The GLP-1 Revolution

Cardiometabolic diseases are the world’s number one killer, affecting as many as a quarter of adults around the world. Their widespread prevalence has been driven in part by the lack of effective therapies for chronic diseases like obesity.

Now, the emergence of glucagon-like peptide-1 (GLP-1) agonists promises to change the course of the epidemic. The U.S. Food and Drug Administration (FDA) first approved this class of drugs in 2005 for the treatment of type 2 diabetes. More recently, their usage has skyrocketed following the discovery that the drugs are also highly effective in treating obesity.

At Yale School of Medicine, researchers are studying the impact of GLP-1 agonists on cardiometabolic diseases and beyond. They are also exploring the next treatments in the pipeline that could build further on the life-changing benefits the drugs offer.

“Cardiometabolic health is the most pressing problem to humanity in the 21st century,” says Gerald Shulman, MD, PhD, George R. Cowgill Professor of Medicine (Endocrinology) and professor of cellular and molecular physiology. “Every drug we’ve previously had for obesity has been a dismal failure. And now we have the first drug that has been shown in large clinical trials to promote significant weight loss.”

GLP-1 agonists are a class of drugs that activate the GLP-1 hormone receptor. This activity has a widespread effect on a range of metabolic factors, including increasing insulin secretion from the pancreas and inhibiting the release of glucagon, which helps lower blood sugar.

When the drugs first became available in the 2000s, clinicians primarily used them to treat type 2 diabetes. GLP-1 agonists had significant benefits over insulin therapy, which doctors at the time considered the most powerful glucose-lowering medication. For instance, GLP-1 agonists did not increase the risk of hypoglycemia (low blood sugar) or cause weight gain. “That was a real game changer in our field,” says Silvio Inzucchi, MD, professor of medicine (endocrinology). “We could have a powerful glucose-lowering agent without all the baggage.”

In fact, experts realized that the drugs significantly reduced weight well beyond what the researchers had previously seen with other pharmaceuticals, especially when the drugs were given at higher doses. Beyond hormonal changes, they found, these drugs also slowed gastric emptying and food transit time through the gastrointestinal tract, increasing the feeling of satiety after eating. Drug manufacturers began testing GLP-1 agonists at these higher doses as a treatment for obesity. Clinical trials then revealed that the drugs have just as prominent an effect on weight loss in people without diabetes. “It was a totally serendipitous finding,” says Shulman.

Researchers now understand that GLP-1 agonists treat the underlying pathology of obesity by targeting what doctors call the body’s fat mass set point. In the context of obesity, the parts of the brain that regulate body weight are altered due to a range of factors that include genetics, environment, stressors, lack of sleep, dietary behaviors, and patterns of physical activity.

“Our brain tells our body to maintain a certain amount of energy storage as body weight,” says Mona Sharifi, MD, MPH, section chief of general pediatrics and associate professor of pediatrics (general pediatrics) and of biostatistics (health informatics). “This set point becomes altered to a degree where we’re holding onto more body fat than we need or that’s healthy for our bodies.” GLP-1 agonists help to reset this point, reducing the body’s drive to consume and store excess energy.

A pediatrician, Sharifi is especially interested in studying the use of these drugs and their effects in adolescents and young adults. The FDA approved Saxenda^® and Wegovy^® for patients as young as 12 in 2020 and 2022, respectively.

Sharifi and her collaborators at Yale’s Bright Bodies program—which offers exercise and nutrition education for parents and children between the ages of 7 and 16—have seen firsthand the positive effects the medications can have on youth struggling with obesity. Many participants become more committed to engage in the program after seeing results that lifestyle changes alone didn’t provide. “The patient reports are very compelling,” she says. “For the first time, they don’t hear that constant food chatter and are seeing more progress.”

Sharifi was on the committee that created the 2023 American Academy of Pediatrics guidelines, which included such significant updates for pediatric obesity treatment as the use of medications for eligible adolescents as an adjunct to lifestyle interventions. Since the guidelines’ release, Sharifi’s team has conducted surveys and interviews with primary care clinicians across the country to better understand their attitudes and practices, including the usage of anti-obesity medications following the release of the new recommendations. “Not surprisingly, the vast majority are not comfortable with prescribing or discussing medications because they are so new in their approval for teenagers,” she says.

This hesitation in regard to GLP-1 agonists is not the first time pediatricians have expressed initial reluctance in regard to prescribing a new medication. There was similar hesitancy to prescribe medications like antidepressants and drugs for attention-deficit/hyperactivity disorder when they first became available for young people, but that eased over time, Sharifi says. “We can learn from these past experiences and try to support primary care clinicians to increase their comfort with prescribing these medications.”

In another study, Sharifi and her colleagues estimated the number of adolescents and young adults who are eligible to receive a GLP-1 agonist. Their finding was staggering—nearly 17 million met the FDA criteria for eligibility. Only a tiny fraction of eligible people actually receive treatment, however. Sharifi and her team’s study, led by Yale medical student Ashwin Chetty, found that one in five eligible young adults are uninsured, and a third reported that they lack routine health care. In ongoing research, her team is investigating how factors including lack of insurance coverage and the changing landscape of coverage might be worsening known disparities in obesity. “We’re really interested in dissecting whether these barriers are differentially impacting people and putting us at risk of worsening obesity disparities instead of making them better.”

In future trials, the team plans to investigate whether combining lifestyle intervention programs like Bright Bodies with anti-obesity medications might lower the dosage needed to achieve the desired benefits.

Now that clinicians finally have a tool to address obesity before further complications arise, researchers are investigating how obesity medications are already changing the trajectory of cardiometabolic diseases. Inzucchi has been involved in clinical trials measuring the impact of GLP-1 agonists on cardiovascular outcomes in participants with type 2 diabetes. The analyses show that the drugs reduce the risk of adverse cardiovascular events by 14%.

“What was really surprising was that the patients who lost more weight during the trial didn’t seem to benefit any more than those who lost less weight—it’s eye-opening,” says Inzucchi. “It suggests that weight may not be the key driver of cardiovascular benefits.” He hypothesizes that it’s not simply weight loss, but rather a myriad of factors working together, including changes in glucose levels, blood pressure, lipids, and inflammation levels that contribute to the drugs’ cardiovascular benefits.

Tariq Ahmad, MD, associate professor of medicine (cardiovascular medicine), recognizes that benefits like these are bringing the treatment of cardiometabolic diseases into a new era. “Our paradigm right now is reactive,” he says. “We essentially wait for people to develop all the things downstream to cardiometabolic disease.”

As chief of the Heart Failure Program at Yale Medicine, Ahmad is working to pivot towards a more preventative approach to cardiovascular care at Yale. He and his colleagues use electronic health records from Yale New Haven Health System to better understand the characteristics of the population they serve. When they identify at-risk patients with obesity or diabetes who are eligible for anti-obesity medications, they take a team approach to help them obtain a prescription as well as to connect them with nutrition and behavioral health specialists. “We have a 360-degree look at individual patients, and see what we can do in order to get them the best possible therapies for their chronic disease,” he says.

Easing the burden of cardiometabolic disease might just be the beginning. Wajahat Mehal, MD, DPhil, professor of medicine (digestive diseases), is among the many researchers now investigating the broader effects of GLP-1 agonists. Mehal’s team is specifically interested in the medications’ effects on the liver. Because emerging evidence suggests that the drugs may reduce alcohol cravings, scientists are investigating their potential for the treatment of alcohol use disorder and alcohol-associated liver disease. But Mehal’s team has found that they also have direct protective effects on the liver. In mice, GLP-1 agonists reduced the level of an enzyme that metabolizes alcohol, which in turn decreases the production of toxic alcohol metabolites.

Now, his team is investigating whether GLP-1 agonists affect alcohol metabolism in other tissues as well, including the brain. “If GLP-1 agonists actually reduce metabolism of alcohol in the brain in the same ways that they do in the liver, they might actually reduce some of the cognitive effects of alcohol,” Mehal says.

The laboratory of Mandar Deepak Muzumdar, MD, associate professor of genetics and of internal medicine (medical oncology), investigates the connection between obesity and cancer. Obesity is associated with over a dozen types of cancer, including breast cancer, colorectal cancer, and pancreatic cancer. Now, Muzumdar is investigating whether obesity medications can alter cancer risk.

His team is engineering animal models that mimic the features of human cancers to better understand how obesity drives these cancers. For instance, they’re studying whether weight loss induced by GLP-1 agonists affects cancer growth in the pancreas. The researchers are also investigating whether the drugs impact the pancreas directly to modify cancer development, and if so, what molecular mechanisms are involved. “As GLP-1 agonist use increases, we need to understand their potential impacts better, including reducing or possibly enhancing cancer risk,” says Muzumdar.

While the wide range of potential benefits of GLP-1 agonists seems almost miraculous, the full impact of GLP-1 agonists is yet to be understood, says Tamas Horvath, DVM, PhD, chair and Jean and David W. Wallace Professor of Comparative Medicine. “We don’t really understand how these drugs work precisely.”

Horvath’s laboratory is investigating the mechanisms of GLP-1 agonists in the brain, which areas of the brain are most affected, and how the drugs might be changing its physiology over the long term. Emerging research suggests that GLP-1 agonists affect many parts of the brain. “These drugs are going to be continuously impacting the receptors in the brain and the rest of the body,” Horvath says. But more research will be needed to understand how long-term exposure in the brain might impact brain function and behavior. “The question is, do they have long-term effects in a way that we don’t yet anticipate?”

The GLP-1 agonists available today are just the beginning. New and improved anti-obesity drugs will become available over the next several years as researchers study over 100 different candidates. For all their benefits, the current anti-obesity drugs have some major downsides: They must be injected, must be stored in the refrigerator, and are costly. Drug manufacturers, however, are developing new oral options. And because pills are cheaper to make than injectables, experts are hopeful that these new formulations will be easier on the wallet, and therefore more widely accessible.

Researchers are also exploring medications that activate two or more hormone receptor systems. Ania M. Jastreboff, MD, PhD, Harvey and Kate Cushing Professor of Medicine (Endocrinology) and professor of pediatrics (pediatric endocrinology), is the founding director of the Yale Obesity Research Center (Y-Weight). Y-Weight runs clinical-translational and outcomes research to facilitate the development and appropriate application of novel therapies that target disease mechanisms of obesity and improve health outcomes.

Jastreboff has led clinical trials for numerous anti-obesity medications. One, retatrutide, is the first triple hormone receptor agonist that targets GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG), and it resulted in a nearly 25% body weight reduction with less than a year of treatment, studies found. Another, maridebart cafraglutide, is the first GIP antagonist and GLP-1 agonist designed for monthly or less frequent administration by self-injection.

Many more trials are ongoing at Y-Weight, including trials of survodutide (a GLP-1/GCG receptor agonist), cagrilintide/semaglutide (an amylin analogue paired with semaglutide), and semaglutide in adolescents and children with severe obesity.

“We are at a watershed brought on by the recent introduction of highly effective obesity medications. They are enabling us to safely and effectively treat obesity, and in doing so, potentially prevent, mitigate, or treat over 200 obesity-related complications, including cardiovascular disease and type 2 diabetes,” Jastreboff says. “These medications are transformational for medicine and the lives and health of people with obesity—they hold promise for the health of our nation and world.”

On the other hand, GLP-1 agonists cause not only weight loss but also loss of muscle mass. This side effect can have negative implications, particularly in older adults. “We all lose muscle mass as we age, and this may promote more fragility in older individuals,” Shulman says.

Shulman’s laboratory is leading the charge on studying the use of compounds called protonophores (which facilitate the movement of protons across cell membranes) to promote increased energy expenditure without reductions in muscle mass. His team studies the additive effects of using GLP-1 agonists and protonophores in animal models. The researchers are finding that not only does this combination lead to more weight loss compared to GLP-1 agonists alone, but it also does not promote additional loss of muscle mass—and the decrease in body weight persists even when the GLP-1 agonist is stopped. Shulman says he hopes to see protonophores available in the clinic within the next five to 10 years.

Furthermore, Horvath’s team is studying hypothalamic circuits in the brain that play a role in appetite. The researchers are investigating whether targeting pathways within this circuit can promote appetite suppression without inducing the side effects associated with current anti-obesity medications. “There are neural circuits in the brain that determine when you are hungry or not hungry,” he says. “By targeting these areas specifically, we may be able to more selectively impact these functions without broadly impacting other aspects of brain function.”

When the American Academy of Pediatrics released its updated guideline in 2023, it placed acknowledgment of the harms of weight bias and stigma front and center. “Early in my medical school training, people actually thought that shaming patients into taking their obesity seriously was a good strategy,” says Sharifi. “Since then, we’ve learned so much about how harmful and demotivating that is. It violates the ‘First, do no harm’ principle.”

The rise of GLP-1 agonists is sparking discussions that challenge previously held beliefs about obesity, experts say. Jastreboff has been an advocate for patients with obesity, engaging in conversations to begin to move away from a world in which patients are shamed and blamed toward one in which they receive compassionate care.

As a result of overtures like these, clinicians are finally recognizing that obesity is not driven by a lack of willpower, and that it requires therapies targeting its underlying biological mechanisms. Sharifi’s surveys indicate that the majority of clinicians agree that obesity is a chronic disease, and that about half feel concern about causing harm by the way they talk about it with their patients. She is optimistic that the availability of effective anti-obesity medications will encourage more discussions between doctors and patients about obesity.

“I’m really thrilled by our advancement in understand- ing obesity as a disease that’s multifactorial, and that it’s not a choice,” says Sharifi. “I think it’s going to encourage clinicians to be able to talk about obesity in non- stigmatizing patient-centered ways.”