carol Wysham, MD: Hello. I’m Dr Carol Wysham. Welcome to the second season of Medscape’s InDiscussion series on type 2 diabetes. Today we’ll be discussing insights into the importance of weight management for treatment options in diabetes. First, let me introduce my guest, Dr Carel Le Roux. Dr Le Roux is a professor of experimental pathology at University College Dublin School of Medicine. Welcome to InDiscussion.
Carel Le Roux, MD, PhD: Thank you very much.
Wysham: I always like to start by asking my guests some icebreaker questions. I’ve followed your career for a long time. You’ve established a world reputation in the obesity field. What motivated you to enter this field?
Le Roux: It is an interesting question. In 2000, I thought that obesity would be one of those diseases that’s like a balloon: If you squeeze it on one side, it’ll just pop out on another side because there’s so much redundancy in the system. I thought it was an important question to address, and I was fortunate enough to have great mentors and great opportunities. As they say, the rest is history.
Wysham: Let’s get into our discussion. As you know, the new American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) recommendations for the treatment of patients with type 2 diabetes have elevated the management of weight as an important focus, almost a co-primary endpoint, to the importance of treating hyperglycemia. I really like your insight as to how and why you think that has developed now compared with the past couple, three decades where we’ve known that weight was the underlying pathophysiology of diabetes.
Le Roux: I want to commend the ADA and EASD. You know, sometimes an idea has just the right timing, and I think this is what happens when we talk about treating the disease of diabetes by also treating the disease of obesity. We are now developing the evidence that it doesn’t matter what modality you use — whether or not you use nutritional therapy, a pharmacotherapy, or even a surgical therapy — we can disrupt diabetes by intentional weight loss of more than 10% or 15%. I think the evidence, therefore, was just overwhelming. The ADA and EASD are made up of smart people; they worked out that this is a great opportunity now that we have these tools to apply to our clinical practice. That’s why I think it happened. It’s a fantastic opportunity for us as clinicians. It’s going to make a massive difference to our patients who are living with type 2 diabetes.
Wysham: I like to think of this as almost as important as back in the early 1980s, when I started my practice, and we started understanding the importance of good glycemic control, and at the same time we’re having better and better tools to allow us to do so. I think that the importance and the timing couldn’t be better. Let’s talk a little bit about the role of obesity in the pathophysiology — of not only the complications of diabetes, but also the very frequent comorbidities that coexist in our patients with diabetes. What evidence do we have that weight loss will improve these?
Le Roux: I think when we go back, we have to learn from type 2 diabetes. Twenty, 25 years ago, people did not take type 2 diabetes seriously. We did not think that it was a real disease. We thought it was a lifestyle choice, but it was the UKPDS and other similar studies that changed our minds and showed that this is a disease that causes complications, serious complications like microvascular complications, and that when we intervene, we can really make a difference. Fast-forward 20, 30 years and we are repeating that with obesity, where for the first time we are understanding that obesity is not a choice. It is a disease, and when left untreated it could have serious complications. One of the most common complications is type 2 diabetes, which then spins out of control and gets amplified by the disease of obesity at the same time. Similar to type 2 diabetes, the turning point was when we developed treatment tools that we could scale, and where we could show that we can have 10%, 20% weight loss in people with type 2 diabetes and understand the benefits of that — not only from a weight loss point of view, but also from a health gain point of view. In summary, we understand obesity as a disease. We understand that we can treat it, and when we do treat obesity effectively, we can prevent the complications such as type 2 diabetes. We can also improve the complications such as type 2 diabetes and the microvascular side effect.
Wysham: It’s also quite interesting to be thinking about how many other conditions people with type 2 diabetes have besides the hyperglycemia and the intended complications of diabetes per se.
Le Roux: I want to comment on that because you are so right. When I treat my patients in the diabetes clinic and they have 10%, 15% weight loss, I ask them, “What’s the most important thing to you?” Of course, I’m delighted with their hemoglobin A1c that’s improved or the cardiovascular risk that’s improved, but so many patients with type 2 diabetes say, “You know what? The most important thing is that I can cut my toenails,” or “I can get on an airplane without an extension seatbelt.” These are so-called nonscalable victories. That’s what drives the quality of life of our patients. I cannot agree with you more that we need to think of this in a holistic way to help our patients with type 2 diabetes — not only from a glycemic point of view, but also these important aspects that drive quality of life.
Wysham: Yes, I love that term “holistic view” of taking care of our patients. I think your point on the nonmedical aspects of treating obesity is something that we have not spent enough time on. I appreciate you bringing that up. Can we go back to some of the other comorbidities, medical comorbidities, that our patients are facing? Let’s discuss what you would recommend in terms of weight loss and the amount of weight loss necessary to improve some of these, such as cardiovascular disease, nonalcoholic fatty liver disease, and other complications of diabetes.
Le Roux: When we think about patients with type 2 diabetes and obesity, we really think of these complications in a mechanical way, in a metabolic way, and also mental and even monetary. Those are the four M’s that we are talking about. Depending on the complications of the specific patients, we may have to streamline how much weight the patient needs to lose. It’s not necessarily the starting rate that’s important; it’s the amount of weight loss that we need to disrupt these complications. The glycemic control is the most sensitive of all the complications. We know that only 5% weight loss can be incredibly powerful in preventing people from developing type 2 diabetes. We saw that with the National Diabetes Prevention Program and the Finnish Diabetes Prevention Study. But if you have type 2 diabetes, then it appears that we need about 15% weight loss to put the diabetes in remission or really to disrupt it. When we think about cardiovascular complications, the Look AHEAD study would suggest that those patients who have more than 10% weight loss also had a cardiovascular benefit. So, I think the industry standard when it comes to weight loss is changing. In the past we talked about 5% as a target, but I don’t think 5% is good enough anymore. I think we really need double-digit weight loss, and when we are thinking about double-digit weight loss, it appears that 15% is better than 10%, and it may even be that 20% is better than 15%. I would aim, in my patients with type 2 diabetes, to achieve at least 10% weight loss when we set weight loss as a target.
Wysham: Obviously, diet, exercise, and behavior modification have to be a part of the plan. We do have some very powerful medications now that can help our patients with diabetes — and, for that matter, patients without diabetes — lose weight. I’d like to start with the glucagon-like peptide-1 (GLP-1) receptor agonists. As we know, they’re the most powerful medications we’ve had up until the past couple of years. It strikes me that they’re not all the same. Can you comment about why you think semaglutide seems to have so much greater benefit compared with the other agents in that class?
Le Roux: I think it’s correct, what you say, and I would agree with you that lifestyle treatments remain the cornerstone of everything that we do. We also need to appreciate that nutritional therapies and exercise therapies are similar to all our other therapies in that we find responders and nonresponders. We find that about 2 in every 10 people respond very well to a nutritional therapy. For the 8 out of 10 people who don’t respond, it’s not because they’ve done anything wrong or they’re not listening; they just don’t have a biological response. I agree with this idea that we start, and if it works, we continue; and if it doesn’t work, we escalate. What you’re saying about the pharmacotherapy, especially the GLP-1s for people with type 2 diabetes, that’s been very powerful. When we look at treatments like semaglutide, it appears that when you have a molecule that can effectively penetrate the subcortical areas of the brain and really penetrate those tissues, then you have a treatment that is highly effective also for the disease of obesity. That’s an important concept because many of our diabetology colleagues will know that if we treat diseases of the subcortical areas of the brain, the hypothalamus, the pituitary, etc., these are difficult diseases to treat. And we are now thinking of obesity as a neurologic disease, a neuroendocrine disease of the subcortical areas of the brain. Therefore, it makes sense to us that if we are able to penetrate the GLP-1 receptors that sit in the area postrema or the nucleus tractus solitarius, or the hypothalamus, if we have those agents, then those agents are going to be more effective than other GLP-1 analogs that, for example, don’t penetrate those areas. I think understanding the anatomy, understanding the organ of interest when it comes to the disease of obesity, helps us understand why we see the responses that we do.
Wysham: Thank you. Well, now we have this new kid on the block, tirzepatide. I’m interested in your comments again, reviewing the benefits that were seen in people with diabetes and in those without diabetes. And perhaps some comments on why you think people with diabetes typically don’t lose as much weight as patients who don’t have diabetes who are using the same treatments.
Le Roux: Carol, that is the million-dollar question. I have been asking the smartest people in the world and we all have our little pet theories, but I think there’s no consensus. It’s a really important question that we need to address: Why is it that people with type 2 diabetes with the same therapy lose less weight than people who don’t have diabetes? I think some of the insight is going to come when we treat more people with type 1 diabetes, and obesity, of course, is an epidemic also for people with type 1 diabetes. Now, when we are using these same agents, not from a glycemic point of view but from a weight loss point of view in type 1 diabetes, the very early data would suggest that the people with type 1 lose the same amount of weight as people who don’t have diabetes. That’s really interesting. There’s something in people with type 2 diabetes that’s different to type 1 diabetes or people who don’t have diabetes. I think we need to address this. We don’t have a good answer. Let’s look at tirzepatide, an amazing drug: 22% weight loss in people without type 2 diabetes, but only 12% weight loss on average in people with type 2 diabetes. It will tell us that there will be people who will respond to these drugs, but we will have more nonresponders among people with type 2 diabetes when we use these very powerful new, third-generation antiobesity treatments. I would just say at this point that if you do treat the patient with a great new drug and they don’t respond, it’s not because you’re a bad doctor or it’s a bad drug or it’s a bad patient. It is that the biology of the disease is not the right biology to be responding to that intervention. Don’t despair; there are other treatments. And feel free to use other interventions, like nutritional therapies or even bariatric surgery, which remains a very good treatment for our patients.
Wysham: I think you bring up a really good point. And in fact, if you look at the data with the weight nonresponders to GLP-1, it’s probably as much as 15%. However, looking at the waterfall plots in the presentation of the obesity study for tirzepatide, those numbers were more like 5%. Now, not everybody lost 15%, 20%. There were a few who just lost 5%. It appears for some reason that tirzepatide seems to have a greater chance of helping people lose weight compared with even the best GLP-1.
Le Roux: You are correct. And we see that same pattern. It’s a sort of a Gaussian distribution of weight loss. We see that same pattern with nutritional therapies, and we see the same pattern with bariatric surgery. All that happens is that the median is just shifted, and with a very effective treatment like tirzepatide, it is certainly shifted to the right, meaning more median weight loss and fewer patients who don’t respond or have less than 5% weight loss. We will still have patients who don’t respond, and I think once we’ve gotten over the euphoria of these wonderful new treatments that we have — and it truly is a deserved euphoria — we also need to pay attention to those patients who don’t respond. We see that people with type 2 diabetes, especially people with obesity, suffer a lot of stigma. You can imagine how stigmatized you would be if you take a great drug, from a great doctor, and you don’t respond. Unfortunately, as doctors, we very often blame our patients, and we need to be careful with that. There will be nonresponders. Fortunately, they’ll be few and far between, but if that happens, we need to support those patients and also manage and work out the alternatives. The pipelines are rich when it comes to companies bringing new treatments forward. I think we will find treatments that will help our patients. Maybe they are 4, 5 years away, but I’m very confident that we will find more treatments for our patients.
Wysham: I recognize that we don’t have a lot of evidence in terms of clinical trial use of combinations of medications with GLP-1s or dual agonists. Do you have experience in the clinic in using other antiobesity medicines on top?
Le Roux: Again, I think type 2 diabetes is a wonderful example for this work, and we don’t have to reinvent the wheel. We can use different classes of medication to attack the disease from different angles. Hypertension is another great example, and what we are seeing is that when we combine treatments, very often the effects are amplified. I think some of the best evidence now is patients who have had type 2 diabetes, who had bariatric surgery, who may have had a good response initially, but then may have had some weight regain or relapse of type 2 diabetes. When we add these therapies — for example, GLP-1s or combinations of GLP-1s/glucose-dependent insulinotropic peptides (GIPs) after bariatric surgery — patients appear to respond in the same way as they would have responded pre-surgery. It means that we will end up with more combination therapies, be it combinations between drug classes or even combinations between surgical treatments and medications.
Wysham: I think I’m hearing you say that, yes, you will look at the patients and treat them with safe combinations that you think might be effective at helping them reach their goals.
Le Roux: You are correct. But also it’s incumbent on us to do the science, because it’s not good enough for me to go back into my clinic and come up with all types of concoctions. We need to test these prospectively and we also need to support the industry to do these studies. Even if we think about combination studies of people with type 2 diabetes and GLP-1s and SGLT2s, those quality studies are still lacking. I know that some of them are underway, but that’s an example where things have crept into our guidelines without very robust evidence. I think we really need to provide the evidence to support that clinical practice.
Wysham: That’s wonderful. Any last comments that you would like to make before we close up today?
Le Roux: I think the future is incredibly bright for us as clinicians to be able to treat the disease of type 2 diabetes, but also for patients living with type 2 diabetes. I think we will be able to drive down the metabolic complications. I also think we will be able to improve the mechanical complications, and I specifically think the quality of life around the functional domains is going to improve dramatically. It’s going to be a pleasure to work in those clinics and help patients with highly effective treatment options.
Wysham: I couldn’t agree with you more. Dr Le Roux, it’s been a true pleasure talking with you about this very important subject. Today we’ve talked about the importance of monitoring weight and treating weight for our patients with diabetes, not only to improve their glycemic control but also to help improve their complications and comorbidities, as well as their quality of life. I want to thank the audience for joining us. This is Dr Carol Wysham with InDiscussion.
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