Yale School of Medicine endocrinologist, Dr. Ania Jastreboff, MD, PhD talks about a diabetes drug that could possibly help people lose weight.
Interview conducted by Ivanhoe Broadcast News in 2022.
What have researchers been looking at in terms of helping people with obesity move the needle?
JASTREBOFF: Sure, absolutely. So there are several anti-obesity medications that are FDA approved and there are other things that are used as well. These medications have been around for some time and now we’re moving into an era where we have highly effective and safe, well tolerated medications for obesity treatment. And let me just underscore that these medications are not weight-loss medications. They’re not appetite suppressants, they’re anti-obesity medications. And that distinction is really important and let me explain why. So obesity, as I said, is a chronic disease. It has a complex pathophysiology. So what happens when we have obesity? Basically what happens is that our body defends a higher fat mass. So let me explain that a little bit more. So our body has this very important interest in carrying an appropriate amount of fuel. We want to be able to do the things that we do every single day. Now, that appropriate amount of fuel will call the defendant fat mass. And that’s because the way that our body likes to carry fuel is by carrying fat. Now, on a population level, what’s happened is in our obesogenic environment, this environment filled with all delicious foods that we don’t have to run and chase after all aspects of our life where we’re very stressed, where we don’t get enough sleep. All of these different things, they all contribute to this obesogenic environment. On a population level, what’s happened is that our defended fat mass has been pushed up. It’s dysregulated. And so the point of these new anti-obesity medications is to re-regulate that defendant fat mass to a place where it’s healthier for our bodies.
How did the drugs do that? What are they doing within the body?
JASTREBOFF: Yeah, that’s a great question. So our brain is what sets the defendant fat mass. And so these medications work in the brain. There’s receptors in the brain for various things that they target. The newer medications they specifically mimic specific hormones in our body. And those hormones are nutrients stimulated hormones. So what does that mean? That means that when we eat, these hormones get released and these medications mimic those hormones. And there’s receptors for those hormones in our brain. And basically they help us to feel full earlier. But most of all, it’s that they re-regulate that defended set point of fat mass. We don’t know exactly how that is done yet. There’s lots of research and work that needs to be done, but we do think that that’s how they work. They reset that defendant fat mass.
When it’s reset, what happens in the body?
JASTREBOFF: So that’s a great question. So when that defended fat mass set point is reset, what happens is that we, as a consequence, loose weight. So when we stop the medicine, that set point goes back up and we regain the weight. So just like you would need to take a medicine, let’s say for high blood pressure for your life to make sure that your blood pressure stays within a better range. In the same way you would need to take an anti-obesity medicine chronically because you want to maintain that re-regulated or decreased defendant fat mass.
Let’s talk a little bit about the new drug that’s already FDA approved for diabetes that now researchers are looking at how efficient or efficacious it is for the people with obesity. Can you talk to me a little bit about that?
JASTREBOFF: So the surmount one trial was a phase 3 trial that was specifically designed to look at the efficacy and safety of a novel GIP and GLP-1 receptor agonists cultures appetite. So as I mentioned, so GIP and GLP-1 are two of those nutrients stimulated hormones. And this medication basically mimics those hormones. So the study included 2,539 individuals who have obesity. And they participated in the trial for 72 weeks. And they were randomized to four different groups, placebo or three different doses of this new medication, Trazapotide. And at the end of the 72 weeks, the group that received the highest dose of Trazapotide on average lost 22.5 percent of their total body weight. So what does that translate to in terms of absolute pounds or kilograms? That is about 52 pounds of weight reduction or 23 kilograms of weight reduction at 72 weeks. So there’s also a lot of variability in terms of how much weight people loose. And this is true for any anti-obesity medication and it’s also true for surgery, different people will lose different amounts of weight. So this means that the average was 52 pounds, but that means some people lost 15 or 20 pounds, whereas other people lost over 100 pounds in the trial.
What happened with the placebo group?
JASTREBOFF: The placebo group on average lost 2.4 percent of their total body weight. So they did loose some weight, and it was standard of care, lifestyle intervention. So meaning the type of lifestyle recommendations that you would receive when you see your doctor in most cases. And so that is what they received. The medication groups also received that standard of care lifestyle intervention.
What does this suggest to you?
JASTREBOFF: So I think in terms of looking at tirzepatide in this norval agent and how significant it is, let me put it in another way. So somebody who may have been in the trial who weighed 200 pounds would have lost down to on average 150 pounds. Actually, let me take that back. I’m going to take that away because this has to be paired with another sentence. So let me pair it with this other sentence because that is an overstatement. So the individuals who received the highest dose of the medication, 15 milligrams of tirzepatide, 40 percent of them lost greater than or equal to 25 percent of their total body weight. So that would be someone who weighed 200 pounds, losing down to 150 pounds. These types of results we have not seen with any other phase III trial in individuals with obesity with any other agent, so definitely very significant. It used to take us one or two medications to get to that type of weight reduction and that efficacy in terms of treating obesity and now we can potentially do that with this medicine depending on how much somebody weighs to start with.
When you have a patient who goes for 200-150, what does that do in terms of their health? Does that reduce their likelihood of heart disease, diabetes, stroke, all the things that come with being overweight?
JASTREBOFF: So currently studies are ongoing to investigate the health outcomes when you have such significant weight reduction. Those studies have been done and are ongoing in studies of bariatric surgery. In terms of anti-obesity medications, these studies are ongoing now for example, to look at cardiovascular outcomes and to look at health outcomes in terms of morbidity and mortality. I think that depending on the type of disease that you’re trying to improve in addition to of course obesity, different degrees of weight reduction are required. The SURMOUNT-1 trial has an extension. It’s a two-year extension looking at the individuals who specifically had pre-diabetes in this trial to see whether their pre-diabetes resolves or whether they progress to Type II diabetes. Within that first year of the SURMOUNT-1 trial, 40 percent of individuals did start off by having pre-diabetes at baseline, and over 95 percent of them reverted to normal glycemia. So over 90 percent ended up having normal blood sugars by the end of the 72 weeks.
What were the risks? Were there any side effects from taking medication?
JASTREBOFF: Sure. So in terms of anti-obesity medications, there’s a common theme and that theme is to titrate up slowly, so to go up on the dose slowly. And the reason why I say this is because with this medication, as with others, what we saw was that most people, if they had side effects, they were gastrointestinal. Most of them occurred during dose escalation so as the dose was increased, and most of them were transient. So once that dose escalation phase was over and you were into a maintenance dose, you did not have those side effects or they were much less significant. So most side effects were mild to moderate in nature, and they basically were transient in the dose escalation phase. The most common gastrointestinal side effects were nausea, diarrhea, and constipation. But I would say that overall the medication was tolerated very well. And similar to other medications of this type, such as semaglutide, which is a GLP-1 receptor agonists that was FDA approved last year, last summer for obesity treatment.
We started up by mentioning the fact that this is not FDA approved for obesity yet, what are the next steps? How optimistic are you that at some point this will be an option?
JASTREBOFF: So as you mentioned, tirzepatide is currently FDA approved for Type II diabetes, not FDA approved for obesity treatment or chronic weight management at this time. It is fast-tracked, meaning that the FDA will review it for chronic weight management or obesity treatment and we’re hopeful that will have a positive outcome. Definitely as demonstrated by the SURMOUNT-1 trial, this has great significance for our patients. And I would just say that in terms of the overall view of what this study means and the significance of this study is that again, obesity is a chronic treatable disease and we need to be treating it with interventions that target disease pathophysiology. And I think that given that this agent was so highly effective as well as well-tolerated, it speaks to the fact that the medicine was targeting physiology and was impacting that defendant fat mass.
We talk about obesity as an epidemic. How serious is it right now as we sit here at the end of 2022?
JASTREBOFF: So obesity is a very serious epidemic. So by 2030, it is estimated that about half of Americans will have a body mass index of greater than or equal to 30. So half of us will be characterized as having obesity if we’re using the BMI criteria. Currently one in five adolescents have obesity. So 20 percent of adolescents in the United States have obesity. So again, this affects everyone, basically. Either we ourselves have obesity or someone that we care about or love, have obesity. Obesity results in or contributes to over 200 obesity-related diseases. So I think that the important thing and the take-home is if we treat the disease of obesity with these types of interventions, we can be impacting and treating over 200 other weight-related diseases.
Is there anything that would you want people to know?
JASTREBOFF: So currently, we often say obesity is a disease. The AMA deemed it to be a disease in 2013, but we don’t treat it like a disease, and we really have to be doing that. We must be treating obesity like we treat any other chronic disease.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
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