Publisher Health

Researchers at the Hubrecht Institute have laid the foundation for the development of a gene therapy for the genetic heart disease arrhythmogenic cardiomyopathy (ACM). Their approach, based on replacement of the PKP2 gene, led to significant structural and functional improvements in laboratory models of the disease. The study by the group of Eva van Rooij was published on 7 December 2023 in Nature Cardiovascular Research. Multiple clinical trials will start in 2024 in the United States to explore the clinical potential of this approach in ACM patients with PKP2 mutations.
Arrhythmogenic cardiomyopathy (ACM) is a genetic heart disease that affects 1 in 2,000 to 1 in 5,000 people worldwide. It is characterized by arrhythmias and can lead to sudden cardiac arrest. Current treatment of the disease usually consists of antiarrhythmic drugs and implantable cardioverter-defibrillators (ICDs), which are focused solely on treating the symptoms rather than targeting the root of the problem. The disease is progressive, with an increasing part of the heart muscle being replaced by fat tissue and heart function deteriorating over time. This can eventually lead to heart failure. In severe cases, a heart transplantation can be performed as a last resort, but this is complicated by long waiting lists as a result of the limited availability of suitable donor hearts. There is therefore an urgent need for effective treatments that target the cause of ACM.
Disease of the desmosome
The mutations at the basis of ACM often occur in genes related to the desmosomes. These protein structures form the connections between adjacent heart muscle cells. Not only do they provide a structural link, but they also ensure that the heart muscle cells contract synchronously, allowing the heart to pump blood in a coordinated manner. The most frequently affected gene in ACM is PKP2, which encodes the plakophilin-2 protein, an essential part of the desmosomes. First author of the study Eirini Kyriakopoulou explains the effect of PKP2 mutations: “Patients with mutations in this gene often have lower levels of the plakophilin-2 protein in their heart muscle cells. The result is that the desmosomes, which are normally built up by meticulously binding all proteins together, now start to fall apart and are broken down by the cell. This weakens the connections between the heart muscle cells, which makes it difficult for them to work together in synchrony, leading to the development of arrhythmias.”
Gene therapy
With the molecular cause of ACM in mind, the researchers set out to develop a therapeutic approach that would target this cause and not just the symptoms. “For many patients with PKP2 mutations, the root of the problem is insufficient levels of plakophilin-2. Therefore, we explored the potential of gene therapy in ACM. We hypothesized that by introducing the healthy PKP2 gene into affected heart muscle cells, we might be able to restore plakophilin-2 levels to normal, thereby reinforcing the desmosomes and reducing the occurrence of arrhythmias in these patients,” says Kyriakopoulou.
Improved heart function in the laboratory
Using several laboratory models of ACM, Kyriakopoulou and her colleagues demonstrated both the feasibility and the efficacy of delivering the healthy PKP2 gene to diseased heart muscle cells. “We showed that plakophilin-2 levels were restored after delivery of the gene to human heart muscle cells grown from stem cells. It also improved their sodium conduction, which is important for their ability to contract. We then confirmed this improvement of contractility in engineered human heart muscles, which are ring-shaped structures that we can grow in the lab. Heart muscles with a PKP2 mutation contracted better after receiving the healthy PKP2 gene. Finally, we wanted to test this strategy in vivo, so we applied PKP2 gene replacement in our mouse model of ACM. This led to recovery of their desmosomes and heart function,” Kyriakopoulou explains.
From the lab to the clinic
Following the promising laboratory results, the next step is to investigate the clinical potential of this gene therapy approach in ACM patients with PKP2 mutations. “Three companies in the United States have announced that they will start clinical trials next year to test the therapeutic effect of this approach in patients, which is of course great news,” says Kyriakopoulou. The researchers at the Hubrecht Institute hypothesize that gene replacement therapy would be most useful in the early stages of the disease. Kyriakopoulou: “Once the disease has progressed so much that parts of the heart muscle have already been replaced by fat tissue, it is uncertain whether this approach would reverse already existing damage. Instead, we believe that it might be possible to prevent progression of early-stage disease to more severe stages.” Although the pre-clinical results and upcoming trials hold great promise, Kyriakopoulou emphasizes that the commercial availability of this approach could still take several years. “Apart from the evident need to confirm its efficacy in patients, it is also crucial to address and eliminate any safety concerns before considering its clinical application. Nevertheless, our work provides an important basis to build on.”

A new study demonstrates that the human gut microbiome may be a factor in breast health. Lifestyle and diet have long been known to affect human health. In the study, flaxseed components called lignans were shown to influence the relationship between gut microorganisms and the expression of mammary gland microRNAs (miRNAs). A subset of these miRNAs regulates the genes involved in breast cancer, including genes that control cell proliferation and migration. The study was published in Microbiology Spectrum, a journal of the American Society for Microbiology.
“The gastrointestinal microbiota plays an important role in modifying many components of our diet to impact human health,” said Jennifer Auchtung, Ph.D., Assistant Professor in the Food Science and Technology Department at the University of Nebraska — Lincoln, the editor who coordinated the review of the paper. “In this study, we found correlations between diets enriched in flaxseed, cecal microbiota composition and miRNA profiles in the mammary gland that regulate many pathways, including those involved in cancer development. This preliminary study supports further research into the role that the microbiota plays in dietary approaches to reduce risk factors associated with disease.”
The researchers studied the effects of flaxseed lignans on the microbiota of young female mice. Lignans, fiber-associated compounds found in many foods and particularly plentiful in flaxseed, are associated with reduced breast cancer mortality in postmenopausal women. The researchers found that lignan components generate specific miRNA responses in the mammary gland. miRNAs are short, noncoding RNAs that regulate gene expression by targeting the 3′ untranslated region of target mRNAs.
To determine whether the relationship between the microbiota and mammary gland miRNAs could be manipulated to reduce the risk of breast cancer, the researchers fed flaxseed lignan components to female mice to determine whether gut cecal microbiota profiles are related to miRNA expression in the mammary gland. The cecum, the first part of the colon, located in the right lower abdomen near the appendix, is believed to have a role in production of short-chain fatty acids and has been proposed to serve as a reservoir of anaerobic bacteria.
One flaxseed oil lignan requires microbial processing to release bioactive metabolites, small-molecule chemicals produced during metabolism that influence physiology and disease — in this case having antitumor effects. The researchers found that the microbiota and mammary gland miRNA are related and that flaxseed lignans modify the relationship to be non-cancer causing.
“If these findings are confirmed, the microbiota becomes a new target to prevent breast cancer through dietary intervention,” said Elena M. Comelli, Ph.D., Associate Professor in the Department of Nutritional Sciences and the Temerty Faculty of Medicine, University of Toronto, the corresponding author on the paper.

Previous studies shown that women who have had a C-section tend to have more problems conceiving a baby than ones who have had normal, vaginal birth.
“Many of these studies have utilized inter-pregnancy intervals to measure women’s fertility,” researcher Yeneabeba Sima at the University of Bergen, explains. She points out:
“However, a measure of inter-pregnancy interval cannot distinguish between voluntary and involuntary delay in getting pregnant.”
Asking women if they planned their pregnancies
Using data from The Norwegian Mother, Father and Child Cohort Study (MoBa) linked to the Medical Birth Registry of Norway (MBRN), Sima and colleagues assessed women’s fertility.
The MoBa questionnaire inquired whether or not women planned their pregnancies.
“For those who actively tried to have a baby, we examined the time it took for them to conceive. If they had tried for a year or more before getting pregnant, they were considered to have reduced fertility,” says Sima.

The researchers examined differences in time spent trying to conceive among 42,379 MoBa participants, all of whom had at least one previously registered birth in the MBRN. The findings indicated that women with a prior C-section had a 10% decreased chance of conceiving their next pregnancy during a given menstrual cycle compared with those who had prior vaginal deliveries.
Women with fertility problems also had more C-sections
The researchers also explored the association in the other direction, between reduced fertility and later C-section. Among 74,025 MoBa participants, 11% reported trying for more than one year before getting pregnant. They found that women who took one year or longer to conceive were 21% more likely to be delivered by C-section, as compared with women who spent less than 12 months trying to conceive.
“In our study, women with difficulty conceiving have a higher prevalence of pregnancy complications. There is also a higher prevalence of chronic health issues like diabetes mellitus and high blood pressure among these women. However, the increased risk of having a C-section still existed for women who didn’t have these health issues,” said Sima.
The associations between C-section and reduced fertility might not be causal
Previous studies concluded that reduced fertility following C-section could be a side effect of the surgical operation. However, Sima and colleagues suggest that common underlying risk factors could contribute to both reduced fertility and C-section:
“Maternal stress might be one reasonable explanation connecting challenges in conceiving and an elevated risk of labor difficulties, ultimately leading to a higher likelihood of C-section,” Sima explains, and adds:
“Our findings suggest that the observed reduced ability to conceive after C-section may be linked to underlying maternal conditions not registered in our data or not yet clinically emerged, and the surgical procedure may not directly influence this pathway.”

Research reveals that around 20 per cent of all cases of the most severe form of breast cancer may arise from the small group of normal tissue cells carrying an epimutation of a specific gene.Research reveals that around 20 per cent of all cases of the most severe form of breast cancer may arise from the small group of normal tissue cells carrying an epimutation of a specific gene.
Cancer is a major health challenge worldwide, affecting many lives. Despite progress in understanding its causes, most cancer forms, including breast cancer, continues to increase in many countries.
Scientists have been looking closely at both genes and the environment, trying to figure out what sets the stage for cancer. One interesting area of study is something called “epimutations.” Instead of changes to the actual genes, these are changes in how our genes are turned on or off.
In a recent study investigators at the University of Bergen, in collaboration with the US Women’s Health Initiative, the investigators found a link between certain epimutations in a gene called BRCA1 and a higher risk of triple-negative breast cancer (TNBC), the most severe type of breast cancer.
“This higher risk was found despite the fact that epimutations affected a very small portion of normal cells in the affected individuals,” says professor Per Eystein Lønning.
May originate from the pregnancy
While this was a breakthrough, it left the researchers wondering when and where these epimutations happen. In a new study now featured in the journal Genome Medicine the Bergen Group, and to be presented at the international SABCS, the worlds largest breast cancer conference in San Antonio on December 6, in collaboration with other Norwegian researchers, the Bergen researchers dug deeper. Analysing DNA from both breast tissue and white blood from over four hundred breast cancer patients, they made several important discoveries providing new light on the subject.

For many cases of TNBC, BRCA1 gene epimutations were found in both the white blood cells and tumour tissue. Moreover, epimutations in the white blood cells and tumour tissue from the same individual revealed the same profile.
“This suggests they might have a common cell origin, possibly occurring very early during pregnancy,” says Lønning.
Gender differences not previously recorded
The findings also indicate that as many as around 20 per cent of all TNBC may arise from the small group of normal tissue cells carrying BRCA1epimutations.
Analysing blood samples from newborns, they found similar BRCA1epimutations as those detected in cancer patients. Surprisingly, these epimutations happened twice as often in girls than in boys. Finally, no concordance in epimutations between newborns and their parents was observed, arguing against direct inheritance.
“The fact that epimutations might be happening early during pregnancy challenges conventional theories on carcinogenesis and cancer risk. Moreover, the fact that they occur twice as common in girls than boys reveal an important gender difference not previously recorded,” says Lønning.
Could be a game changer
This discovery is opening new avenues for research. The Bergen Breast Cancer Group now works on the exact mechanism of early life epimutations. In addition, in collaboration with WHI investigators, they study whether epimutations in other genes might be linked to other types of cancer.
“Understanding this could potentially be a game-changer in how we approach and prevent cancer in the future,” Lønning concludes.

Dental plaque, gut bacteria and the slippery sheen on river rocks are all examples of biofilms, organized communities of microorganisms that colonize our bodies and the world around us. A new study led by Penn State researchers reveals exactly how growing biofilms shape their environments and fine-tune their internal architecture to fit their surroundings. The findings may have implications for a wide variety of applications, from fighting disease to engineering new types of living active materials.
“In the case of bacteria, they grow, divide, and apply forces to each other and their surroundings,” said Sulin Zhang, professor of engineering science and mechanics and of biomedical engineering at Penn State and corresponding author on a paper about the discovery, recently published in the journal Nature Physics. “As such, growing bacteria have the potential to shape the environment, changing the environment they live in, so we were interested in understanding the reciprocal interactions between the growing biofilm and environment where it grows.”
Zhang collaborated with an interdisciplinary team of researchers from the Massachusetts Institute of Technology and Yale to study that interaction on all fronts: theoretically, experimentally and computationally. The researchers used biofilms made by Vibrio cholerae, which can cause cholera, as a model system to demonstrate the self-shaping and self-organizing capability of a 3D growing system.
In nature, biofilms tend to grow in tight, confined spaces, Zhang explained, so the team grew the biofilm between a soft hydrogel and a stiff glass substrate. They analyzed the growing biofilm using single-cell imaging, agent-based simulations and continuum mechanics theory. The researchers found that the biofilms shape both themselves and their boundary into an efficient formation known as “active nematics,” the arrangement of self-propelled molecules in parallel lines instead of layers.
“We found that biofilms take advantage of growth-induced stresses to shape their environment and create a nematic structure,” said Jing Yan, assistant professor of molecular, cellular and developmental biology at Yale University and co-corresponding author on the paper. “This takes us a lot closer to being able to control the morphology, the packing and ordering of the biofilm.”
Zhang explained that understanding the feedback loop between biofilm growth, growth generated stress, and its environment could pave the way for controlled growth of beneficial biofilms, the elimination of harmful ones and even the potential development of new classes of active growing materials that can respond to — and actively alter — their environment.”
Yan added that this is especially valuable information in the field of health care. Biofilms play a substantial role in disease growth in humans and animals, as they can evade the immune response. The coordinated nature of bacterial biofilms makes them highly resistant to conventional antibiotics, so they are extremely difficult to treat. In fact, the majority of chronic antibiotic resistant-infections are caused by biofilms, according to the American Society for Microbiology.
“When a bacteria enter into the body, they grow into an infection as biofilms — and they’re in a confined environment: your gut,” Yan said.
A better understanding of how biofilm-driven disease can grow in such an environment will allow researchers to develop new ways to disrupt such growth, he added.
“What we’ve learned will aid in developing strategies to tackle these infections,” said Changhao Li, a doctoral candidate in computational mechanics at Penn State and co-author on the paper. “The phenomena discovered here could lead to new strategies to suppress the growth of harmful biofilms and give us the ability to design and program beneficial ones.”

A preclinical study by Weill Cornell Medicine investigators shows that a specific human genetic variant of a receptor that stimulates insulin release may help individuals be more resistant to obesity. The researchers discovered that this variant behaves differently in the cell which may contribute to more efficient metabolism.
The study, posted online in Molecular Metabolism on Nov. 2, provides new insight into how human genetic variations affect an individual’s susceptibility to weight gain. The researchers developed mice with a human genetic variant in the glucose-dependent insulinotropic polypeptide (GIP) receptor associated with leaner body mass index (BMI). They found that the mice were better at processing sugar and staying leaner than mice with a different, more common variant of the receptor. The discovery may point to new potential strategies to treat obesity, which affects more than a 100 million adults in the United States according to the Centers for Disease Control and Prevention.
“Our work demonstrates how basic science research can yield important insights about complex biology,” said the study’s senior author Dr. Timothy McGraw, a professor of biochemistry in cardiothoracic surgery and in biochemistry at Weill Cornell Medicine. “These GIP receptors and their behavior at the cellular level profoundly impact metabolism and weight regulation.”
Genetic Variants of the GIP Receptor
Genetic variants are differences in DNA sequence that occur naturally between individuals in a given population. Genome-wide association studies, which use statistics to carefully link genetic variants to particular traits, show about 20 percent of people of European descent have one copy of the GIP receptor with the Q354 gene variant and about 5 percent have two copies of the variant. The GIP receptor interacts with a hormone released in response to glucose levels after a meal. “Studies suggest that people with at least one copy this GIP receptor variant have altered metabolism that reduces their risk of developing obesity,” said the study’s lead author Dr. Lucie Yammine, a post-doctoral associate in biochemistry at Weill Cornell Medicine.
To understand how this gene variant may be decreasing the risk of obesity, the team used CRISPR-Cas9 technology to genetically engineer mice with the variant in the gene encoding the GIP receptor, similar to the human version. They found that female mice with the variant were leaner on a typical mouse diet than female litter mates without it. Male mice with the gene variant were about the same weight as litter mates without it while consuming a regular diet, but the gene variant protected them from weight gain when fed a high-fat diet, which caused obesity in litter mates.
“We found that a change in one amino acid in the GIP receptor gene affected the whole body in terms of weight,” Dr. Yammine said. Mice with the variant were more sensitive to the GIP hormone that triggers the release of insulin which controls blood sugar levels and helps the body convert food into energy.

How the Variant May Provide an Advantage Against Obesity
The researchers compared what happened to mouse cells with and without the variant when exposed to glucose or the GIP hormone. Pancreatic cells from mice with the genetic variant produced more insulin in response to both glucose and the GIP hormone, which may explain why they are better at processing glucose.
“What’s interesting about these receptors is their location in the cell has a big impact on how they signal and their activity,” Dr. McGraw said. He explained that when the GIP hormone binds to the receptor, the receptor moves from the cell surface to inside the cell. When the GIP hormone eventually falls off the receptor, the receptor returns to the cell surface.
The team found that the GIP receptor variant stays inside the cell compartment four times longer than the typical receptor. Dr. McGraw suggested that this may allow the receptor to send more messages to the machinery inside cells, which helps in processing sugar more efficiently.
Still, more research is needed to confirm the effects of this variant on the receptor’s behavior. The researchers also want to learn if there are differences in the receptor’s behavior in other cell types, like brain cells, which play a crucial role in regulating hunger.
Recently, the Food and Drug Administration has approved several weight loss drugs that mimic natural hormones in the body and interact with receptors like GIP, including semaglutide (Wegovy) and tirzepatide (Zepbound). This has increased the interest in studying new ways to target the GIP receptor for obesity.
“Our work suggests that the movement of the receptor from the cell surface to the interior is an important factor in controlling metabolism. Therefore, drugs that could regulate the GIP receptor behavior and location could provide an important new avenue to combat obesity,” said Dr. Yammine.
In the meantime, Dr. McGraw noted that it is essential to understand how people with different genetic variants in the GIP receptor respond to currently available weight loss medications. “A better appreciation of how different variants of receptors impact metabolism might allow for a precision medicine approach — matching a specific drug to a genetic variant — for weight loss,” he said.

Patients who received the anticoagulant drug warfarin after bioprosthetic aortic valve replacement had lower incidence of mortality and a decreased risk of blood clots, according to a retrospective study published in Mayo Clinic Proceedings.
The use of bioprosthetic aortic valve replacement has increased significantly during the past decade. Among its advantages is that most patients can avoid warfarin for anticoagulation treatment. Even so, research has been conflicting on whether patients would benefit from more aggressive early postoperative anticoagulation treatment.
Mayo Clinic researchers analyzed nationwide data on more than 10,000 patients who underwent bioprosthetic aortic valve replacement. Warfarin use was associated with a 32% reduction in mortality risk. Patients treated with warfarin early postoperatively also had an increased risk of major bleeding events.
“The findings support early warfarin use in appropriately selected patients, such as patients with low bleeding risk,” says Hartzell Schaff, M.D., a Mayo Clinic cardiovascular surgeon who contributed to the study. “There’s often reluctance to prescribe anticoagulant treatment early after surgery due to concerns about bleeding and uncertainty about benefits. Our research finds that the small increased hazard of bleeding (4% versus 2.3%) may be an acceptable risk given the benefits in terms of mortality risk as well as reduced risk of thromboembolism.”
The Mayo Clinic study analyzed deidentified patient data from 2007 to 2019 using OptumLabs Data Warehouse, which contains claims data of commercially insured and Medicare Advantage enrollees of all ages and races throughout the U.S.

Despite the Roman Empire’s extensive military and cultural influence on the nearby Balkan peninsula, a DNA analysis of individuals who lived in the region between 1 and 1000 CE found no genetic evidence of Iron Age Italian ancestry. Instead, a study published December 7 in the journal Cell revealed successive waves of migrations from Western Anatolia, central and northern Europe, and the Pontic-Kazakh Steppe during the Empire’s reign.
From the 7th century CE onwards (coincident with the fall of the Western Roman Empire), large numbers of people emigrated from Eastern Europe, likely related to the arrival of Slavic-speaking populations, which resulted in present-day Balkan residents having 30%-60% Slavic ancestry seen in present-day Balkan peoples.
“We found this genetic signal of Slavic migration all across the Balkans,” says senior author and paleogenomicist Carles Lalueza-Fox of the Institute of Evolutionary Biology (IBE:CSIC-Universitat Pompeu Fabra) and Museu de Ciències Naturals de Barcelona. “This could have important social and political implications given that the Balkans has had a long history of conflict associated with their perceived identities.”
Most ancient DNA studies focus on pre-history — before the written record — but ancient DNA methods can also provide insight into more recent historical periods, especially when used in combination with historical and archeological information.
“Ancient DNA can give a lot of insight into historical periods, especially for regions where historical sources are scarce or when we don’t know whether sources are biased or not,” says first author and population geneticist Iñigo Olalde of the University of the Basque Country (UPV/EHU). “For example, most historical sources from the Balkans are written from the side of the Romans because the Slavic people didn’t write at that time.”
Previous studies have investigated the ancestry of people who lived in Italy and England during and after the fall of the Roman Empire, but little is known about demography and ancestry of the Balkans during this time. “This region was one of the distant frontiers of the Roman Empire, which makes it interesting to study because this is clearly a place where you would expect people to come in contact with people from outside the Empire, so you can test things such as globalization,” says Olalde.
To explore the population history of the Balkans and examine the influence of the rise and fall of the Roman empire, the researchers extracted DNA from 136 ancient individuals excavated from 20 different sites across the Balkans — defined as the region bounded by the Adriatic, Central Mediterranean, and Aegean Seas and the Middle and Lower Danube and Sava Rivers. These sites included large Roman cities, military fortresses, and small rural towns. The team focused on three periods: during the expansion and height of the Roman empire (1-250 CE), during the late Imperial period (circa 250-550 CE), and following the Western Empire’s collapse (550-1000 CE).

To provide cultural and historical context for the genetic data, the team collaborated with local archeologists and historians. For each grave, they documented burial type, as well as any objects buried alongside the individuals, such as coins, jewelry, pottery, tools, and weapons. The researchers also used radiocarbon dating to verify the age of 38 of the ancient individuals, which generated isotopic data that provide a window into those individuals’ diets.
The researchers were surprised to find no evidence of Italian Iron Age ancestry in the Balkan populations during the height of the Roman Empire. Instead, they showed that there was an influx of people from Western Anatolia, another part of the Roman Empire, during that period. They also found evidence of individual migrations into the Balkans from both within and outside the Roman Empire. Notably, a 16-year-old male who was excavated from a necropolis in a large Roman city was of 100% East African ancestry. The individual was buried with an oil lamp depicting Jupiter-related eagle iconography, but isotopic analysis of his teeth indicated that he had consumed marine protein sources during his childhood and therefore had likely grown up in a distant location.
“This was the only full Eastern African individual that we analyzed, and he was also a clear outlier with respect to the diet compared to the rest of the individuals buried in the same necropolis, which tells us that this individual clearly grew up outside the borders of the Roman Empire,” says Lalueza-Fox.
During the late Imperial period, between 250 and 550 CE, the researchers detected migrants with mixed ancestry from Northern Europe and the Pontic-Kazakh steppe. “We found that those two ancestries — central/northern European and Sarmatian-Scythian — tended to come together, which suggests that these are likely to have been multi-ethnic confederations of moving people,” says senior author and population geneticist David Reich of Harvard University.
However, these sources of ancestry disappeared after 700 CE. From 600 CE, shortly after the fall of the Western Roman Empire, there was a major influx of individuals from Eastern Europe. After 700 CE, individuals in the Balkans had very similar ancestral composition to present-day groups in the region, suggesting that these migrations resulted in the last large demographic shift in the area. These migrations coincide with recorded Slavic migrations, but the DNA analysis provides insight into the scale of these migrations that is impossible to glean from historical resources.
“There have been debates about how impactful these migrations were and to what extent the spread of Slavic language was largely through cultural influences or movements of people, but our study shows that these migrations had a profound demographic effect,” says Reich. “More than half of the ancestry of most peoples in the Balkans today comes from the Slavic migrations, with around a third Slavic ancestry even in countries like Greece where no Slavic languages are spoken today.”
The team are already planning what they call “version two” of the study, which will take advantage of improvements in ancient DNA technologies. “We are now able to sequence hundreds of individuals from the same site, so we can go to another level of resolution and start to understand more about the social interactions and kinship between the different individuals,” says Olalde.
This research was supported by the Spanish Ministry of Science of Innovation, ‘la Caixa” Foundation, the Natural Sciences and Engineering Research Council of Canada, the Ministry of Science and Education of the Republic of Croatia, the National Institutes of Health, the John Templeton Foundation, the Allen Discovery Center, the Paul G. Allen Family Foundation, and the Howard Hughes Medical Institute.

A groundbreaking study by researchers at Case Western Reserve University suggests a class of medications used to treat type 2 diabetes may also reduce the risk of colorectal cancer (CRC).
The findings, published today (Dec. 7) in the journal JAMA Oncology,support the need for clinical trials to determine whether these medications could prevent one of the deadliest types of cancers. Eventually, the medications may also show promise in warding off other types of cancer associated with obesity and diabetes.
“Our results clearly demonstrate that GLP-1 RAs are significantly more effective than popular anti-diabetic drugs, such as Metformin or insulin, at preventing the development of CRC,” said Nathan Berger, the Hanna-Payne Professor of Experimental Medicine at the Case Western Reserve School of Medicine and the study’s co-lead researcher.
Glucagon-like peptide-1 receptor agonists, or GLP-1 RAs, are medications to treat type 2 diabetes. Usually given by injection, they can lower blood-sugar levels, improve insulin sensitivity and help manage weight. They’ve also been shown to reduce the rates of major cardiovascular ailments.
Importantly the protective effect of GLP-1 RAs are noted in patients with or without overweight/obesity.
“To our knowledge,” said co-lead researcher Rong Xu, a professor at the School of Medicine, “this is the first indication this popular weight-loss and anti-diabetic class of drugs reduces incidence of CRC, relative to other anti-diabetic agents.”
Berger and Xu are members of the Case Comprehensive Cancer Center.

National health problem
Being overweight or obese or having diabetes are risk factors for increasing incidence of CRC and for making its prognosis worse.
The National Institutes of Health (NIH) defines being overweight and obese as an increase in size and amount of fat cells in the body above certain levels. These conditions are common nationally and are caused by several factors — among them diet, lack of sleep or physical activity, genetics and family history.
Healthcare providers use body mass index to measure body fat based on height and weight. Nearly 75% of adults ages 20 or older in the United States are either overweight or obese, and nearly 20% of children and teens ages 2 to 19 have obesity, according to the NIH.
Obesity is a chronic health condition that raises the risk for heart disease — the leading cause of death in the United States — and is linked to many other health problems, including type 2 diabetes and cancer.
The American Cancer Society estimates CRC is the third-leading type of cancer in both sexes, with 153,000 new cases per year. It is also the second-leading cause of cancer mortality with 52,550 deaths per year.

The study
Since GLP-1 RAs have been shown to be effective anti-diabetic and weight-loss agents, the researchers hypothesized they might reduce incidence of CRC.
Using a national database of more than 100 million electronic health records, the researchers conducted a population-based study of more than 1.2 million patients. These individuals had been treated with anti-diabetic agents from 2005-19; the CWRU team examined the effects of GLP-1 RAs on their incidence of CRC, as compared to those prescribed other anti-diabetic drugs.
Population-based research means matching as many people as possible with the same characteristics — sex, race, age, socio-economic determinants of health and other medical conditions — to accurately compare the drug’s effects.
Among 22,572 patients with diabetes treated with insulin, there were 167 cases of CRC. Another 22,572 matched patients treated with GLP-1 RAs saw 94 cases of CRC. Those treated with GLP-1 RAs had a 44% reduction in incidence of CRC.
In a similar comparison of 18,518 patients with diabetes treated with Metformin, compared to 18,518 patients with diabetes treated with GLP-1 RAs, had a 25% reduction in CRC.
“The research is critically important for reducing incidence of CRC in patients with diabetes,with or without overweight and obesity,” Berger said.

Post-surgery pain relief has shifted away from opioid-containing medications over the past seven years, but the downward trend has slowed since 2020, a new study shows.
Overall, the rate of surgery-related opioid prescriptions dropped by 36% from 2016 to the end of 2022, and the average amount of opioids in those prescriptions dropped by 46%, the study of pharmacy data finds.
That combination of declines means that the total amount of opioids dispensed to surgical patients in late 2022 was 66% lower compared with early 2016, according to the findings published in JAMA Network Open by a team from the University of Michigan.
But the rate of decline was much faster before the pandemic, the researchers report after comparing surgical opioid patterns before and after 2020. That’s even after they took into account the unusual circumstances of spring 2020, when most elective surgery temporarily stopped to free up hospital capacity for COVID-19 patients and reduce unnecessary exposure to the SARS-CoV-2 virus.
Even with the overall declines, American surgery patients in late 2022 still received the equivalent of 44 5-milligram pills of hydrocodone from pharmacies after their operations on average. That’s far higher than what patients need for most procedures.
“These data suggest surgical teams have substantially reduced opioid prescribing, but also suggest that efforts to right-size opioid prescriptions after surgery must continue,” said Kao-Ping Chua, M.D., Ph.D., the senior author of the new study and an assistant professor of pediatrics at U-M. He worked with first author and former U-M research assistant Jason Zhang, who is now in medical school at Northwestern University.
The researchers also find that some types of surgeons have reduced the amount of opioids dispensed to patients more than others. For instance, reductions were particularly large in cardiothoracic surgery and ophthalmology.

Orthopedic surgeons still account for more than half of all surgical opioids dispensed to American patients, even as the rate and size of prescriptions filled by their patients dropped.
Right-sizing prescribing
The authors note that surgeons should not strive to eliminate opioid prescribing altogether.
“The goal should be to ensure that opioids are only prescribed when necessary, and that the amount of opioids prescribed matches the amount that patients need,” said Zhang. “Achieving these goals could help reduce the risk of opioid misuse, persistent opioid use, and diversion of pills to other people besides the patient.”
The potential for accidental exposure to opioids by others in the household, and interactions between opioids and other substances including alcohol and prescription drugs, are other reasons to focus on non-opioid surgical pain care.
Chua and colleagues have studied procedure-related opioid prescribing multiple times, including a recent study showing that the reduction in the rate of dental opioid prescribing has similarly slowed in recent years.

They have worked with the Michigan Opioid Prescribing Engagement Network (OPEN) to develop prescribing guidelines for adult and pediatric surgical care available at https://michigan-open.org/prescribing-recommendations
Surgical organizations and the Centers for Disease Control and Prevention have advised surgeons to rely less on opioid-based acute pain relief for their patients since the mid-2010s. But no studies have examined surgical opioid prescribing trends using pandemic-era data.
The new study is based on data from a company called IQVIA that tracks prescriptions dispensed at 92% of U.S. pharmacies.
In addition to Chua and Zhang, the study’s authors include OPEN co-directors Jennifer Waljee, M.D., M.P.H., M.S. and Chad Brummett, M.D. All except Zhang are members of the U-M Institute for Healthcare Policy and Innovation, and Brummett co-directs the U-M Opioid Research Institute.
Chua is a member of the Susan B. Meister Child Health Evaluation and Research Center in the Department of Pediatrics, which also provided some of the funding for the study.
The study reported in this press release was funded by the National Institute on Drug Abuse of the National Institutes of Health (DA057284, DA056438, DA048110), the Benter Foundation and the Michigan Department of Health and Human Services. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.