Overactive bladder drugs and the risk of dementia

Whether anticholinergic overactive bladder drugs cause dementia remains unproven; however, judicious use is essential

Overactive bladder affects 50% of people over age 75 years¹ and is typically treated with anticholinergic drugs or mirabegron, a β3 receptor agonist. While a growing body of evidence has indicated an association between use of anticholinergic drugs and dementia, few studies have focused specifically on drugs for overactive bladder.² Therefore, whether these commonly prescribed drugs actually increase the risk of dementia is unknown.

Two new case-control studies published in BMJ Medicine examine this association. Using a primary care database representing only 4.5% of the UK population (doi:10.1136/bmjmed-2023-000799), Iyen and colleagues found a modest association between anticholinergic treatments for overactive bladder and dementia (adjusted odds ratio 1.18; 95% confidence interval (CI) 1.16 to 1.20) but they could not draw meaningful conclusions about mirabegron because most mirabegron recipients had previously received anticholinergic drugs.³ Using data from four nationwide registries in Denmark (doi:10.1136/bmjmed-2024-001125), Pourhadi and colleagues found a stronger association between anticholinergic bladder drugs and dementia (incidence rate ratio 1.44; 95% CI 1.40 to 1.48). However, to manage protopathic bias (as might result when drugs for overactive bladder are prescribed for urinary symptoms presaging dementia), they used an active comparator, finding no increased risk with anticholinergic drugs relative to mirabegron.⁴

As with most observational studies, the central question is whether the observed associations reflect cause and effect. In favour of causation is biological plausibility (acetylcholine has a key role in cortical activation; anticholinergics impair cognition while most dementia treatments enhance cholinergic transmission) and, in the study by Pourhadi and colleagues, a modest dose-response gradient. The case for causation is weakened by several observations, including a low-to-modest effect sizes; unexpected associations (trospium, which should not cross the blood-brain barrier, was associated with dementia in both studies); and no differential risk relative to mirabegron, which suggests protopathic bias. In summary, these new studies fall well short of establishing cause and effect.

Even without compelling evidence for causality, the case for judicious use of drugs for overactive bladder is easily made. Four steps should be routinely considered before initiating drug treatment. Firstly, establish the cause of urinary incontinence. Drugs for overactive bladder are not indicated for stress incontinence. Secondly, identify contributing factors, including medications and comorbidities. For example, drugs such as cholinesterase inhibitors and loop diuretics can exacerbate urinary symptoms, triggering prescribing cascades in which a second drug is prescribed to treat an adverse effect of another. Improving control of diabetes mellitus and sleep apnoea might also alleviate symptoms.⁵ Thirdly, implement non-drug interventions. Behavioural interventions such as pelvic floor muscle training and bladder training (scheduled voiding at gradually increasing intervals) could outperform drug treatments without adverse effects.⁶ Lifestyle changes such as reducing caffeine intake, weight loss in individuals with obesity, and optimising fluid intake are also recommended.^{5 7 8} Lastly, weigh the expected benefits and risks of drug treatment. While the urge to do something for urinary incontinence can be strong, drugs for overactive bladder reduce incontinence by about half an episode per day.^{9 10} Consequently, for patients with multiple episodes of incontinence per day, the marginal benefit might not outweigh potential side effects.

β3 agonists are typically considered a second line option, prescribed only when anticholinergics fail, are intolerable, or are contraindicated.^{5 7 11 12} This practice is surprising given their comparable efficacy and more favourable adverse effect profile.^{10 13} β3 agonists are not expected to worsen cognition, and short term studies show no association with cognitive decline.¹⁴ Anticholinergic drugs, in contrast, can affect cognition and cause or worsen dry mouth, dry eyes, blurred vision, and constipation.¹⁰ For older adults, particularly those who are especially vulnerable because of cognitive impairment, heightened fall risk, or concurrent use of other anticholinergic drugs, mirabegron should be the preferred option.⁷

With any drug treatment, the goal is always to impart more benefit than harm. Whether this goal has been met only becomes apparent in hindsight after treatment has been used, and then only if the full range of harms is recognised. Assessing the balance of benefits and harms can be challenging with anticholinergic drugs because their adverse effects sometimes mimic the effects of ageing and disease.¹⁵ Despite uncertainty about the role of drugs for overactive bladder in the genesis of dementia, clinicians should not be shy about deprescribing these drugs if this goal has not been decisively met, especially in patients with cognitive impairment. Indeed, deprescribing should be accompanied by serial cognitive assessment, because improvements could suggest that drugs for overactive bladder were in fact part of the problem.

While a causal link between anticholinergic bladder drugs and dementia remains unproven, the important message for clinicians remains simple: many strategies can lessen symptoms of overactive bladder; drug treatment is only one option and should be used judiciously.