Nearly a decade ago, a thin, soft-spoken woman in her twenties named Megan came to my office and presented me with a meticulously handwritten 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 undergone to remove diseased parts of her bowels, and the array of symptoms she suffered from, including nausea, having a dozen bowel movements a day, and a total reliance on nutrition obtained through her veins, known as total parenteral nutrition (TPN). Instead of the typical 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.
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 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.
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 obesi
