GLP-1 diabetes drugs likely trump metformin for curbing dementia risk in type 2 diabetes, study finds

In continuation of my update  "Metformin"

GLP-1 receptor agonists, a class of drug used to treat type 2 diabetes, likely trump the widely prescribed metformin for curbing dementia risk in people with the condition, finds the largest study of its kind, published in the open access journal BMJ Open Diabetes Research & Care.

The findings suggest that future clinical guidelines for the treatment of type 2 diabetes would do well to consider prioritizing drugs with both blood glucose and neuroprotective effects, say the researchers.

Published research suggests that both GLP-1 receptor agonists and metformin, which are widely used to treat type 2 diabetes, protect the brains of people with the disease. But as yet there have been no direct real-world comparisons of the potential impact of these drugs on dementia risk—a risk that is around 70% higher in people with type 2 diabetes.

To explore this further, the researchers drew on anonymized electronic health records from a global health research network (Trinetx) spanning the period 2004 to 2024 to track the development of dementia in patients with type 2 diabetes, treated with either GLP-1 receptor agonists or metformin (87,229 patients in each group; average age 58) for at least six consecutive months.

There was no significant difference in vascular dementia risk between the two types of drug when used as first line therapy.

But GLP-1 receptor agonist use was associated with a significantly lower cumulative (10%) risk of developing dementia, overall, with an incidence of almost 2.5% (2,130 people) compared with an incidence of nearly 5% (4,215 people) for metformin.

And specifically, taking this type of drug was associated with a 12% lower risk of developing Alzheimer's disease, and a 25% lower risk of developing non-vascular dementias than metformin use.

Further in-depth analyses showed that these positive effects were evident across all age groups, but with the strongest effect among the over 60s, women, and those of white ethnicity.

Risk of death from any cause was also lower: nearly 5% of those treated with GLP-1 receptor agonists died compared with nearly 9% of those treated with metformin.

"Both medications demonstrate neuroprotective properties, such as reducing neuroinflammation and oxidative stress, improving insulin sensitivity, and enhancing cerebrovascular health, which likely contribute to their benefits in overall dementia," explain the researchers.

But unlike metformin, whose benefits primarily derive from systemic metabolic effects, GLP-1 receptor agonists exert direct central nervous system effects by crossing the blood-brain barrier, they add.

"However, the multifactorial nature of [vascular dementia], driven by cerebrovascular damage, such as small vessel disease and white matter lesions, poses significant challenges for pharmacological interventions targeting metabolic or neurodegenerative pathways," they continue.

This is an observational study, and as such, no firm conclusions can be drawn about cause and effect. And the researchers point out that the tracking period, while sufficient for observing dementia outcomes, may not fully capture long-term cognitive effects, especially given the progressive nature of Alzheimer's disease.

But they nevertheless conclude, "Given the severe societal, familial, and economic burden of diabetes-related dementia, these findings raise important considerations about the role of GLP-1 [receptor agonists] as first-line therapies in [type 2 diabetes] management.

"While further long-term studies are warranted to validate these results, integrating GLP-1 [receptor agonists] as primary therapeutic agents may represent a paradigm shift in preventing the cognitive complications of diabetes."

Ref: https://en.wikipedia.org/wiki/Metformin

FDA Approves Ibtrozi (taletrectinib) for Advanced ROS1-Positive Non-Small Cell Lung Cancer

Nuvation Bio Inc. announced the U.S. Food and Drug Administration (FDA)  approval of  Ibtrozi (taletrectinib) for the treatment of adult patients with locally advanced or metastatic ROS1-positive (ROS1+) non-small cell lung cancer (NSCLC). Ibtrozi is a highly selective, next-generation oral ROS1 tyrosine kinase inhibitor (TKI) designed to address some of the outstanding challenges of treating ROS1+ NSCLC. It has demonstrated high response rates with durable benefit and intracranial activity and is generally well tolerated, providing a new treatment option for patients with advanced ROS1+ NSCLC.

“The FDA approval of Ibtrozi marks a major milestone in the evolution of targeted therapy for advanced ROS1-positive NSCLC,” said David Hung, M.D., Founder, President and Chief Executive Officer of Nuvation Bio. “We believe one of the greatest threats to ROS1-positive lung cancer patients is disease progression, especially in the first-line setting. In pivotal trials, Ibtrozi delivered high response rates with sustained durability—truly meaningful benefits for patients. With its clinically proven efficacy and safety profile, we believe Ibtrozi has the potential to become a new standard for what targeted therapies can achieve in this type of lung cancer. With approvals for Ibtrozi now in the U.S. and China, and additional global filings underway, we remain committed to delivering innovative therapies that help patients stay ahead of their disease.”

ROS1+ NSCLC is a rare and aggressive form of lung cancer, accounting for approximately 2% of new NSCLC cases, or about 3,000 new diagnoses of advanced disease annually in the U.S. The median age at diagnosis for patients with this type of lung cancer is approximately 50 years old, and the disease is more likely to occur in people who have never smoked. Brain metastases are common and a leading cause of disease progression and mortality in this population.

“For people living with advanced ROS1-positive lung cancer, who tend to be diagnosed at a younger age, having another treatment option can make a real difference for them and their loved ones,” said Janet Freeman-Daily, Co-Founder and President of The ROS1ders. “The approval of this new targeted therapy is a meaningful step forward for the advanced ROS1+ lung cancer community and offers hope for patients facing the added challenge of cancer spreading to the brain.”

The FDA approval of Ibtrozi is supported by one of the largest global clinical trial programs in ROS1+ NSCLC to date, with over 300 patients enrolled in the pivotal TRUST-I and TRUST-II studies.

In TRUST-I, Ibtrozi achieved a confirmed overall response rate (cORR) of 90% in TKI-naïve patients. These findings were reinforced by the TRUST-II results, with a cORR of 85% in TKI-naïve patients. The median duration of response (DOR) was not yet reached for either trial, based on a cutoff date that is nearly five months later than that of the pooled TRUST-I and TRUST-II analysis published in April in the Journal of Clinical Oncology. For TRUST-I, with a median follow-up for responses of 40 months, the longest DOR was observed at 46.9 months and ongoing. For TRUST-II, with a median follow-up for responses of 19 months, the longest DOR was observed at 30.4 months and ongoing as of October 2024. Given the single-arm nature of the TRUST clinical studies, median progression-free survival (PFS) is not provided in the label.

Across the pivotal studies, consistent results were also observed among patients who were previously treated with a ROS1 TKI (TKI-pretreated). In TRUST-I, treatment with Ibtrozi achieved a cORR of 52% and median DOR of 13.2 months for TKI-pretreated patients, with median follow-up for responses of 33 months. In TRUST-II, treatment with Ibtrozi achieved a cORR of 62%, and as of October 2024 the median DOR was 19.4 months in these patients, with a median follow-up for responses of 19 months.

Brain metastases are among the most common and devastating complications in advanced ROS1+ NSCLC. Ibtrozi was designed to penetrate the central nervous system (CNS) and has demonstrated consistent intracranial responses in patients with measurable brain metastases at baseline. An intracranial response was achieved in 73% of TKI-naive patients (11/15) and 63% of TKI-pretreated patients (15/24).

“Patients living with advanced ROS1+ non-small cell lung cancer and their healthcare providers are in need of new treatment options,” added Nathan Pennell, M.D., Ph.D., TRUST study investigator and Professor of Medicine at the Cleveland Clinic. “Ibtrozi’s durability of response and ability to effectively penetrate the brain, coupled with a well-characterized and manageable safety profile, further addresses these critical needs for patients. I believe this now-approved therapy offers providers and patients a promising new option for the treatment of advanced ROS1+ non-small cell lung cancer.” Dr. Pennell is a compensated member of Nuvation Bio’s advisory committee.

Ibtrozi was generally well-tolerated, with most adverse events being low grade, transient and manageable. Patients infrequently (7%) discontinued treatment due to treatment-emergent adverse events (TEAEs). The most common adverse reactions (≥20%) included diarrhea (64%), nausea (47%), vomiting (43%), dizziness (22%), rash (22%), constipation (21%), and fatigue (20%). Overall, the majority of CNS events were mild to moderate (~90%) and resolved within days, and dose modifications due to these events were low (~5%). Approximately 90% of reported cases of dizziness were Grade 1 (mild) and transient. Liver enzyme elevations (AST 87%/ALT 85%) and QT prolongation (19%) were manageable with standard monitoring and dose modifications. Ibtrozi is approved as a 600 mg once-daily oral dose, supported by a half-life of approximately 66 hours and broad tissue distribution, including the brain, enabling sustained systemic and CNS exposure.

FDA Approves Ibtrozi (taletrectinib) for Advanced ROS1-Positive Non-Small Cell Lung Cancer

FDA Approves Zusduri (mitomycin) for Recurrent Low-Grade Intermediate-Risk Non-Muscle Invasive Bladder Cancer

UroGen Pharma Ltd. announced the U.S. Food and Drug Administration (FDA) approval of  Zusduri, the first and only FDA-approved medication for adults with recurrent LG-IR-NMIBC. Zusduri consists of mitomycin and sterile hydrogel, using UroGen’s proprietary sustained release RTGel® technology. Zusduri has been designed for potent tumor ablation. This landmark approval is based on the positive results from the Phase 3 ENVISION trial that demonstrated Zusduri delivers 78% complete response (CR) for patients at 3 months, and of those patients 79% remained event-free 12 months later.

“The approval of Zusduri represents a significant step forward for our company and for the treatment of recurrent LG-IR-NMIBC," said Liz Barrett, President and CEO of UroGen. "For the first time, the estimated 59,000 U.S. patients facing recurrent LG-IR-NMIBC each year have access to an FDA-approved medicine. This historic achievement is a bold leap forward in our mission to redefine uro-oncology and bring innovation to patients who need it most. We are deeply grateful to the FDA for their collaboration and to the investigators, patients, and caregivers whose commitment made this milestone possible. Their contributions have been essential in bringing meaningful innovation to the bladder cancer community.”

The existing standard of care for LG-IR-NMIBC is a surgical procedure typically performed under general anesthesia called transurethral resection of bladder tumor (TURBT). Due to high recurrence rates of LG-IR-NMIBC, repeat TURBTs may be necessary.

"Zusduri marks a breakthrough in uro-oncology, offering a new alternative for recurrent LG-IR-NMIBC patients who can live for many years with the disease but often endure multiple resections, under general anesthesia,” said Dr. Sandip Prasad, MD, M.Phil., Director of Genitourinary Surgical Oncology at Morristown Medical Center/Atlantic Health System, NJ, and principal investigator of the ENVISION trial. “For decades, TURBT has been the standard approach for bladder cancer treatment. That’s why innovative treatments like Zusduri are essential, especially for those adult patients with recurrent low-grade, intermediate-risk NMIBC.”

The most common (≥ 10%) adverse reactions, including laboratory abnormalities, that occurred in patients were increased creatinine, increased potassium, dysuria, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, increased eosinophils, decreased lymphocytes, urinary tract infection, decreased neutrophils, and hematuria. Serious adverse reactions occurred in 12% of patients who received Zusduri, including, urinary retention (0.8%) and urethral stenosis (0.4%).

REF ;https://en.wikipedia.org/wiki/Mitomycins