A Promising Obesity Drug with Robert Kushner, MD

Haleigh Ehmsen, MS [00:09] This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Haleigh Ehmsen, research communications manager at Feinberg. Today we are re-sharing an episode that was released in February 2021 about semaglutide, a drug that showed promise that treating obesity through clinical trials at Northwestern. Semaglutide is the active ingredient in the popularly-known weight loss medications Ozempic and Wegovy. Robert Kushner, professor of Medicine in the division of endocrinology, discusses the results of the clinical trial published in the New England Journal of Medicine. In April 2022, Kushner was awarded the prestigious Herbert Pardes Clinical Research Excellence Award from the Clinical Research Forum for this research. Erin Spain is host of the show, and she'll take it from here. Let's jump right in. 

Erin Spain, MS [01:01] Thank you so much for joining me today to talk about this study. 

Robert Kushner, MD [01:04] Thank you, Erin. It's a pleasure to be here. 

Erin Spain, MS [01:07] What is the latest on the obesity epidemic in America and around the world? What are you seeing? 

Robert Kushner, MD [01:13] Well, according to the latest CDC information, approximately 42 percent of adults in America have obesity. And if you add overweight to that, now you're up to three out of four adults in America. It's also rising across the country. We, we are the epicenter, of populations, that are suffering from obesity. I could tell you it's not getting better. It's only getting worse.  

Erin Spain, MS [01:42] You lead a team at the Northwestern Medicine Center for Lifestyle Medicine. What treatments are currently available for people with obesity and what is the most effective and how important is it to be investigating new treatments?  

Robert Kushner, MD [01:55] The Center for Lifestyle Medicine at Northwestern Medicine is an interprofessional team approach to help people manage their weight. So we have medical providers, we have registered dieticians, we have health psychologists, and we also work side by side with the Bariatric Surgery Center. We use a medical model for the treatment of obesity, which we consider a chronic relapsing disease like diabetes or hypertension. What a medical model is starting with the foundation of lifestyle treatment, which is diet, physical activity, sleep hygiene, positive behaviors, mindset, and so forth. And then for those that need more aggressive treatment, we'll use modalities such as medication or pharmacotherapy, and then also bariatric surgery. So each person is looked at individually and we decide upon a treatment course that best fits their lifestyle and their risk factors. 

Erin Spain, MS [02:53] This idea that we need to be looking for new treatments all the time. Why is that so important?  

Robert Kushner, MD [02:59] Obesity is very difficult to treat. I could tell you it's, it's more effective to prevent obesity than to currently treat it. And the reason is that it's, it's multifactorial. There are many causes why one weighs what they weigh. Starting with genetics and biology. You know, we all, we're all familiar with the fact that our hair color, eye color, skin color, um, our risk for medical problems is often genetically determined, right? We look at our family history and we tend to look like and act like our siblings or our parents. Obesity is no different. If you come from a family of individuals or are suffering from their weight, you have, you have a higher risk of developing obesity yourself. So it, it's hardwired in a lot of us. And on top of that, it's how we live our lives, the decisions we make, the life events that we undergo. Some medications we take can be weight gaining. So there's so many factors that lead into what we weigh. It's very, very difficult to treat. And I think anyone who suffers from having obesity, will often say, you know, I can lose weight. It's keeping the weight off is where I struggle. And that's where we spend a lot of our time working with our patients. 

Erin Spain, MS [04:12] Well, there is some promising news. So let's talk about this drug semaglutide that was used in this landmark study you led recently published in the New England Journal of Medicine. Tell me about this drug. How does it work? 

Robert Kushner, MD [04:23] I used the word game changer journal, a lot of the interviews that I've been doing. And, and that's, and that's really how I look at it. It's the first time that we have seen this magnitude of weight loss, compared to currently, medications on the market for obesity. It's one and a half to two times more effective than currently available drugs we have on the market. Now, how the drug works, semaglutide mimics a gut hormone called GLP1, or glucagon-like one peptide. And this naturally occurring hormone in the body. And this hormone is responsible for helping us end a meal. So when we all eat, at some point we're no longer hungry, we start feeling full or satiated and we stop eating. So there's a lot of factors that lead to having us feel full. GLP1 is one of those hormones that does it. Semaglutide is a, mimic, or it's an analog, it's a lookalike of this gut hormone. So the Novo Nordisk manufacturer was able to develop a compound that acts like our naturally occurring GLP1. So when we give it, it tends to slow stomach emptying. So we get a little more full in the belly and the receptors in the stomach stretch, so we start feeling full. But the main effect of the drug is because there's receptors for this hormone in the brain, in the appetite center and the reward center. So when we take the medication, our brain starts sensing that you're full, you're less hungry in many people, less thoughts about food and more contentment between meals, and that's what leads to weight loss. Individuals eat less food, they reduce their calories and their content doing that. 

Erin Spain, MS [06:08] How is this different from other drugs that have been brought to market for obesity? 

Robert Kushner, MD [06:12] It's about one than half to two times more successful, or more effective than those drugs. And those drugs work through different mechanisms. They, they, they all, every, all of them except Orlistat, which, which is a fat blocker trade name is Ally, which you could purchase over the counter. But other than that one, which fat blocks, the amount of, of fat in our intestine, all the other drugs do work up in the appetite center of the brain, through different signaling mechanisms, that make us feel full or reduced hunger. The difference is they're not as effective as semaglutide. 

Erin Spain, MS [06:47] How is the drug used in this phase three clinical trial? And you already mentioned some of the results, but tell me a little bit about the trial and how it worked. 

Robert Kushner, MD [06:53] So the trial was conducted at 129 sites in 16 countries. So this really was a global study, and one of the center, sites was here at Northwestern. Individuals, who, who wanted to participate in the research study were randomized by a flip of the coin to either taking the medication or taking what's called a placebo and, and the, and the subjects and the investigators did not know, which, one the individual or participant was getting. The way the medication is given is by a weekly injection. It starts at a low dose and it takes about a month to slowly escalate the dose to the full dose. And then it is given once a week for 68 weeks. That's how long the trial lasts, a little bit over a year. All participants, you got the study drug or placebo, met with a registered dietician on a monthly basis to receive guidance on how to eat healthy, how to be more physically active and how to strategize to take better care of yourself. So it was grounded in a healthy lifestyle program. And the primary outcome of the study was weight loss. Other outcomes, which are of course equally important in someone who's struggling with their weight and has illnesses, is what is the effect on blood pressure, blood fats, blood sugar control, inflammation markers, as well as quality of life measurements. So that's how the study was conducted, and it ran for 68 weeks.  

Erin Spain, MS [08:23] Did people do the injection themselves or were they coming into the study center site to receive it? 

Robert Kushner, MD [08:29] The injections were self-administered. Any anyone who has diabetes or has illnesses where using injection like inflammatory bowel disease, rheumatoid arthritis or psoriasis, these are, these are called biologics, and they're probably familiar with giving yourself an injection, typically with a pen right under the skin. And, and that's how this was given. Currently available Diabetes drugs are often given this way through an injectable pen. So subjects were, were trained on how to do it within the first one or two weeks, and the rest of the time, they gave themself an injection once a week at home. 

Erin Spain, MS [09:03] And what did study participants who actually received the drug, what did they have to say about their results?  

Robert Kushner, MD [09:08] You know, directly what they said, by the, by the patient reported outcomes. Because we looked at, we looked particularly at physical functioning using, different surveys such as, are you able to walk faster? Are you able to climb a flight of stairs? Are you feeling better? And everyone on, the majority of individuals who took the injection did feel better, had an improved functional score. Now, they did have side effects as well, which need to be highlighted. The most common side effects from a drug like this are gastrointestinal, things like nausea, diarrhea, some people had vomiting and constipation. In general, they were mild to moderate. They were transient, so they were short acting and they tended to go away. I think an interesting point about the side effects is only seven percent of individuals on this study drug, had to drop out, which means they just could not tolerate the side effects of the medication. In contrast, 93 out of a hundred, or, you know, 93 percent were able to stay in the trial, and did very well. 

Erin Spain, MS [10:15] Well, that's good news. There were, there were also some limitations in this study. Describe those. 

Robert Kushner, MD [10:20] From my point of view some of the biggest limitations are we, we were unable to recruit as a diverse population of individuals as we would like. So for example, three, three quarters of the participants were women, and three quarters of the participants were Caucasians, whites. So we would want to study this medication in a much more diverse population. More men as well as more individuals like Blacks, Hispanic individuals, Asian individuals and so forth. I guess you can consider another potential limitation is that it ended at 68 weeks, and I think everyone wants to know is, is the, the drug had a, had a really fabulous outcome. I'd mentioned a third of individuals lost over 20 percent of their body weight, which is just spectacular. But you know, what happens when you stop the medication? And, and that is an ongoing observation. Now, a portion of the study individuals are in a follow up study in which we're gonna follow them up for one year. 

Erin Spain, MS [11:20] Okay. Have there been anything that you could share right now that's happened so far with those individuals who are in the follow up study? 

Robert Kushner, MD [11:27] No, that, that won't be, the study ended about a year ago. A little less than that. So these individuals will be followed for one year. So those results are not available right now.  

Erin Spain, MS [11:37] Maybe by the summer will learn more about it's use. And could it be used, would it be used in centers like your center at Northwestern Medicine? How would people be able to access this drug?  

Robert Kushner, MD [11:48] Well the drug is not approved by the FDA yet. It was submitted for application in December 2020. And by FDA standards, it takes about six months for the FDA review process to go forward.  

Erin Spain, MS [12:03] I think we're going to be hearing more about this medication. I know there's been some previous studies for non-alcoholic fatty liver disease. It looks like there's other diseases that some phase three clinical trials will be launching soon. Do you think this is going to become more of a household name, semaglutide? 

Robert Kushner, MD [12:20] Yeah, that's a great question, Erin. And from my point of view, as not only clinical researcher, but by Director of the Center of Lifestyle Medicine, I'm very involved in how do we educate and empower our primary care providers to work with patients, their patients, to guide them in managing their weight and providing a range of services. This medication, if, and hopefully it'll be approved sometime this summer. The next hurdle is how do we get the medication in the hands of providers so that they can provide the, meet the needs of their patients. There are too many individuals who are struggling with their weight to stand in line to go to a specialized center like mine. I would envision that when we have a tool that is this powerful, this medication. It could be available in the primary care office, working with your own physician and perhaps a referral to a registered dietician so they can provide the care that we know is going to be so helpful. 

Erin Spain, MS [13:22] And it sounds like it's coming along at just the right time. As these numbers continue to rise and we see more and more people with obesity. 

Robert Kushner, MD [13:31] First of all, the medication will be investigated in different patient populations. Like I said, hopefully a greater diverse population, but also, in other disease categories. Individuals who are suffering from knee arthritis. What's the effect of weight loss? Individuals with sleep apnea, you know, the weight loss helps that. Fatty liver disease, you mentioned, congestive heart failure. There's all kinds of, of disease, categories that this may be helpful. Also, teens, it hasn't been studied in children. So that that's something we're, we're hoping to do. A lot of us in this, in the obesity space have talked about this as, as a potential anchor drug for obesity. Now that's yet to be tested, but, this drug being so successful, beyond any of the other drugs we have, I would envision that this will become the drug of choice to start treatment with. If, if it's appropriate for the person and they can tolerate it, and then potentially add it to other drugs as well. But this, this drug is so effective. I'm hoping it's going to change the landscape of how, of when we treat individuals with obesity and how we treat individuals with obesity, who are having health complications. Individuals are, are struggling to manage their weight. They're frustrated that they, their difficulty not only losing weight, but as I said before, difficulty keeping their weight off. And they're looking for help and they're looking for resources. So the more tools we can put in our toolbox — how to guide them on healthy eating, being more physically active, having the mindset around being healthy and, and sustaining those behaviors. And if needed, having effective tools to escalate that treatment to things like pharmacotherapy. And you mentioned earlier, bariatric surgery. These are all the modalities that we have available to help people, uh, who have obesity and health problems related to it. 

 Erin Spain, MS [15:32] Well thank you so much Dr. Robert Kushner for sharing all this information. And we hope to have you back in the future, perhaps once this is being used by patients in your clinic. 

Robert Kushner, MD [15:41] Thank you. And, and I would also encourage all the listeners, if you want a variety of resources to learn about obesity, as well as to take a quiz to learn more about yourself and what to work on, I would encourage you to visit www.drrobertkushner.com.  

Erin Spain, MS [16:08] You can head to feinberg.northwestern.edu to listen to past episodes of the show and claim CME credit for listening to this episode. Be sure to subscribe on Apple Podcast or wherever you download your podcast, so you never miss an episode. Thanks for listening.