This transcript has been edited for clarity.
Silvio Inzucchi, MD: Welcome to Medscape InDiscussion. I’m Dr Silvio Inzucchi, and today we’re talking about obesity and type 2 diabetes. It’s a long-standing concern, but one with a great deal of potential for success on the horizon, which we’ll talk about very shortly.
First, let me introduce my guest, who is an obesity expert and a colleague of mine: Dr Ania Jastreboff. She is associate professor of medicine at Yale School of Medicine and director of Yale Weight Management and Obesity Prevention at the Yale Stress Center. In addition to being an endocrinologist for both adults and children, she’s also board-certified in obesity medicine. We’re very fortunate today to have a true expert with us. Welcome, Ania.
Ania Jastreboff, MD, PhD: Thanks for having me, Silvio. It’s my pleasure to be here today.
Inzucchi: Before we get into our main discussion, can you tell us a little bit about why you got into working in the field of obesity medicine?
Jastreboff: Deep down from the very beginning, I never thought that obesity was not a disease, and I didn’t understand why we didn’t treat it as such. Looking at what we had advised our patients for years in terms of moving more and eating less, is that how we advise for any other disease? Patients can have resources, they can have education, and yet there was something driving [obese individuals] to maintain that higher weight. I became interested in understanding what is the pathophysiology of obesity. What drives people to gain weight and then not be able to lose that weight? Or even if they do lose that weight, why is it so difficult to maintain that weight loss?
Inzucchi: There’s been a lot of progress in that specific area, and I know you’ve worked in that area as well. Let’s talk about patient management. Diet and exercise have traditionally been the cornerstones of obesity management, particularly in patients with type 2 diabetes. Now, of course, bariatric surgery has become very popular over the past 10 or 15 years. Can you speak to the changes? I think it’s probably just in the past 3-4 years, maybe, the changes in the field of obesity medicine, particularly as related to pharmacologic management?
Jastreboff: It’s an extremely exciting time for obesity medicine and for treating patients with obesity. In terms of available anti-obesity medications, they have exploded and are going to continue to explode over the next 3-5 years and then into the next decade. In 2012 and 2014, two new agents were FDA approved in each of those years for obesity treatment. Efficacy was similar to what we had seen with past agents. But then just this past summer, what we saw is the FDA approval of a newer agent, semaglutide. It’s a newer agent, but not a new class of medications: a glucagon-like peptide 1 (GLP-1) analog. The efficacy for this agent is significantly higher than any of the other anti-obesity medications we’ve seen in the past. This is just the first agent that opens the door for many, many other GLP-1–based medications for the treatment of obesity. It’s a truly exciting time — ushering in this era where we have new treatments for all of our patients with obesity.
Inzucchi: You touched upon the GLP-1 analogs (or, as some people call them, the GLP-1 receptor agonists). These are so-called incretin-based therapies. Can you update us on how they work, both in terms of lowering glucose in patients with diabetes but also specifically how they get patients to lose weight?
Jastreboff: As endocrinologists and in primary care, we’ve been using GLP-1 analogs for more than 15 years. They were FDA approved some time ago, but specifically for the treatment of type 2 diabetes. In 2014, it was the first time that a GLP-1 analog, liraglutide 3 mg, was FDA approved for obesity. Then in June 2021, semaglutide 2.4 mg was FDA approved, also for obesity treatment, not just for type 2 diabetes. In terms of the way these medications work, they’re incretins, so basically, they’re responsible for a majority of the insulin that we release in response to nutrient intake. That’s how they help in terms of type 2 diabetes, and they obviously lower blood sugars.
In terms of obesity, the mechanism is quite different. Initially, it was thought that potentially it was because these incretins also slow gastric emptying. But what’s been found more recently, in animal studies, is that they work in the brain on hunger satiety regions, as well as potentially other regions of the brain, such as those associated with reward and motivation. What they basically do is increase satiety, so patients who respond to these medications will finish eating earlier or they won’t go back for seconds. A lot of patients report a significant decrease in hunger and a significant decrease in wanting to eat. Some patients also report some changes in craving. These are all things that we need to explore further. But basically, in terms of obesity, patients tend to eat less and they don’t mind — meaning that it’s not a struggle. They just naturally eat less when they take these GLP-1 analogs.
Inzucchi: Now, the rap on these medications was that the GI side effects were driven by the effects of the GLP-1 analogs on the gastric emptying. People would say, my patients aren’t eating because they’re always nauseous. But it’s beyond that, correct? The effect on gastric emptying is not necessarily sustained.
Jastreboff: Yes, that’s absolutely accurate. What we do with these medicines is we titrate them up very slowly, and that helps to mitigate those side effects of nausea that patients have. So, going up on the dose very slowly and allowing their body to get used to it is important. There is a published study that looked at delayed gastric emptying, and based on that, it looks like after about 8 or 9 months, nausea resolves. There are GLP-1 receptors in the area postrema, so it does make sense that there is nausea associated with that; it’s not just the delayed gastric emptying. Over time, nausea does not persist in the majority of patients, especially if you titrate the dosage very slowly. So, the impact in terms of eating less is not because of the side effect of nausea, because months down the road, patients don’t experience nausea and they’re continuing to eat less. We don’t think that’s the reason why. We think the direct effect on those hunger satiety centers is what’s doing it.
Inzucchi: So, we have weekly formulations. The ones that are most used would be semaglutide and dulaglutide. And then there are still some daily formulations, specifically liraglutide that you mentioned before. Do you still use the daily ones? Some physicians prefer to start with the daily formulations, then move to the weekly ones if they’re well tolerated. Is that necessary? Can you just start with the weekly version?
Jastreboff: If the weekly version is covered by insurance, semaglutide does have the highest efficacy in trials. If a patient doesn’t have type 2 diabetes, the average weight loss was 15% of total body weight. One third of the patients lost 20% or more of their total body weight. That would translate to, if a patient weighs 200 lb, they would get down to 160 lb. That’s very significant.
Now, with patients with type 2 diabetes, the weight loss is a bit less. On average, instead of losing 15% of total body weight, it’s closer to 10% of total body weight. So, if you weigh 200 lb, you would lose 20 lb instead of 30. The effect is a bit attenuated, but weekly semaglutide is still the one that has the most efficacy in terms of weight loss. Using the daily formulation may have some advantages in terms of blood sugar control. The other thing is that patients can be titrated up to a higher dose more quickly.
But overall, if you’re looking for that weight loss effect, which is critical when treating patients with type 2 diabetes — 89% of patients with diabetes have obesity — why not treat the root cause of their type 2 diabetes? That is very important to consider. But there’s no reason to not start with a weekly dosing regimen if you have insurance coverage for it.
Inzucchi: What’s been your experience once you get to the top doses of these medications in a patient with type 2 diabetes? Moving to the obesity doses, clearly you get more weight loss, but do you get any more effect on the glycemia?
Jastreboff: This has been looked at, especially with liraglutide. That’s the consideration in terms of why the highest dose for type 2 diabetes is 1.8 mg of liraglutide vs 3 mg for obesity. It does look like the glycemic effect is a bit less in terms of the amount of benefit you’re going to get from a higher dose, but there is still some benefit when you go up to the higher dose. So, I don’t think it’s negligible. But if you’re working with your patient, and they’re doing well, and they’re tolerating the higher doses, I don’t see why not to go up.
The times not to go up are if patients are having side effects at higher doses that aren’t mitigated over time. Another reason would be insurance coverage. The last thing would be if your patient’s BMI starts to get really low, which we have seen; patients going well below a BMI of 25 with these types of agents and the newer ones that are coming down the pipeline. So, those would be additional reasons to potentially back off on the dose.
Inzucchi: Like with anything, individualization here is key.
I want to get to other topics, but I did want to pick your brain on the notion of using these medications intermittently. Obviously, obesity is a chronic disease, and there’s no reason we shouldn’t treat it. This is not bronchitis, after all, that we’re treating. But patients don’t like that. They want a fix, and they want to be able to titrate themselves off the medications eventually, or at least to lower doses. Is that possible? Can you use these medications at higher doses, get patients to a more reasonable weight, and then begin to think about tapering the medication dose?
Jastreboff: The question that I would ask is, if you start a patient on insulin and their A1c is below 7, would you say, “Well, now we can stop the insulin” or “Now we can titrate off the insulin”? What’s going to happen? Their blood sugars are going to go back up, right? Same thing with hypertension. You wouldn’t stop an antihypertensive because now the blood pressure is normal.
In terms of obesity, the same thing happens. This is a key concept, because when we’re treating obesity, we’re not treating to weight loss per se. That’s the outcome, like blood sugars are an outcome with diabetes. What we’re treating is a dysregulated body fat mass set point, and that’s set by your brain. So, if you give someone an anti-obesity medication and their set point is reset to a lower place — that’s what we want — the weight loss follows. But what happens when we take away that medicine? That set point goes right back up.
In terms of decreasing doses that’s an interesting question. Usually, when my patients ask to either stop or lower a dose of the medication that they’re taking, I say, “Okay, well, we’ve talked about how what is likely to happen is weight regain.” We saw that in one of the STEP trials and one of the semaglutide trials; it’s beautifully demonstrated. What I say is, “Why don’t we do this? Why don’t we go down by one dose and see what happens?” Usually, what patients report is that they’re maintaining most their weight loss, but it’s a struggle. They’re having difficulties maintaining that weight loss.
I’ll never forget what one of my patients shared with me — and I think we learn everything from our patients. What she said to me, when she had lost over 85 lb with one of these medications, was, “You know, it’s just as easy to lose weight as it ever was to gain weight.” That’s what I want for every single one of my patients: I want it to be just as easy to lose weight as it ever was for them to gain weight. We can try to lower the doses, but it’s going to be harder for them. And going off the medications, if they’ve lost a significant amount of weight, it’s likely that over time, they will regain that weight.
Inzucchi: So, basically, you’re saying it isn’t bronchitis?
Jastreboff: It’s not. It’s not bronchitis. It’s diabetes. It’s like hypertension. It’s like any other complex chronic disease.
Inzucchi: Let’s move away from GLP-1 agonists for just a second. Obviously, the field of obesity medicine has changed a lot, but medications for weight management date back decades, and they’ve had a bit of a bad reputation. Lots of side effects. Some have been pulled off the market. Very limited efficacy. But I know you’re a big believer in combination therapy in some patients with obesity. So, what other medications might we use — non–GLP-1 receptor agonists that you’ve used in your practice with success?
Jastreboff: I do absolutely endorse combination therapy, just like we would for any other complex chronic disease. The example would be someone who has type 2 diabetes: Do we make the assumption that the only thing they’ll ever need is metformin? Not likely. Not for a majority of the patients that we see and that we treat.
For obesity, it’s the same thing. Why would we think that there’s one magical pill or one magical injection that would just work for everyone and help them to get to a goal and sustain that? By sequentially adding on medications, we can achieve weight loss of 50, 60, even 100 lb for many of our patients without bariatric surgery. Some of the other medications are combinations — so, for example, the combination of naltrexone and bupropion or the combination of phentermine and topiramate. Those are medications that we can also use. We can add them on if we’re using a GLP-1 receptor agonist, or we can even start with them. And we can use them individually, so we can use topiramate alone or phentermine alone. I tend to use the lowest effective dose for any given patient and just sequentially add on until we get to a goal. Specifically, for patients with type 2 diabetes, as they lose weight, their diabetes medications can then be titrated back, and that’s also an excellent outcome.
Inzucchi: When we’re talking about these medications for obesity, obviously they have different mechanisms of action. We may not fully understand the mechanisms of action, but we know, at least in part, how they might work. Are there any tricks you can give us in terms of matching a drug to a patient in terms of the type of eating behaviors that they may have demonstrated?
Jastreboff: That’s a great question — one that I think a lot of us in the obesity medicine field are actively pursuing and trying to sort out. There’s not a roadmap yet. Obviously, what we would like is biomarkers. We would like to be able to test patients and figure out exactly what they’re going to respond to. Right now, it’s more of trial and error. With GLP-1 receptor agonists, it’s a little bit different. With semaglutide, approximately 87% of people who don’t have diabetes respond. If they do have diabetes, two thirds of people respond in terms of weight loss. So, that’s a little bit reassuring.
In terms of these other medicines, though, to answer your question: For example, if a patient has significant cravings or really enjoys alcohol, I might tend toward something like naltrexone with the combination of bupropion. On the other hand, some patients report decreases in cravings with GLP-1 receptor agonists, so it’s not to say that they won’t necessarily respond to that. If a patient has anxiety, I will not use bupropion or phentermine unless the anxiety is controlled in other ways. If they have depression, I won’t tend toward topiramate. On the other hand, if they have insomnia, I might try topiramate, because then they’ll sleep better as well — potentially because of the side effect of drowsiness from topiramate. I look for other clues that the patient is sharing with me. I also ask about side effects and how they’ve done with other things in the past, to kind of assess where they are.
But there’s no roadmap yet. We need to understand the physiology better to be able to really target pathophysiology.
Inzucchi: That’s really helpful. We’ve talked a lot about starting medications for obesity. What about stopping medications that are fighting patients in terms of their weight loss goals? These are obesogenic medications, and I know when you lecture, I’ve heard you talk about them. Sometimes I’m surprised that certain medications that are commonly used both by endocrinologists, as well as by family docs and internal medicine doctors, can actually promote weight gain. What are the drugs that we should keep in mind, that we should think about stopping when managing patients with obesity?
Jastreboff: It’s always critical to consider that we actually contribute to our patients’ obesity by trying to help them with other diseases. So, that’s a great point. The Endocrine Society put together a pharmacotherapy guideline in 2015 that has a table of the medications that contribute to weight gain, as well as the anti-obesity medications. It’s a relatively inclusive list, so I would refer listeners to that. It’s not just steroids and it’s not just antipsychotics that have weight gain as a side effect. Sometimes it’s medications like beta-blockers. Sometimes it’s antihistamines. It’s different for every patient in terms of those medications.
What I usually do is I try and take a temporal history. I say, “When you started taking metoprolol, what happened? Do you know if your weight changed?” or “Do you remember when you started it?” And then I look in their electronic medical record to try and assess. There are other types of beta-blockers or antihypertensives that maybe wouldn’t contribute to weight gain in that patient. So, I’m really looking at, is there something that they started? For example, SSRIs: In some patients, there’s no weight change, but in other patients, there’s a clear relationship.
For diabetes, culprits may be insulin, sulfonylureas, thiazolidinediones (TZDs), although we can argue in terms of the benefit of what it does to your fat and distribution of fat. But if we can, we decrease the doses of insulin or replace sulfonylureas with medications that contribute to weight loss, such as GLP-1 analogs, SGLT2 inhibitors, or metformin — which is either weight neutral or mildly weight loss–promoting. Pramlintide is another one, and I think one that we’ll see used more as we see the combination of GLP-1 receptor agonist and amylin in cagrilintide plus semaglutide, and other agents down the road, like the combination of GLP-1 receptor agonist and glucose-dependent insulinotropic polypeptide (GIP).
Inzucchi: In primary care and even in endocrine practices, we have such limited time with our patients. Can you give us some quick diet or lifestyle tips that we as providers can give our patients who are trying to lose weight?
Jastreboff: For treating obesity, I really endorse targeting the pathophysiology. That would be with medications or surgery. But in terms of diet, exercise or physical activity, and healthy habits, those are all important for our overall health.
When you do have a limited amount of time with a patient, I generally focus on the low-hanging fruit. What is easily changeable for the patient? Or what is something that they are interested in changing? And I focus on one thing: listening to the patient. If they endorse that they’re drinking sugar-sweetened beverages, can they switch that out for a non–sugar-sweetened beverage? If they are drinking a lot of their calories through alcohol, what are ways that we can help them to potentially decrease that? Are there ways to incorporate movement into their day — whether it’s parking farther away or, during COVID times, using the commute time during which they’re not commuting right now to taking a walk or something like that? I’m really looking into how they can incorporate these healthy habits into daily life, rather than throwing out all the food in their kitchen and starting from square one. Those drastic changes are not sustainable. So, focus in on what the patient wants to do and what they can change.
Inzucchi: I find that the consumption of sugared beverages to be extraordinary in some patients, and just even reducing that can lead to significant weight loss. I think that’s really an important point.
We’re almost running out of time, Ania, but can you give us some tips in terms of the language that we use in our offices when dealing with patients with obesity?
Jastreboff: This is critical for all our patients, and especially for our patients with obesity. It’s important to use patient-first language — so saying a “patient with obesity,” rather than an “obese patient.” Just like we would say a “patient with diabetes,” rather than a “diabetic patient.” We’re not defining our patients by their disease.
Also, with our patients, the word “obesity” may carry some connotations that are negative. They’ve faced shame and blame throughout their life. So, just being cognizant of that and not shying away from the medical diagnosis of obesity, but also being gentle and cognizant and compassionate when we speak with our patients. As you’re getting to know the patient, you may say, “You know, it’s really difficult in terms of carrying extra weight; this is not your fault; this is not something that you chose any more than you chose to have type 2 diabetes” — really focusing in on the biology and that there is the diagnosis of obesity, but that this is not their choice. They are not to blame, and we’re going to help them. The way we’re going to help them is by specifically targeting the pathophysiology and treating their obesity.
Inzucchi: It is a chronic disease, as you’ve said, and it requires long-term measures to address.
Jastreboff: Yes, absolutely.
Inzucchi: Dr Ania Jastreboff, I want to thank you so much for joining us today in our brief discussion on obesity management in patients with type 2 diabetes. Thanks so much for joining me.
Jastreboff: Thank you, Silvio.
Inzucchi: And thank you for listening. I’m Dr Silvio Inzucchi, for Medscape InDiscussion.