Radically different
Nature Medicine, Published online: 13 May 2026; doi:10.1038/s41591-026-04386-7
As presented at the European Congress on Obesity, this randomized, placebo-controlled trial demonstrates that oral orforglipron, a nonpeptide GLP-1 receptor agonist, preserves weight loss and cardiometabolic benefits achieved with injectable GLP-1 receptor agonist therapies, making it a viable oral maintenance strategy.
Nature Medicine, Published online: 13 May 2026; doi:10.1038/s41591-026-04394-7
In a randomized trial, pasteurized Akkermansia muciniphila improved weight loss maintenance and metabolic health after a low-energy diet, especially in individuals with initially lower Akkermansia levels. The work suggests leveraging gut A. muciniphila as a potential target for weight management.
Prescribing low-dose digoxin for patients with heart failure may reduce hospitalizations and cardiovascular complications when the drug is added to current guideline-directed therapy, according to three studies led by researchers at the University Medical Center Groningen (UMCG). The findings, published in Nature Medicine, showed that a meta-analysis combining data from the DECISION clinical trial with two earlier randomized studies found hospitalizations were reduced by 25% achieved by a reduction in worsening heart failure events.
Heart failure affects roughly 60 million people worldwide. Standard treatments currently rely on four medications commonly referred to as the “Fantastic Four.” The Groningen investigators examined whether digoxin, a drug that has been used for centuries in cardiovascular medicine, could serve as an additional therapy alongside those treatments.
The core study in the newly published research was the randomized, double-blind, placebo-controlled DECISION trial, which enrolled 1,000 patients with symptomatic chronic heart failure and a left ventricular ejection fraction of 50% or less at 43 centers in the Netherlands. Participants received either low-dose digoxin (600) or placebo (400) in addition to standard therapy with a median follow-up of 36.5 months.
The trial found that low-dose digoxin reduced the combined rate of worsening heart failure events and cardiovascular mortality by 19%, a figure that was not statistically significance. But when these data were then combined with two earlier randomized trials that evaluated digitalis glycosides—the same class of drugs as digoxin—in heart failure, the pooling of data from the three studies was able to demonstrate a statistically significant benefit.
The data from DECISION showed 238 primary outcome events among patients receiving digoxin compared with 291 events in the placebo group. The number of worsening heart failure events was also lower in the digoxin arm, with 155 events compared with 203 among placebo-treated patients.
One of the earlier studies, the DIG trial, published in 1997, had researched digoxin in patients receiving diuretics and angiotensin-converting enzyme inhibitors. While this combination did not reduce all-cause mortality, it demonstrated a 28% reduction in hospitalization for worsening heart failure. Subsequent analyses of the DIG data also suggested that lower serum digoxin concentrations were associated with more favorable outcomes, while higher concentrations above 1.2 ng ml−1 were linked to increased mortality.
The other earlier study, DIGIT-HF, had evaluated low-dose digitoxin added to contemporary heart failure therapy. In this study, the researchers reported a 15% reduction in the combined endpoint of all-cause death and first hospitalization for heart failure.
The third and current study from the Groningen researchers followed about 600 patients who had participated in the DECISION clinical trial after study treatment ceased. In this case, the team found that patients who discontinued digoxin experienced more problems during the first six weeks after withdrawal than patients who had never received the drug. Among 288 patients who stopped digoxin, 14 were hospitalized or died.
The studies all focused on low-dose digoxin because earlier analyses had suggested that lower serum concentrations of the drug produced benefit without the adverse effects created by higher dosing levels. In the past, higher doses were used to increase heart muscle contraction, but the researchers found that this approach was not beneficial in weakened hearts. Instead, lower doses appear to blunt adverse compensatory responses in heart failure.
The DECISION study also provided new randomized data regarding the safety of low-dose digoxin in women and in patients with atrial fibrillation, populations that had been considered at risk from higher doses. The investigators reported that low-dose digoxin did not increase adverse effects or pacemaker implantation and produced similar findings in men and women.
These new data could change heart failure guidelines in the future by including the use of digoxin as an additional therapy in patients with reduced or mildly reduced ejection fraction. Further, because digoxin therapy costs less than ten cents per day, it could offer a low-cost treatment option compared with newer therapies that cost several dollars daily.
The researchers said future work should further define which heart failure populations benefit most from low-dose digoxin and continue evaluating its role alongside contemporary guideline-directed therapies, including sodium-glucose cotransporter-2 inhibitors and other newer agents.
The post Low‑Dose Digoxin Shows Benefit in Heart Failure Treatment appeared first on Inside Precision Medicine.
Fractyl Health has received regulatory approval in the Netherlands to start the first-ever clinical trial for a gene therapy to treat type 2 diabetes. The upcoming Phase I/II clinical trial will test the safety and preliminary efficacy of RJVA-001, a gene therapy designed to locally deliver GLP-1 receptor agonist drugs with the goal of reducing the side effects associated with oral administration.
“GLP-1 medicines have changed what is possible in obesity and type 2 diabetes, but they require chronic, high-dose systemic exposure that many patients cannot or do not sustain,” said Harith Rajagopalan, MD, PhD, co-founder and CEO of Fractyl Health. “RJVA-001 takes a different path: a potential one-time, pancreas-targeted gene therapy designed to enable the body to produce GLP-1 in response to meals: physiology, not pharmacology.”
Based in Burlington, Massachusetts, Fractyl Health develops novel approaches to treating obesity and type 2 diabetes. The company’s lead program, an endoscopic procedure to maintain weight loss after discontinuing GLP-1 treatment for obesity, is currently being evaluated in a pivotal clinical trial.
RJVA-001 leverages an engineered version of the human insulin promoter to trigger the production of GLP-1 in pancreatic beta cells when glucose levels rise after eating. The gene therapy is delivered using a minimally invasive endoscopic infusion directly into the pancreas, which is guided by ultrasound.
The Phase I/II study will evaluate the safety, tolerability, and preliminary efficacy of three escalating doses of the gene therapy. Participants will include adults with type 2 diabetes who have previously responded well to oral GLP-1 treatment yet continue to experience difficulties controlling their blood sugar levels.
“With this authorization, RJVA-001 becomes the first AAV gene therapy candidate to enter clinical development for type 2 diabetes,” said Rajagopalan. “We expect to dose the first patient and report initial data in the second half of 2026.”
Later this year, Fractyl expects to expand the study to additional sites in Australia, where the company has already submitted a clinical trial application and is currently awaiting a response from regulators.
RJVA-001 will be the first candidate from Fractyl’s Rejuva platform to enter clinical development. This smart GLP-1 gene therapy platform focuses on the development of next-generation adeno-associated virus (AAV)-based gene therapies that are locally delivered to the pancreas. Another candidate developed through this platform includes a dual GIP/GLP-1 gene therapy to treat obesity, currently in preclinical development.
“For decades, we have managed [type 2 diabetes] as a chronic, progressive disease that inevitably worsens over time. With this authorization, we are preparing to test, for the first time in humans, whether a one-time, pancreas-targeted gene therapy delivered via a routine endoscopic procedure could provide durable metabolic control by enabling physiologic, nutrient-responsive GLP-1 expression at the source of disease,” said Jacques Bergman, MD, PhD, professor of gastrointestinal endoscopy and deputy chair of the department of gastroenterology and hepatology at Amsterdam UMC, and a principal investigator of the upcoming clinical trial.
“Patients who remain inadequately controlled despite maximally tolerated GLP-1 receptor agonists and multiple oral agents represent a population with significant unmet need. If successful, RJVA-001 could transform how we think about [type 2 diabetes], from a chronic disease you manage every day to one that could potentially be treated once.”
The post First Clinical Trial for a GLP-1 Gene Therapy Greenlit in Europe appeared first on Inside Precision Medicine.
Nature Medicine, Published online: 12 May 2026; doi:10.1038/s41591-026-04362-1
In a first-in-human trial combining the transplantation of CD33-negative CRISPR-edited hematopoietic cells with the CD33-targeted antibody–drug conjugate gemtuzumab ozogamicin, all transplanted patients achieved primary engraftment, and the treatment was well tolerated.
Nature Medicine, Published online: 10 May 2026; doi:10.1038/s41591-026-04408-4
As presented at the 2026 ESC Heart Failure Congress, in a phase 2 randomized trial in patients with heart failure with reduced left ventricular ejection fraction after myocardial infarction, treatment with CDR132L, an antisense oligonucleotide inhibitor of miR-132, was well tolerated but did not have a significant effect on measures of left ventricular structure or function.
Background: Marijuana initiation among adults aged 50 years and older has increased substantially. Although acute tetrahydrocannabinol exposure can impair psychomotor function, less is known about how real-world medical marijuana initiation relates to functional tasks such as driving in mid-to-late life. Objective: The objective of our study was to evaluate the feasibility of recruiting and retaining adults aged 50 years and older, who are newly registered for medical marijuana, and matched non–marijuana-using controls, into a longitudinal high-fidelity driving simulator protocol, and to explore preliminary associations between medical marijuana initiation and simulated driving performance. Methods: This prospective, nonrandomized feasibility cohort study enrolled adults aged 50 years and older who are newly registered in the Florida Medical Marijuana Use Registry, along with age-, race-, and sex-matched controls. Assessments occurred at baseline (T1; preinitiation) and at 1 month (T2). Primary feasibility outcomes included recruitment, retention, simulator completion and tolerance, and exposure verification. Exploratory outcomes included reaction time and divided attention (DA) performance, which are measured using an immersive, high-fidelity driving simulator. Results: Recruitment and exposure verification procedures were feasible, but simulator sickness contributed to substantial missing data. Exploratory analyses suggested group differences in select DA outcomes at T2. At T2, reaction time to DA situation 3 (DA3) was significantly shorter in the medical marijuana group (n=14, mean 2.57, SD 1.63) than in the control group (n=7, mean 5.79, SD 4.32; =−2.50, =.02, =−1.11, 95% CI −2.04 to −0.16). These findings should be interpreted cautiously, given the small sample size, missing data, and multiple comparisons. Conclusions: A prospective protocol examining medical marijuana initiation and simulated driving among mid-to-late-life adults is feasible, but future studies should incorporate design and analytic refinements to address simulator sickness and missing data and to better characterize exposure timing and patterns. Trial Registration: ClinicalTrials.gov NCT04629716; https://clinicaltrials.gov/study/NCT04629716
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Background: Society faces multiple challenges, including lifestyle diseases and global climate change. Framing health education within sustainable development may enhance motivation for behavior change because proenvironmental behaviors, as well as healthy behaviors, often rely on the same behavior change principles. Combining these perspectives may therefore reinforce health behaviors and climate-friendly choices. Objective: This pilot study aims to explore changes in dietary intake, diet-related carbon footprint, and physical activity among office workers receiving sustainable plus healthy lifestyle (sustainable lifestyle arm) or healthy lifestyle education (healthy lifestyle arm) alone. It also aims to assess the feasibility of the intervention functions, including workshop attendance rate, participants’ dietary goals, social support, and facilitators and barriers to behavior change. Methods: A 2-armed participant-blinded cluster randomized study, including an experimental intervention arm (sustainable lifestyle; n=19) and a control intervention arm (healthy lifestyle; n=14), was conducted in Sweden. The study lasted 8 weeks and included 6 workplace-based workshops and was framed by the behavioral change wheel and the socioecological model. Diet, carbon footprint, and physical activity were assessed using the web-based questionnaires Meal-Q and Active-Q. Attendance rate, individual goals, social support, and facilitators and barriers were assessed using printed questionnaires. Results: The reduction of total diet-related carbon dioxide equivalents (COe) was 0.8 kg and 0.4 kg per day for the sustainable and healthy lifestyle arm, respectively. Also, there was a statistically significant interaction between time and lifestyle when the carbon footprint was expressed as a qualitative aspect of diet, that is, COe kg per 1000 kcal per day (=.05). Moreover, the intake of vitamin C, a marker for fruits and vegetables, increased to 8.0 and 12.5 mg per 1000 kcal per day for the sustainable and healthy lifestyle arms, respectively. In addition, total sedentary time decreased by 0.4 hours per day in the sustainable lifestyle arm, but not in the healthy lifestyle arm. This indicates that the educational workshops in respective arms had different impacts on health behavior over time. Minor differences were found in dietary goals, with the sustainable lifestyle arm setting more goals related to ecological and vegetarian foods. No differences were seen between arms regarding barriers or facilitators. Conclusions: This study suggests that embedding healthy lifestyle recommendations within a sustainable development context may be an efficient way to reduce carbon footprint and increase healthy behavior among office workers. Given the ongoing global epidemic of metabolic diseases, climate change, and environmental degradation, promoting a sustainable lifestyle in a workplace context has the potential to counteract these trends. Trial Registration: ClinicalTrials.gov NCT06698094; https://clinicaltrials.gov/study/NCT06698094
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