Ariana Smith: Thank you, Dr. Wein. It's only because I've learned from the very best. So, thank you for inviting me back to UroToday. We're going to talk on oral pharmacotherapy for overactive bladder. So, we'll get into the two main categories of overactive bladder medications, our safety concerns with antimuscarinics, and then ideal initial therapy for overactive bladder. In 2024, the new SUFU/AUA overactive bladder guideline was developed. And statement 16 states that clinicians should offer antimuscarinic medications or beta-3 agonists to overactive bladder patients to improve symptoms. This is a strong recommendation with grade A evidence supporting the use of medications to improve overactive bladder symptoms. So, how do these medications work? We'll start with antimuscarinics. Contrary to popular belief, antimuscarinics are not primarily working by blocking bladder contractility.
They are working on sensory afferent nerves in the urothelium, the lamina propria, and in the detrusor smooth muscle during bladder filling. So by blocking the muscarinic receptors, these drugs will dampen the afferent noise from the bladder to the central nervous system, which helps to reduce urinary urgency and frequency without impairing normal voiding contraction. Many studies have been performed proving their efficacy with improvements in frequency, urgency, urge incontinence, and quality of life. While higher doses and at-risk patients can see impact on bladder contractility, when the dosing is kept in the green therapeutic window, this is uncommon. Antimuscarinic drugs have been around for several decades, and newer agents were brought on the market to improve on the side effect profile of earlier agents. Efficacy is similar across all of these agents, but side effects are better with extended-release formulations. And trospium offers reduced or no transmission of the drug across the blood-brain barrier.
So, what about beta-3 agonists? How do they work? They work by selectively stimulating the beta-3 adrenoceptors in the detrusor muscle of the bladder, which leads to smooth muscle relaxation during the storage phase, essentially increasing bladder capacity and reducing involuntary detrusor contractions. It's also been found that these drugs directly inhibit afferent nerve activity, and suppress acetylcholine release from the bladder nerves, again, dampening that abnormal sensory signaling from the bladder. So, fairly similar effects of these two medications through different mechanisms of action, and leading to different side effect profiles. Few studies have directly compared the antimuscarinics to the beta-3s, but those that have, demonstrate no real difference in symptom control. So, what does the 2024 AUA/SUFU guidelines say about safety? Well, clinicians should counsel patients on side effects.
Treatments should be chosen based on side effects, and in the context of shared decision-making, and clinicians should discuss the potential for developing dementia and cognitive impairment with antimuscarinics. The adverse effects of antimuscarinics include dry mouth, constipation, rare cardiac complications, blurred vision, incomplete emptying, and not so rare, cognitive dysfunction. In fact, 46 studies, including over 60,000 patients, have found increasing anticholinergic load was associated with significant decline in cognitive ability. A two-year follow-up of more than 13,000 patients over age 65, showed significant decline in Mini-Mental Status Exam with anticholinergic use. JAMA Neurology published a longitudinal study on the association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in normal older adults, and they found increased brain atrophy, dysfunction, and clinical decline with the use of anticholinergics. Beta-3 agonists, on the other hand, have fewer side effects with lower rates of dry mouth, constipation, urinary retention.
There are potential effects on blood pressure, heart rate, and cardiac arrhythmias, but initial studies of mirabegron, the first beta-3 to come to market, reported mild increases in systolic blood pressure in the range of one to three millimeters of mercury. And pooled analyses of the phase three randomized controlled trials on mirabegron suggest no significant difference in the incidence of hypertension between mirabegron, placebo, and tolterodine. So, mirabegron is not recommended at this point in time in patients with severe uncontrolled hypertension due to fear of worsening hypertension, but vibegron, the second drug in class to come to market does not carry this warning. I will say the major toxicity that's associated with both of these drugs is financial as these agents are costly, preventing the use of them in many patients. So, what is the ideal therapy for overactive bladder? Well, this is the art.
This is the art of what we do, and it's not the same for every patient. It's best achieved through shared decision-making with the patient, which means we need to meet the patient where they're at with their understanding of overactive bladder, and their bother from the condition, and provide them with the options that align with their preferences, and their goals for treatment. In some patients, there's a lot of room for behavioral modifications and lifestyle changes to improve symptoms. Comorbidity management can certainly improve things like glucosuria, and treatment of sleep apnea can improve the circadian release of vasopressin and compression stockings and leg elevation can help mobilize peripheral edema and improve conditions like nocturia or symptoms like nocturia. Pelvic floor muscle therapy can be a great option for some patients. And when medications are needed, I certainly prefer beta-3 agonists over antimuscarinics due to their more favorable side effect profile, but also, the option to skip pharmacologic therapy altogether, and go to advanced therapies like botulinum toxin injection, neuromodulation may be a good option for some patients who cannot afford beta-3 agonists, and want to avoid the potential cognitive side effects of antimuscarinics. So, really ideal initial therapy can include all of these things. Thank you, Alan, for having me on today.
Alan Wein: Great summary. So, if an elderly patient, let's say, comes to you with overactive bladder symptomatology, has, let's say, moderate symptoms, nothing that you would go to more aggressive therapy in, but is on a long-term antimuscarinic, do you suggest to those people that they change to a beta-3 agonist?
Ariana Smith: I do. I do. I make that an important part of our initial conversation, talking through what the science has currently taught us about the long-term use of these medications, and why we need to consider changing the course of therapy. For some patients, they're afraid to stop, and I'm not going to take it away abruptly, or immediately. I'm first going to try to get them an alternative agent and talk through the options, but that's a really important part of my initial conversation with them.
Alan Wein: So, it sounds like your preference in treating either a younger or older patient, if you're going to add pharmacologic therapy is going to be a beta-3 rather than an antimuscarinic. I mean, assuming that the financial toxicity is not so great that it's really going to harm them.
Ariana Smith: Yeah, absolutely. I do find there are times where there's no way we're going to get the insurance to approve the beta-3. And in those situations in the elderly, I certainly lean into trospium. And with trospium, it's a quaternary amine, so we have more confidence that it's not going to cross the blood-brain barrier, and create these cognitive side effects and lead to dementia over time. I think that it's probably also fair to say that it's safer to initiate in younger patients, although we haven't really studied the use of antimuscarinics in really young people over time. And gosh, if it were me or my child, I'm not sure I really want them on those kinds of agents long-term. So, I'm certainly going to try based on what I know to get every patient I can, a beta-3 agonist if they elect for pharmacologic therapy.
Alan Wein: So, trospium has been around a long time. Why do you suppose it's not used more frequently? I mean, if you look at the usage patterns, I mean, oxybutynin in some form is still first overall, and then come the other antimuscarinics. And at the bottom is trospium, but it has at least the theoretical advantage, as you said, that it doesn't cross the blood-brain barrier, at least in a healthy person. And actually, I think Staskin measured cerebrospinal fluid levels even, and it didn't get through the blood-brain barrier. So, why do you suppose there's a reluctance to use it? Is there something else about trospium that makes it an unpopular medication, relatively?
Ariana Smith: Yeah, I think that the answer to that may be twofold. One is knowledge, prescriber knowledge. Prescribers need to know what to prescribe to get the right drug to the patient. And I think a lot of the folks who are prescribing oxybutynin may not be aware of this option. I think by the time you make your way to a urologist, that knowledge is there, and the understanding is there. I think the second component is insurance coverage. I think for many primary care providers, they're very busy. They're seeing a lot of patients, treating a lot of conditions. When they see medication rejections, it's a lot of work. It's a lot of time. It's difficult. And oxybutynin never gets rejected. It always gets approved. So, I think those two things make prescribing an agent like trospium more difficult. As far as I'm aware, there's nothing specifically difficult about the drug. I mean, originally it was brought on the market at 20 milligrams BID, but then the 60 milligram extended-release came on the market, making it even more desirable option among the antimuscarinic agents. So, I'm not aware, maybe you know. Is there anything I don't know about trospium that I should be aware of?
Alan Wein: Well, I've always been puzzled by the fact that no one has taken trospium as a separate drug, or any of the drugs as separate drugs, except maybe for oxybutynin immediate-release, and studied them specifically for cognitive dysfunction over a period of time. With all the publicity about cognitive dysfunction with antimuscarinics, I mean, you would think that someone would've separated out the various antimuscarinics because the EAU guidelines still say that there are certain antimuscarinics that haven't been shown to cause cognitive dysfunction, which is interesting. They change every year. I don't know what the 2025 version is, but certainly the ones before have always pointed that out. Of the beta-3 agonists, when you're going to prescribe one for someone, do you think except for the one dosage formulation of vibegron as opposed to the two dosage formulations of mirabegron, that there's a difference in either efficacy or safety?
Ariana Smith: I don't think so. I think they're similarly efficacious, and we have some early data to suggest that's true, and I think we're going to find that the safety profiles are very similar. I think with larger post-marketing studies, looking at patients who are susceptible to hypertension, I think we're going to see similar low rates of findings in both groups. I think the insurance coverage issue is still a problem with these drugs as well, and getting vibegron approved by the insurance companies is still really challenging, and I think it is limiting its use in practice, whereas Myrbetriq has certainly found its way onto some of the formularies, making it a little bit easier for patients to get.
Alan Wein: Are there any new developments that you know of in either the antimuscarinic space, or the beta-3 agonist space that you can expect to see either in trials, or on the market in the next couple of years?
Ariana Smith: Yeah, no, I was very much expecting to see a combination therapy, especially with Astellas having both mirabegron and solifenacin. I thought potentially we would see a drug formulated together, but potentially the fear about cognitive effects and dementia may be preventing the interest in development in that space. I love your idea. Let's study trospium in the elderly, and let's take a look and see how safe it really is, and can we get to a better financial place with the management of this condition by using a less expensive agent?
Alan Wein: Last question. Do you think there's a value? Let's say someone is on a beta-3 agonist, you don't get an optimal result. Do you think there's a value in adding an antimuscarinic to it? Let's say you were going to add trospium. Do you think there's an additive effect of the two, or not?
Ariana Smith: I do. I do think you get additional effect, and I think it's because of that slightly different mechanism. And while they're producing a similar experience for the patient with a reduction in frequency and urgency, they're doing it by slightly different mechanisms. And because the side effect profile's not overlapping, I think you can safely add these antimuscarinics in. The preference for me is trospium to avoid the cognitive side effects in the older population, but even carefully can be done with the other agents, especially in the younger population. And then I really want to make sure patients are monitoring for symptom improvement, that we don't just prescribe it, and set it and never look at it again, that they actually go home and keep a record of how things are changing. So, we're only continuing to refill that medication over time if they're seeing an improvement.
Alan Wein: I remember one last question. Stop therapy to see if being off therapy, the patients have similar relief. In other words, over a period of time, do you ever just stop it, give them a test run for two or three weeks or not, or you don't think that's a useful thing?
Ariana Smith: I think it's a tremendously useful thing. In fact, I wish we had written that into our SUFU/AUA guidelines just about the importance of life changes over time. Comorbidities change, treatments change. These weight loss medications are really changing a lot of patients' lives. And I think it is possible that we are going to see not only decline in OAB over time like we have traditionally believed, but we know some patients get better for no great reason. Now we've got great reasons to expect that they may be getting better if they're losing weight, if their diabetes is better controlled, or if they're just taking better care of themselves. So, I think it's a really important thing to do with patients, and it's really great for patients to know what the drug is doing for them. So, stopping it for a week can sometimes allow patients to say, "Am I any worse? Am I any worse?" And then if they're not, they have the confidence to stay off it a little longer, and really try to understand if that medication is providing any benefit.
Alan Wein: Terrific. Great discussion. Listen, thanks so much for taking your time. I know things are busy up there, so hope to see you at a meeting soon.
Ariana Smith: Yes. Thank you, Alan.