Prior placebo-controlled randomized controlled trials of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and tirzepatide have shown that these medications are associated with an increased risk for gastrointestinal-related adverse events; however, whether individual GLP-1 RAs and tirzepatide have different gastrointestinal safety among patients with type 2 diabetes in clinical practice remains unclear. Researchers from Brigham and Women’s Hospital and Harvard Medical School and colleagues used data from Optum’s deidentified Clinformatics Data Mart database to emulate three clinic trials of adults with T2D initiating dulaglutide, subcutaneous semaglutide, or tirzepatide between 1 January 2019 and 30 August 2024. They assessed 65,238 matched pairs in the semaglutide versus dulaglutide cohort, 20,893 in the tirzepatide versus dulaglutide cohort, and 46,620 in the tirzepatide versus semaglutide cohort. The primary outcome was a composite of severe gastrointestinal AEs resulting in an inpatient and/or emergency department encounter. The hazard ratio of gastrointestinal events was 0.96 (95% CI, 0.87 to 1.06) in the semaglutide versus dulaglutide cohort, 0.96 (CI, 0.77 to 1.20) in the tirzepatide versus dulaglutide cohort, and 1.07 (CI, 0.90 to 1.26) in the tirzepatide versus semaglutide cohort. These findings were consistent across subgroups and sensitivity analyses. The results align with those seen in head-to-head randomized clinical trials and may help physicians when determining the benefits and risks of prescribing these popular medications.

Abstract: https://www.acpjournals.org/doi/10.7326/ANNALS-25-01724

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The CODA study findings were to be reported Monday, Oct. 26, 2021, in the New England Journal of Medicine.

“In the first three months after taking antibiotics for the condition, nearly 7 in 10 patients in the antibiotic group avoided an appendectomy. By four years, just under 50% had the surgery,” said Dr. David Flum, co-principal investigator and professor and associate chair of surgery at the University of Washington (UW) School of Medicine. “Other outcomes favored either antibiotics or surgery. Putting it all together, antibiotics look to be the right treatment for many, but probably not all, patients with appendicitis.”

CODA is the largest-ever randomized clinical trial of appendicitis treatment. At 25 hospitals across 14 states, 1,552 patients with appendicitis consented to participate and were randomized to receive antibiotics or to undergo an appendectomy.

“While there were advantages and disadvantages to each treatment, we found that both treatments are safe, and patients will likely value these outcomes differently based on their unique symptoms, concerns and circumstances,” Flum said.

Patients with an appendicolith, a calcified deposit found in about 25% of cases of acute appendicitis, were associated with more complications and a higher chance of appendectomy in the first 30 days. At 90 days out, however, there was no greater chance of appendectomy in patients with an appendicolith.

“Given these results and new treatment guidelines, it is important for surgeons and patients to discuss the pros and cons of both surgery and antibiotics in deciding on the treatment that’s best for that person at that time,” said Dr. Giana Davidson. She is a UW associate professor of surgery and director of the CODA trial’s clinical coordinating center.

To foster those conversations, CODA investigators created an online decision-making tool for patients (http://www.appyornot.org). It includes a video (currently in English and Spanish, with other languages to come) and a mechanism to help patients choose a direction that may better suit their individual circumstances.

“In the emergency setting, patients with appendicitis can make a treatment decision hurriedly,” Davidson said. “This online tool was built to help communicate the CODA results in laymen’s terms, and to spur a conversation between patients and surgeons about potential benefits and harms of each approach.”

University of Washington School of Medicine/UW Medicine

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But a University of Notre Dame study has found a much greater genetic component at play than was once known.

In the study, published recently in Science, researchers discovered that most bacteria in the gut microbiome are heritable after looking at more than 16,000 gut microbiome profiles collected over 14 years from a long-studied population of baboons in Kenya’s Amboseli National Park. However, this heritability changes over time, across seasons and with age. The team also found that several of the microbiome traits heritable in baboons are also heritable in humans.

“The environment plays a bigger role in shaping the microbiome than your genes, but what this study does is move us away from the idea that genes play very little role in the microbiome to the idea that genes play a pervasive, if small, role,” said Elizabeth Archie, professor in the Department of Biological Sciences and a principal investigator on the study who is also affiliated with the Eck Institute for Global Health and the Environmental Change Initiative.

The gut microbiome performs several jobs. In addition to helping with food digestion, it creates essential vitamins and assists with training the immune system. This new research is the first to show a definitive connection with heritability.

Previous studies on the gut microbiome in humans showed only 5 to 13 percent of microbes were heritable, but Archie and the research team hypothesized the low number resulted from a “snapshot” approach to studying the gut microbiome: All prior studies only measured microbiomes at one point in time.

In their study, the researchers used fecal samples from 585 wild Amboseli baboons, typically with more than 20 samples per animal. Microbiome profiles from the samples showed variations in the baboons’ diets between wet and dry seasons. Collected samples included detailed information about the host, including known descendants, data on environmental conditions, social behavior, demography and group-level diet at the time of collection.

The research team found that 97 percent of microbiome traits, including overall diversity and the abundance of individual microbes, were significantly heritable. However, the percentage of heritability appears much lower — down to only 5 percent — when samples are tested from only a single point in time, as is done in humans. This emphasizes the significance of studying samples from the same host over time.

“This really suggests that in human work, part of the reason researchers haven’t found that heritability is because in humans they don’t have a decade and half of fecal samples in the freezer, and they don’t have all the initial host (individual) information they need to tease these details out,” said Archie.

The team did find evidence that environmental factors influence trait heritability in the gut microbiome. Microbiome heritability was typically 48 percent higher in the dry season than in the wet, which may be explained by the baboons’ more diverse diet during the rainy season. Heritability also increased with age, according to the study.

Because the research also showed the significant impact of environment on the gut microbiomes in baboons, their findings agreed with previous studies showing that environmental effects on the variation in the gut microbiome play a larger role than additive genetic effects. Combined with their discovery of the genetic component, the team plans to refine its understanding of the environmental factors involved.

But knowing that genes in the gut microbiome are heritable opens the door to identifying microbes in the future that are shaped by genetics. In the future, therapies could be tailored for people based on the genetic makeup of their gut microbiome.

The Amboseli Baboon Project, started in 1971, is one of the longest-running studies of wild primates in the world. Focused on the savannah baboon, the project is located in the Amboseli ecosystem of East Africa, north of Mount Kilimanjaro. Research teams have tracked hundreds of baboons in several social groups over the course of their entire lives. Researchers currently monitor around 300 animals, but have accumulated life history information on more than 1,500 animals.

The research was funded by the National Science Foundation.

Journal Reference:

1. Laura Grieneisen, Mauna Dasari, Trevor J. Gould, Johannes R. Björk, Jean-Christophe Grenier, Vania Yotova, David Jansen, Neil Gottel, Jacob B. Gordon, Niki H. Learn, Laurence R. Gesquiere, Tim L. Wango, Raphael S. Mututua, J. Kinyua Warutere, Long’ida Siodi, Jack A. Gilbert, Luis B. Barreiro, Susan C. Alberts, Jenny Tung, Elizabeth A. Archie, Ran Blekhman. Gut microbiome heritability is nearly universal but environmentally contingent. Science, 2021 DOI: 1126/science.aba5483

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The stents are coated in a smooth layer of plastic etched with small “needles” that pop up when the tube is stretched, allowing the needles to penetrate tissue and deliver a payload of drug-containing microparticles. Those drugs are then released over an extended period of time after the stent is removed.

This kind of localized drug delivery could make it easier to treat inflammatory diseases affecting the GI tract such as inflammatory bowel disease or eosinophilic esophagitis, says Giovanni Traverso, an MIT assistant professor of mechanical engineering, a gastroenterologist at Brigham and Women’s Hospital, and the senior author of the study.

“This technology could be applied in essentially any tubular organ,” Traverso says. “Having the ability to deliver drugs locally, on an infrequent basis, really maximizes the likelihood of helping to resolve patients’ conditions and could be transformative in how we think about patient care by enabling local, prolonged drug delivery following a single treatment.”

Sahab Babaee, an MIT research scientist, is the lead author of the paper, which appears today in Nature Materials.

Stretchable stents

Inflammatory diseases of the GI tract, such as IBD, are often treated with drugs that dampen the body’s immune response. These drugs are usually injected, so they can have side effects elsewhere in the body. Traverso and his colleagues wanted to come up with a way to deliver such drugs directly to the affected tissues, reducing the likelihood of side effects.

Stents could offer a way to deliver drugs to a targeted portion of the digestive tract, but inserting any kind of stent into the GI tract can be tricky because digested food is continuously moving through the tract. To make this possibility more feasible, the MIT team came up with the idea of creating a stent that would be inserted temporarily, lodge firmly into the tissue to deliver its payload, and then be easily removed.

The stent they designed has two key elements — a soft, stretchy tube made of silicone-based rubber, and a plastic coating etched with needles that pop up when the tube is stretched. The design was inspired by kirigami, a technique that Traverso’s lab has previously used to design a nonslip coating for shoe soles.Others have used it to create bandages that stick more securely to knees and other joints.

“The novelty of our approach is that we used tools and concepts from mechanics, combined with bioinspiration from scaly-skinned animals, to develop a new class of drug-releasing systems with the capacity to deposit drug depots directly into luminal walls of tubular organs for extended release,” Babaee says. “The kirigami stents were engineered to provide a reversible shape transformation: from flat, to 3D, buckled-out needles for tissue engagement, and then to the original flat shape for easy and safe removal.”

In this study, the MIT team coated the plastic needles with microparticles that can carry drugs. After the stent is inserted endoscopically, the endoscope is used to inflate a balloon inside the tube, causing the tube to elongate. As the tube stretches, the pulling motion causes the needles in the plastic to pop up and release their cargo.

“It’s a dynamic system where you have a flat surface, and you can create these little needles that pop up and drive into the tissue to do the drug delivery,” Traverso says.

For this study, the researchers created kirigami needles of several different sizes and shapes. By varying those features, as well as the thickness of the plastic sheet, the researchers can control how deeply the needles penetrate into the tissue. “The advantage of our system is that it can be applied to various length scales to be matched with the size of the target tubular compartments of the gastrointestinal tract or any tubular organs,” Babaee says.

GI drug delivery

The researchers tested the stents by endoscopically inserting them into the esophagus of pigs. Once the stent was in place, the researchers inflated the balloon inside the stent, allowing the needles to pop up. The needles, which penetrated about half a millimeter into the tissue, were coated with microparticles containing a drug called budesonide, a steroid that is used to treat IBD and eosinophilic esophagitis.

Once the drug-containing particles were deposited in the tissue, the researchers deflated the balloon, flattening out the needles so the stent could be endoscopically removed. This process took only a couple of minutes, and the microparticles then stayed in the tissue and gradually released budesonide for about one week.

Depending on the composition of the particles, they could be tuned to release drugs over an even longer period of time, Traverso says. This could make it easier to keep patients on the correct drug schedule, because they would no longer need to take the drug themselves, but would periodically receive their medicine via temporary insertion of the stent. It would also avoid the side effects that can occur with systemic drug administration.

The researchers also showed that they could deliver the stents into blood vessels and the respiratory tract. They are now working on delivering other types of drugs and on scaling up the manufacturing process, with the goal of eventually testing the stents in patients.

The research was funded by MIT’s Department of Mechanical Engineering. Other authors of the paper include Yichao Shi, Saeed Abbasalizadeh, Siddartha Tamang, Kaitlyn Hess, Joy Collins, Keiko Ishida, Aaron Lopes, Michael Williams, Mazen Albaghdadi, and Alison Hayward.

Journal Reference:

1. Sahab Babaee, Yichao Shi, Saeed Abbasalizadeh, Siddartha Tamang, Kaitlyn Hess, Joy E. Collins, Keiko Ishida, Aaron Lopes, Michael Williams, Mazen Albaghdadi, Alison M. Hayward, Giovanni Traverso. Kirigami-inspired stents for sustained local delivery of therapeutics. Nature Materials, 2021; DOI: 10.1038/s41563-021-01031-1

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