Nearly a decade ago, a thin, soft-spoken twenty-something woman named Megan walked into my office and presented me with a meticulous hand-written file containing her gastrointestinal history. The file included descriptions of her initial diagnosis of Crohn’s disease as a teenager, the multiple operations she had endured to remove diseased parts of her bowels, and the array of symptoms she suffered with, including nausea, a dozen bowel movements a day, and a total reliance on nutrition obtained through her veins, known as total parenteral nutrition (TPN). Instead of twenty feet of small intestines that most people have, she only had around twenty inches left, and was diagnosed with a condition called short bowel syndrome. We tried a variety of treatments in the ensuing months, but she remained miserable and mostly homebound, unable to concentrate on her studies or to take short vacations with her friends. Finally, I started her on a relatively new injectable drug called Gattex (teduglutide), an analogue of a human hormone secreted by intestinal cells known as glucagon-like peptide-2 (GLP-2). Gattex improved intestinal blood flow and absorption, slowing gastric emptying and increasing the height of the tiny, finger-like projections in Megan’s intestines known as villi. Six months or so after she started the drug, Megan was not only free of gastrointestinal symptoms: she was also able to discontinue her TPN on weekends, a freedom previously unimaginable. Gattex is an expensive drug, and appropriate for use only in certain clinical contexts for rare-disease patients. The drug was slow to garner attention within or outside of gastroenterology. In the years that followed, I continued to use it for patients like Megan. For those patients, it seemed nothing short of a miracle.
[time-brightcove not-tgx=”true”]Today, another glucagon-like peptide, GLP-1, is widely hailed as miraculous. GLP-1, like GLP-2, is a hormone secreted by intestinal cells and is being studied in short bowel syndrome patients. Unlike Gattex, however, drugs that mimic GLP-1 (GLP 1s) are currently prescribed for some of the most common chronic conditions in the U.S. today—diabetes and obesity—and have been showered with media attention over the last couple of years in the context of weight management. Traditionally, GLP-1s were developed to treat type 2 diabetes. These injectable drugs resemble hormones that the body produces after eating, stimulating insulin secretion by the pancreas and lowering blood sugar levels. They slow digestion and decrease appetite. They affect parts of the brain that control hunger, telling your brain to feel full for a longer period of time. Not surprisingly, GLP-1s can lead to lower body fat—a welcome side effect for many diabetic patients struggling with weight issues. Some GLP-1s are now FDA approved for chronic weight management, including Wegovy (semaglutide) and Saxenda (liraglutide), while others like Ozempic (semaglutide) are approved for type 2 diabetes but are used off-label for weight management—including for cosmetic weight loss, after being popularized by celebrities and social media influencers.
If GLP-1 agonists like Wegovy and Ozempic are modern wonder drugs, their effects on body weight and blood sugar are only a part of their sensational story. A lesser-known feature of GLP-1s—and GLP-2s–is their potential to lower local and systemic inflammation within the body, both in the intestines and beyond. We know today that inflammation can be an important risk factor for the development of all kinds of disease. Low-level inflammation is linked to a wide variety of chronic conditions, including heart disease, cancer, obesity, diabetes and neurodegenerative disorders, all of which can be considered, at least in part, chronic inflammatory disorders (CIDs). In obese individuals, excess body fat—particularly the visceral fat stored deep inside the body—churns out low-level inflammation at all hours of the day. Inflammation may be one central mechanism by which obese individuals develop additional CIDs, including top killers like heart disease and cancer. New and emerging research suggests that GLP-1s, acting through anti-inflammatory pathways, may be beneficial in a variety of CIDs, with the potential to aid not only patients with diabetes and obesity but also those without these conditions.
Recent data reveals that GLP-1s are useful in heart disease, a condition that is currently the leading cause of death in men and women worldwide. In August of 2023, a study sponsored by Wegovy manufacturer Novo Nordisk was published in the New England Journal of Medicine (NEJM). Researchers tracked 529 patients with obesity and heart failure, assigning them to receive either weekly semaglutide or placebo for one year. They found that the patients treated with semaglutide had not only greater weight loss than those on placebo but also fewer symptoms and physical limitations as well as improved exercise tolerance.
Read More: Why Ozempic Can’t Fix America’s Obesity Crisis
A few months later, in November of 2023, results from a landmark clinical trial known as the SELECT trial, which was also sponsored by Novo Nordisk, caused a stir. Around 17,000 cardiovascular disease patients who were overweight or obese but did not have diabetes were randomized to receive weekly semaglutide or placebo for several months. At the end of the study period, researchers found that the patients who had received semaglutide not only lost weight: they had a stunning 20% decrease in cardiovascular events, including cardiovascular death, heart attacks, and strokes. In addition, semaglutide decreased heart failure and all-cause mortality by 18% and 19%, respectively. Interestingly, semaglutide seemed to be preventing heart attacks within the first couple of months of taking the drug, before study participants lost much weight, supporting the idea that patients didn’t need to lose weight before starting to experience the drug’s cardiovascular benefits.
Those taking the highest dose of semaglutide in the SELECT trial had drops in systemic inflammation. This reduction in inflammation may be one important mechanism by which semaglutide yields its cardiac benefits. Studies have shown that elevated low-level inflammation is an independent risk factor for the development of heart attacks, strokes and death from cardiac events. Semaglutide also helped to improve traditional risk factors for heart disease, including overweight and obesity as well as elevated blood pressure, blood sugar and cholesterol levels. These traditional risk factors, in turn, are also linked to chronic, low-level inflammation.
Beyond heart disease, GLP-1s may have a role in other CIDs. Over the last few decades, the incidence of early-onset cancer, meaning cancer diagnosed in adults less than 50 years of age, has been on the rise. This emerging global epidemic is thought to be due in large part to environmental and lifestyle factors like a suboptimal diet, lack of exercise and pollution—all of which can trigger inflammation in the body. In December of 2023, researchers at Case Western University published results from a nationwide observational study involving over one million patients with type 2 diabetes who were prescribed antidiabetic medications from 2005-2019. Compared with other antidiabetic medications, including insulin and metformin, GLP-1s were associated with a decreased risk for colorectal cancer, a finding that held fast regardless of whether the patient had diabetes alone or diabetes in addition to overweight or obesity. Observational studies cannot prove causation, and figuring out how GLP-1 impacts cancer will likely be complex given the multifactorial nature of cancer causation, which includes both genetic and environmental influences. Still, we know today that inflammation is one of the hallmarks of cancer. Inflammation, in many cases, fuels the initiation and development of cancer, from early genetic and epigenetic influences that transform normal cells into malignant ones to the continued growth and spread of cancer throughout the body. GLP-1s may influence the pathways that promote cancer not only by controlling weight and blood sugar but also through their anti-inflammatory effects independent of these traditional risk factors.
A significant proportion of patients with diabetes or obesity are destined to develop kidney disease. Practitioners deploying GLP-1s for diabetes noticed that these drugs also seemed to stabilize patients’ kidney function. Both experimental and, more recently, clinical trials have shown that GLP-1s can slow kidney decline and prevent substantial loss of kidney function in diabetic patients. GLP-1s like semaglutide and liraglutide have been shown to protect the kidneys through alteration of fat and energy metabolism. Patients taking GLP-1s tend to have better blood sugar control, lower body weight, and lower blood pressure, all of which can also decrease inflammation and positively impact kidney function. In addition, researchers at Monash University in Australia published a study earlier this year revealing that the GLP-1 agonist liraglutide, with receptors in the kidneys, can suppress inflammation and decrease markers of kidney damage in diabetic and non-diabetic mouse models of kidney disease.
Another common complication in patients with diabetes or obesity is metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD). MASLD is now the most prevalent chronic liver disease in the Western world and affects around a third of the US population. Meanwhile, licensed pharmacotherapies for this disease are lacking. In MASLD, droplets of fat accumulate in the liver, which may in turn lead to liver inflammation and scarring over time—meanwhile, inflammation itself may help to feed this pathway. Weight loss is central to reversing early-stage disease. GLP-1s are currently being evaluated for the treatment of MASLD. Randomized controlled trials show that semaglutide can lower fat and inflammation in the liver and improve markers of liver injury, although it has not yet been shown to improve the stages of liver scarring. Semaglutide treatment is also associated with a decrease in body wide low-level inflammation in patients at risk for developing MASLD. Low-level inflammation is predictive of MASLD and has been linked to the presence and severity of underlying liver scarring. Trials are ongoing to determine if semaglutide will meet the clinical endpoints for FDA approval.
Read More: Ozempic Hurts in the Fight Against Eating Disorders
GLP-1s have received attention in lung and intestinal diseases. Results from a few clinical trials as well as observational studies have shed light on the potential benefits of GLP-1s in asthma, emphysema and chronic bronchitis, although large-scale clinical trials are required to confirm these findings. Obesity, which creates ongoing, chronic inflammation in the body, is increasingly associated with inflammatory bowel disease (IBD) and may negatively influence the disease course. Scientists also hypothesize that obesity contributes to the development of IBD. Some studies have shown that IBD patients taking GLP-1s for diabetes reduce the need for steroids or biologic medications and have fewer hospitalizations or IBD-related surgeries, suggesting that GLP-1s may influence disease activity in IBD. Further research is needed, however, to definitively determine whether GLP-1s are truly beneficial for disease outcomes in IBD patients.
How might GLP-1s decrease inflammation in the body?
Improved control of CIDs like diabetes and obesity lowers body fat and blood sugar levels, which means less inflammation. But GLP-1s have been shown to have anti-inflammatory effects independent of body weight or blood sugar. Human trials reveal that they reduce blood inflammatory biomarkers, especially when compared with other standard anti-diabetic treatments. And they seem to affect both local and body wide inflammation. GLP-1s have anti-inflammatory effects in various tissues, reducing the production of inflammatory cytokines and preventing the movement of immune cells into tissues. Receptors for GLP-1s are expressed on some immune cells–speaking to their potential to modulate the immune system and inflammation—as well as other cells around the body. They are found not only in the pancreas but in a wide variety of organs, including the heart, kidneys, lung, liver, blood vessels, stomach, intestines and brain. In fact, the prevalence of GLP-1 receptors in the body helped to prompt initial interest in studies investigating the use of GLP-1s for disorders other than diabetes.
Yet the distribution of immune cells containing GLP-1 receptors in various tissues is highly unequal, suggesting that the actions of GLP-1s in some organs may be more important than in others when it comes to regulating inflammation. Immune cells activated by GLP-1s are especially replete in the intestines—which house much of the body’s immune system—as well as in the brain. According to Canadian scientist Dr. Daniel Drucker, whose pioneering research gave rise to modern GLP-1 drugs, the gut-brain-immune axis may be central to the ability of GLP-1s to influence inflammation in the body, as his latest study conducted in animals and published earlier this year suggests. The bidirectional communication between the gut and the brain incorporates signals from trillions of gut microbes collectively known as the intestinal microbiota and affects a plethora of processes around the body, including inflammation. GLP-1s may modulate gut microbiota and target immune cells in the brain and in the gut to reduce body wide inflammation.
Given the potential benefits of GLP-1s in the brain, it’s no surprise that there is rising interest in the use of GLP-1s for neurodegenerative diseases. Controlled trials point to the ability of GLP-1s to reduce the rates of dementia in diabetic patients, and large-scale clinical trials are underway to study the effectiveness of these drugs for diseases like Alzheimer’s and Parkinson’s. GLP-1s are thought to modulate immune function in the brain, preventing the continued buildup of misfolded proteins and lowering inflammation—pathways that contribute to Alzheimer’s and other neurodegenerative diseases.
For all the possibilities GLP-1s seem to have in managing inflammation and CIDs, caution must be exercised when evaluating and deploying these drugs outside of their traditional contexts. Their anti-inflammatory effects are broad, targeting different pathways in different tissues, and their range of potential benefits may be accompanied by problems as well. Although GLP-1s are generally well tolerated, with common side effects including gastrointestinal issues like nausea, vomiting, diarrhea and constipation, rare, more serious complications include issues like stomach paralysis, pancreatitis, bowel obstruction, kidney failure and thyroid cancer. Long-term safety data in non-diabetic populations is required for the newer GLP-1s that are more effective for weight loss. The drugs are also expensive, often requiring significant out-of-pocket costs. In short, GLP-1s shouldn’t be used as a quick-fix in order to lose a few pounds, but rather for patients in whom the risk-benefit profile makes sense—in obese individuals at a high risk of developing additional CIDs, for example, in whom the use of GLP-1s seems less concerning than the risks associated with a lifetime of severe weight issues. For many obese individuals, metabolic derangements, including an altered hormonal milieu, can make it tough to lose and keep the excess weight off indefinitely without adjunctive medical or surgical therapies. Unfortunately, the people who most need GLP-1s for weight management often struggle to obtain it.
Prescribing GLP-1s for obesity—or any chronic disorder—doesn’t obviate the need for lifestyle changes, which are paramount to decreasing inflammation and the risk of developing CIDs. In fact, certain lifestyle changes, like incorporating more soluble fiber—a type of fiber that feeds our gut microbes—into the diet, or exercising regularly, can increase endogenous GLP-1 levels. Lifestyle prescriptions may also help to lessen the risks of GLP-1s by allowing patients to be maintained on the lowest effective dose, or to even wean off GLP-1s entirely at some point.
GLP-1 drugs like Ozempic and Wegovy gained immense clinical traction as well as popular cultural fame due to their success in treating overweight and obesity, conspicuous diseases that burden over two-thirds of all American adults. However, their effects may be broader than ever imagined: evidence is accruing on the potential of GLP-1s to combat invisible, low-level inflammation as well as several of the chronic conditions associated with it. But while GLP-1s may hold promise for treating a variety of diseases, more research is needed to establish exactly which patient populations beyond existing ones may benefit from these drugs. In the meantime, patients should discuss the potential utility of GLP-1s for a particular condition with their physicians. And as in the case of my patient Megan, who walked into my office long ago with a dire rare disease, the use of glucagon-like peptides–which are powerful gut hormones–should not be cavalier.
