Any speaker presenting on oral medications used for the treatment of overactive bladder (OAB) knows that, for the discussion to be complete, there must be a section on reports of cognitive dysfunction following the use of anticholinergic medications. Strong articles appeared in JAMA Internal Medicine in 2015 and JAMA Neurology in 2016, and there have been numerous articles supporting this concept since that time, including position papers by both AUGS and SUFU.
A few studies have looked at specific individual drugs, although most have not. Sheyn and associates, from the Urology and Research Education Institutes at University Hospitals in Cleveland, the Center for Brain Health at the Cleveland Clinic, the Department of Neurology at the University of Cincinnati, and the Departments of Obstetrics and Gynecology at Northwestern University and the University of Louisville, used a different data set — the TriNetX Research Collaborative Network — to retrospectively compare the risk of incident dementia among patients prescribed either an anticholinergic medication or mirabegron for OAB.
The anticholinergic medications evaluated included oxybutynin, tolterodine, darifenacin, trospium, fesoterodine, and solifenacin. Vibegron had not yet achieved broad use at the time the data were collected.
The data set included 83,550 subjects, with an average follow-up time of 4.3 years. Patients had to be on the OAB medication for a minimum of 12 months. The data were adjusted for age, sex, comorbidity index, anticholinergic burden score, and average treatment effect. The risk of each medication on incident dementia was then determined. A control group was included, consisting of patients with an OAB diagnosis who were not receiving OAB medication. Patients with a number of preexisting conditions were excluded. Dementia diagnosis was assessed through the prescription of dementia medication and/or the diagnosis of dementia.
Patients were grouped into one of four cohorts:
- High-risk anticholinergic group: oxybutynin, tolterodine, solifenacin
- Low-risk anticholinergic group: darifenacin, fesoterodine, trospium
- Mirabegron group
- Control group: patients with OAB but no OAB medication
The results were interesting and were not in agreement with the majority of previously published findings and opinions. Some of the highlights included:
- The rate of dementia was highest in the low-risk anticholinergic group at 4.4%, followed by the mirabegron group at 3.9%, the high-risk anticholinergic group at 3.3%, and the control group at 2.2%.
- Among patients aged 50–69 years, the highest dementia rate was in the low-risk anticholinergic group at 5.0%, followed by mirabegron at 4.0%, the high-risk anticholinergic group at 3.9%, and the control group at 2.8%.
- Among patients over 80 years of age, the rate of dementia was 12.7% in the high-risk anticholinergic group, 11.1% in the low-risk anticholinergic group, 10.2% in the mirabegron group, and 12.1% in the control group.
- Mirabegron was strongly associated with dementia in women aged 40–69 years, with a hazard ratio of 5.39. Oxybutynin and trospium were also associated with increased risk in this group. Among men, increased risk was observed with oxybutynin, solifenacin, and tolterodine, with a hazard ratio of 3.12. In women aged 60–79 years, all medications except fesoterodine were associated with increased risk, with darifenacin showing the strongest association at a hazard ratio of 1.93. In men, the strongest association was with trospium, with a hazard ratio of 3.43; darifenacin and fesoterodine had no association.
In the results section of the abstract, the authors state that “the only medication found not to be associated with an increased risk of dementia in any group was fesoterodine.” In the conclusion, they state that “patients over the age of 80 without a prior history of dementia appear to be at reduced risk for dementia compared to younger patients.”
Hopefully, the same type of analysis will be performed for vibegron once sufficient numbers and duration of use are available.
This brief article review is not intended to dispute or negate the conclusions and opinions of many learned others, but rather to raise the question of whether other confounding factors, or subtle differences in the ways data were collected and interpreted, could account for the data and conclusions presented here — also collected and interpreted by a group of learned researchers. It may be as simple as undetected drug-drug interactions with non-anticholinergic medications, or as complicated as other risk factors for dementia, including genetic factors.
In any case, the ideal goal — and perhaps artificial intelligence can help with this in the future — is to identify the most efficacious and safest drug for a specific patient with a specific set of diagnoses, medications, and genetic makeup.
Written by: Alan Wein, MD, PhD, FACS, Professor of Clinical Urology, Department of Urology, Desai Sethi Urology Institute (DSUI), University of Miami Miller School of Medicine, University of Miami Health Systems, Miami, FL
References:
- Gray S, et al. Cumulative use of strong anticholinergics and incident dementia. JAMA Internal Medicine. 2015;175:401-407.
- Sacher S, et al. Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy. JAMA Neurology. 2016;73:721-732.
- AUGS Guidelines Committee. Clinical consensus statement: association of anticholinergic medication use and cognition in women with overactive bladder. Female Pelvic Medicine & Reconstructive Surgery. 2021;27:69-71.
- Zillioux J, et al. SUFU white paper on overactive bladder anticholinergic medications and dementia risk. Neurourology and Urodynamics. 2022.
- Sheyn D, et al. Pharmacotherapy for overactive bladder syndrome and the risk of incident dementia. World Journal of Urology. 2025;43:212.