JAMA has released its inaugural Research of the Year collection, featuring nine studies published between October 2024 and September 2025 that editors identified as the most impactful, newsworthy, and novel contributions to medical science.
Kirsten Bibbins-Domingo, PhD, MD, MAS, Editor-in-Chief at JAMA, and Gregory Curfman, MD, Executive Editor at JAMA selected the final studies from nominations by the journal's top editors. "They speak to really hot areas in research right now and to clinical conditions that are of great importance to patients, to clinicians, and to the public health community," said Dr. Bibbins-Domingo. "They also speak to the range of methods that investigators are using to answer important questions," she added.
GLP-1 Receptor Agonists Reduce Heart Failure Mortality
In an observational analysis of US health care claims data, investigators demonstrated that patients with obesity-related heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes who initiated semaglutide or tirzepatide had greater than a 40% lower risk of hospitalization for heart failure or all-cause mortality compared with those using sitagliptin as a placebo proxy.
The observational design allowed for a larger and more diverse patient population than typical randomized clinical trials, involving more than 58,000 participants and exemplifying how real-world evidence can complement randomized trial findings. Head-to-head comparison revealed that tirzepatide, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide (GLP)-1 receptor agonist, offered no meaningful benefit over semaglutide in minimizing heart failure risks.
GLP-1 receptor agonists are "dramatically influencing medical practice and public health" beyond weight loss, said Mary McDermott, MD, Deputy Editor at JAMA. "[The] results from this study will have wide-ranging implications for the millions of patients with HFpEF," she stated.
The study authors noted that their results reinforced the role of GLP-1–based therapies "beyond previously established benefits in the evolving management of cardiometabolic [diseases]."
Shingles Vaccination Associated With Lower Dementia Risk
In an Australian observational study involving more than 100,000 participants, researchers found that eligibility for shingles vaccination was associated with nearly a 2–percentage point lower probability of new dementia diagnosis over approximately 7 years compared with ineligibility.
The researchers leveraged natural randomization created when Australia's National Immunisation Programme began offering free live-attenuated herpes zoster vaccines (Zostavax) to individuals aged 70 to 79 years on November 1, 2016. Thosse born on or after November 2, 1936, were eligible, whereas, those born before weren't.
By comparing individuals based on birthday-based eligibility rather than vaccination choice, the researchers addressed healthy vaccinated individual bias—the tendency for those who choose vaccination to be healthier overall than those who don't. The researchers concluded that shingles vaccination "is a low-cost, high-reward intervention to reduce the burden of dementia."
The study "raises all kinds of questions about the role of viral infection" and its findings are "one more reason to get vaccinated," said Preeti Malani, MD, Deputy Editor at JAMA.
AI Evaluations in Medicine Found Inadequate
In a systematic review of more than 500 studies published between 2022 and early 2024, investigators found that evaluations of large language models (LLM) in health care settings are "fragmented and insufficient," with only 5% of them using real patient data.
Most studies centered on assessing medical knowledge through licensing examination questions and clinical diagnoses. Administrative tasks such as writing prescriptions, assigning billing codes, and clinical note-taking received much less attention despite contributing to physician burnout.
The analysis is a "very timely assessment of LLM evaluation in clinical workflows" and future research should "prioritize real patient care data in evaluations to ensure alignment with real-world conditions," said Linda Brubaker, MD, Deputy Editor at JAMA.
The investigators highlighted six major shortcomings and provided recommendations, including using real patient data, quantifying biases, and prioritizing high-value administrative tasks.
Newborn Genome Sequencing Detects Treatable Conditions
In the GUARDIAN study, researchers demonstrated that targeted genome sequencing analysis is feasible and can improve health outcomes through early detection of treatable conditions beyond standard newborn screening capabilities.
Interim findings from 4,000 patients at six New York City hospitals showed the approach "can identify newborns with conditions that may otherwise be clinically undetected until symptom onset," said Dr. Brubaker.
Seventy-two percent of approached families consented to participate, and 91% of enrollees agreed to participate in optional neurodevelopmental disorder screening, demonstrating high acceptance. Nearly 4% received positive screening results. Among the 120 newborns with true positive findings, 92% had confirmed diagnoses for conditions not included in standard newborn screening.
Conditions detected through genome sequencing alone included long QT syndrome, Wilson disease, and severe combined immunodeficiency disorder. In one case, early detection enabled successful bone marrow transplantation.
The ongoing study aims to enroll 100,000 infants. Newborn genome sequencing is "nearing potential clinical utility," given declining DNA sequencing costs and growing parental acceptance, Dr. Brubaker added.
Structured Lifestyle Intervention Improves Cognition
In the US POINTER trial, researchers randomly assigned approximately 2,100 older adults at risk of dementia to follow either structured or self-guided lifestyle interventions addressing physical activity, cognitive activity, social engagement, cardiovascular health, and diet.
Both groups improved cognitively over 2 years, but the structured intervention group—which participated in 38 team meetings vs six in the self-guided group—demonstrated significantly greater cognitive enhancement.
Patients with lower baseline cognition benefitted more from intervention. Cognitive benefits were equivalent for carriers and noncarriers of APOE epsilon4, a major genetic risk factor for Alzheimer's disease.
The trial is important in confirming "the benefits of a structured multidomain lifestyle intervention in a US population of older adults at risk of cognitive decline or dementia, including those from racial and ethnic groups often underrepresented in dementia clinical trials," noted Christopher Muth, MD, Deputy Editor of JAMA.
The researchers acknowledged that the absence of a no-intervention control group limited their ability to rule out alternative explanations such as practice effects from repetitive testing.
Liberal Transfusion Threshold Benefits Patients With Brain Injury
In the TRAIN randomized clinical trial, researchers demonstrated that the liberal red blood cell transfusion strategy improves neurologic outcomes in patients with acute brain injury.
The multicenter phase III trial included approximately 800 patients with acute brain injury and hemoglobin levels below 9 g/dL within 10 days of injury. The patients received either liberal transfusion (triggered by hemoglobin levels less than 9 g/dL) or restrictive transfusion (hemoglobin levels less than 7 g/dL).
After 6 months, 63% of the patients in the liberal group had unfavorable neurologic outcomes vs 73% of those in the restrictive group. Cerebral ischemic events occurred in 9% of the liberal group compared with 14% of the restrictive group.
"Prior to TRAIN, transfusion thresholds in neurocritical care were based on limited or extrapolated data, and the optimal approach for brain-injured patients was controversial due to conflicting results from smaller studies and meta-analyses," stated Philip Greenland, MD, Senior Editor at JAMA.
Dr. Greenland predicted that the TRAIN trial may "actually change practice" based on its findings and high citation rate.
Active Monitoring Noninferior to Surgery for Low-Risk DCIS
In the COMET trial, researchers compared active monitoring with guideline-concordant care in nearly 1,000 women aged 40 years or older with newly diagnosed hormone receptor–positive, ERBB2-receptor negative, low-risk ductal carcinoma in situ (DCIS).
After a follow-up of 2 years, the cumulative ipsilateral invasive cancer rate was 4.2% in the active monitoring group vs 5.9% in the guideline-concordant care group, achieving noninferiority. Invasive tumor characteristics didn't differ significantly between the groups.
Approximately 10% of the patients receiving standard care underwent mastectomy vs less than 2% in the active monitoring group.
"Over the years, practitioners and patients have had concerns that DCIS is overtreated, resulting in unnecessary morbidity and cost," stated Mary L. Disis, MD, Deputy Editor at JAMA. The data "suggest that active monitoring could be an option for some women with DCIS to avoid more extensive surgical and medical treatments," she continued.
Novel HBV Vaccine Superior in Patients With HIV
The BEe-HIVe trial demonstrated that the hepatitis B virus (HBV) vaccine with cytosine phosphoguanine adjuvant (HepB-CpG) provided superior seroprotection compared with the conventional aluminum hydroxide adjuvant vaccine (HepB-alum) in patients with human immunodeficiency virus (HIV) who were nonresponsive to prior vaccination.
The phase III trial included nearly 600 adult patients with HIV across 41 sites in 10 countries receiving antiretroviral therapy. The results showed that 93% of the participants receiving two HepB-CpG doses and 99% of those receiving three doses achieved protective antibody levels against the virus compared with 81% of those receiving three HepB-alum doses. The HepB-CpG vaccine also elicited more rapid response.
The trial "provides evidence to try this approach in other patients who do not respond to a series of HepB vaccine," noted Dr. Malani. The findings could potentially help extend protection to additional immunocompromised patients, older adults, smokers, and individuals with diabetes or obesity.
Lorundrostat Reduces Treatment-Resistant Hypertension
In the international Launch-HTN phase III trial, researchers showed that lorundrostat, a first-in-class aldosterone synthase inhibitor, reduced blood pressure when added to existing antihypertensive regimens.
The researchers enrolled more than 1,000 adult participants with uncontrolled hypertension taking two to five antihypertensive drugs. The participants received lorundrostat 50 mg daily (some escalating to 100 mg) or placebo for 12 weeks.
At 6 weeks, lorundrostat reduced systolic blood pressure by 16.9 mmHg compared with 7.9 mmHg for placebo. Although hyponatremia, hyperkalemia, and reduced kidney function occurred more frequently with lorundrostat, discontinuation rates as a result of adverse events were less than 1%.
"This agent opens a new approach to the treatment of uncontrolled hypertension, which may affect up to 40% of patients," said Dr. Curfman.
Unlike existing aldosterone blockers that obstruct the hormone's receptor, lorundrostat inhibits the enzyme producing aldosterone itself, representing a novel mechanism of action for patients who have exhausted conventional options.
Disclosures can be found in the published article.
Source: JAMA
