New anti-obesity medications

GREATER KNOWLEDGE OF THE PATHOPHYSIOLOGY of obesity has given rise to new and extremely effective therapeutics. “We are in a new era where these novel anti-obesity medications are transforming the way that we are able to treat our patients with obesity,” says Ania Jastreboff, MD, PhD, associate professor of medicine (endocrinology) and of pediatrics (pediatric endocrinology).

Widely considered a groundbreaker in the development of anti-obesity medications, Jastreboff has led and collaborated on numerous clinical trials. Yale Medicine Magazine recently spoke with her to learn more about the medications’ potential for managing the disease.

What are the underlying causes of obesity? Is obesity a choice?

Let’s start by talking about obesity pathophysiology. Our bodies are really smart. They have this concerted interest in storing an appropriate amount of fuel, and they store that fuel as fat. Our bodies defend a certain amount of fat mass, and we call that the defended fat mass setpoint. How do our bodies do this? How do our brains regulate energy homeostasis? Many researchers are working on figuring this out. There are hormones in our body that communicate with our brain to inform us about energy homeostasis and about how much fat we are storing. Our bodies don’t want to carry too much fat because then we can’t do the activities necessary for daily life, and they don’t want to carry too little fat—and, thus, too little energy—because then we would starve. Our bodies want to carry just the right amount.

So, if our bodies have devised this beautiful system to make sure we store just the right amount of fuel or fat, why is it that so many people have obesity? It turns out that our bodies are impacted by our obesogenic environment, which is one filled with highly processed foods, lack of sleep, lack of physical activity, and increased stress; this environment, in many people, results in an elevated defended fat mass setpoint. Thus, obesity treatment requires resetting the defended fat mass setpoint.

It’s important to understand obesity pathophysiology so that treatments can be developed to target disease mechanisms. It’s also important to talk about the biology of obesity with our patients so that they know and understand that having obesity is not their fault. Obesity is not a choice. It is a biologically driven chronic neurometabolic disease. And we need treatments that target disease pathophysiology and effectively treat obesity.

The prevalence of obesity has increased dramatically over the last decade. Why have nonpharmaceutical approaches like dieting and exercise been ineffective in curbing this rise?

Once the obesogenic environment exerts its impact and contributes to someone developing the disease of obesity, there’s biology at play. So, any treatment that we utilize needs to target that biology. Lifestyle changes, whether it is a more nutritious diet or increasing physical activity, are critical for health. But to treat the disease of obesity, we need interventions that target disease pathophysiology.

How are the treatment options for obesity evolving?

Treatment options for patients with obesity have evolved over the years, and especially more recently with a class of medications called nutrient-stimulated hormone-based medications, which include semaglutide and tirzepatide. In terms of the pathophysiology of obesity, there are hormones in our body that signal to our brain about energy homeostasis—about how much energy or how much fat we are storing. They inform us about food intake, about what foods we crave, about how much food we want to eat, and they also potentially inform about energy expenditure, or how much energy we want to burn. The newer medications like semaglutide [brand names Wegovy® or Ozempic®] and tirzepatide are mimicking these nutrient-stimulated hormones and targeting receptors in the brain to impact mechanisms of energy homeostasis.

In 2022, you were the lead author in the SURMOUNT-1 trial investigating the drug tirzepatide as a treatment for obesity. What is this drug’s mechanism of action?

Tirzepatide [brand name Mounjaro®] is a GIP/ GLP-1 receptor agonist, which is a once-weekly injectable nutrient-stimulated hormone-based medication. It’s currently FDA-approved for type 2 diabetes and is under FDA review for the treatment of obesity or chronic weight management. It targets [glucosedependent insulinotropic polypeptide] GIP and [glucagon-like peptide-1] GLP-1 receptors of these nutrient-stimulated hormones. In the SURMOUNT-1 trial, we investigated tirzepatide for the treatment of obesity.

The response to this medication was quite striking, and not one that we had seen before in Phase 3 trials of a medication for the treatment of obesity. We found that after 72 weeks of treatment, the highest dose of the medication resulted in an average percent body weight reduction of 22.5%. And this translated to an average absolute weight reduction of about 52 pounds. Additionally, nearly 40% of participants lost at least a quarter of their body weight.

If the FDA approves tirzepatide as a treatment for obesity, is it intended to be used alone or with other obesity-fighting strategies?

It can be used in combination with other treatments or as monopharmacotherapy. It is important to consider that there are many different types of obesities with varying pathologies and phenotypes. Medications approved for the treatment of obesity can be used in combination to target different mechanisms. The medications can also be used in combination with bariatric surgery. So, someone can have surgery, and then later on, they can use anti-obesity medications to further treat their obesity. They can also use the medications before they undergo surgery. It is not about one treatment, but rather what are the optimal treatments when we care for patients with obesity.

Additionally, with anti-obesity medications, we include healthy lifestyle changes in the care of our patients. With these medications, especially during the weight-reduction phase, patients will eat less if they are responding. So, we want to make sure that the food our patients are eating is as nutritious as possible; we want to prioritize lean protein and nutrient-dense foods such as vegetables. We also talk about ways to incorporate movement and physical activity into daily life—how do we add in resistance exercise and other forms of movement with the goals of minimizing muscle loss while maximizing fat loss? The important thing is that the focus is on optimizing health. Nutritious eating and increasing movement are things that maximize health as we treat obesity by targeting disease mechanisms with interventions such as medications.

What are the side effects of anti-obesity medications, and how do you counsel patients about them?

The most common side effects of medications such as semaglutide and tirzepatide are gastrointestinal. Most of the time, these side effects are mild to moderate, and most commonly occur during medication initiation and dose escalation. Not everyone has these gastrointestinal side effects, but if they occur, the most common ones include nausea, diarrhea, constipation, and, rarely, vomiting.

How can we mitigate these side effects? The most important way is by going up very slowly on the dose of the medications—always starting at the lowest dose and going up based on how the patient is doing. So, if a patient is experiencing nausea, we would not increase the dose because we don’t want our patient to potentially experience vomiting. We would either go down on the dose; or if the nausea is mild, we would stay on the current dose and give our patient time to adjust to the medication. Once the nausea resolves, we can go up and continue escalating. Bottom line, start low and go slow.

There are also ways that the patient can help mitigate potential side effects. The first way is if they’re experiencing these side effects, it is important to let their doctor know so that they can adjust the dose to diminish the side effects. The second thing is to know that if they’re responding to these medications, they will feel full earlier, so it’s important to not eat past the point of fullness. Patients should also know that they may want to eat more frequently—but consume smaller amounts at a given time rather than meal-size portions. The third thing patients can do is monitor what foods exacerbate their symptoms. For example, if they experience diarrhea and eating fatty foods, such as egg salad or pizza, worsen this side effect, then especially during dose escalation, they should eat less of that food. Once they get to a stable dose—or weight plateau—they may be able to tolerate more of these foods.

Do people who stop taking anti-obesity medications gain back the weight they have lost if they stop taking the medication?

Obesity is a chronic disease, which necessitates continued treatment as with any other chronic disease. Let’s consider an example of a patient with hypertension, or high blood pressure. If a patient has high blood pressure, and they are treated with an antihypertensive, their blood pressure improves. If we were to stop that antihypertensive medication, their blood pressure would go back up. So, in the same way, when we treat a patient with obesity with an anti-obesity medication, their defended fat mass setpoint is decreased. When we stop that anti-obesity medication, that defended fat mass setpoint goes back up, and the weight follows. So, in order to effectively treat a chronic disease, such as the chronic disease of obesity, we have to continue the treatment in order to continue to treat the disease.

Studies have now demonstrated that when anti-obesity medications are discontinued, on average, the weight is regained. The STEP 1 trial extension looked at discontinuing weekly semaglutide 2.4 mg after weight reduction. During the first year off the medication, on average participants gained back most of the weight. So, when these medications are discontinued, the weight is regained.

What is known about the long-term risks of taking anti-obesity medication?

GLP-1 receptor agonists have been FDA-approved for the treatment of type 2 diabetes for over 17 years, so there is data on this class of medications. But overall, while the disease of obesity is not new, the field of obesity medicine is relatively new. In terms of these highly effective treatments, we need to conduct research to investigate long-term outcomes. We need to look at how effective and tolerated these medications are in the clinical setting and in real life, as well as examine long-term health outcomes.

Anti-obesity medications have become very popular. Are you concerned about shortages of these drugs?

The medication shortages underscore the fact that we need to really think as a society about how to treat our patients with obesity, given that it affects such a large proportion of our population. I don’t think we should shy away from this. If we think about diseases like type 2 diabetes, high blood pressure, and hyperlipidemia collectively, [there are] just as many people [who] have these diseases, and we did not shy away from treating these conditions. Furthermore, obesity is associated with over 200 obesity-related diseases. If we treat the disease of obesity, we’re effectively treating the underlying cause or major contributor to over 200 other obesity-related diseases. We could transform our patients’ lives and health and our population’s health by effectively treating this one disease.

What do you foresee in terms of the cost barrier for anti-obesity medications?

Currently, in the United States, we are treating less than 5% of individuals with obesity with appropriate anti-obesity pharmacotherapy or bariatric surgery. Access and affordability are key issues that we need to address as a society, and we need to continue to work to figure out how to make these medications affordable and accessible to all patients with obesity who need them.

Do you expect these new drugs to change societal views on obesity?

These highly effective, novel therapeutics potentially open up the conversation between patients and providers about treatment options. Hopefully, they will also help destigmatize obesity and highlight that there’s this underlying biology, and now we have tools to target and treat the underlying biology of this chronic disease.

How do you see obesity treatments evolving in the future?

We’re at a pivotal point in our ability to effectively treat the disease of obesity with these novel anti-obesity medications. There are over a dozen nutrient-stimulated hormone-based medications in development in Phase 2 and moving into Phase 3, and there are even more in development in Phase 1. There are also additional anti-obesity medications in development that are targeting different mechanisms; for example, treatments that may preserve lean mass while effectively contributing to fat loss, thus improving the quality of the weight lost. Semaglutide and tirzepatide are the beginning of this incredible transformation where we will have many highly effective pharmacotherapeutics for the treatment of obesity. We also need to look beyond “just” weight reduction to treating obesity, to caring for our patients holistically, treating their disease while optimizing their overall health.

You’re also studying retatrutide for weight loss. What can you tell us about this drug, and when it might be reviewed by the FDA?

Retatrutide is a triple-hormone receptor agonist targeting three nutrient-stimulated hormone receptors—GIP [glucose-dependent insulinotropic polypeptide], GLP-1 [glucagon-like peptide 1], and glucagon (GCG). I led a Phase 2 trial of retatrutide evaluating the safety and efficacy of the molecule. And we found that with the highest dose of retatrutide, participants lost nearly one-quarter of their body weight over the 11 months of the trial. Ultimately, the results of the trial supported this molecule moving into Phase 3. [Phase 3 trials are the regulatory trials that are conducted so that the FDA has the information that it needs and requires in order to evaluate the safety and efficacy of a novel agent and can make a decision about whether a specific therapeutic will be FDA-approved.] The TRIUMPH Phase 3 trials evaluating retatrutide are starting this year [2023].

What would you like to say to people with obesity?

Having obesity is not a choice. Having obesity is not your fault. It is a chronic neurometabolic disease. And now we have highly effective treatment options that target the biology of obesity. We will care for you and guide you to treatment options for your obesity as we would if you had any other chronic disease—with kindness, compassion, and evidence-based treatments. I would advise patients to speak with their provider about options and what therapy may best fit their needs and treat their obesity.

Jastreboff serves on the scientific advisory boards for various companies that are developing novel anti-obesity medications, including Novo Nordisk (makers of semaglutide) and Eli Lilly & Company (makers of tirzepatide and retatrutide), which funded the trials.