Mixed urinary incontinence: Are there effective treatments?

Abstract

The aim of this debate article is to discuss whether effective treatments are available for mixed urinary incontinence (MUI). Because patients with MUI have both stress and urgency urinary incontinence (SUI and UUI) episodes and current treatment guidelines currently recommend treating the predominant symptom first, this article presents standard and emerging treatments for both SUI and UUI before discussing how well these treatments meet the medical needs of patients with MUI. Standard treatments presented include noninvasive options such as lifestyle changes and pelvic floor exercises, pharmacological agents, and surgery. Treatment of all three types of urinary incontinence (UI) is usually initiated with noninvasive options, after which treatment options diverge based on UI subtype. Multiple pharmacological agents have been developed for the treatment of UUI and overactive bladder, whereas surgery remains the standard option for SUI and stress‐predominant MUI. The divide between UUI and SUI options seems to be propagated in emerging treatments, with most novel pharmacological agents still targeting UUI and even having SUI and stress‐predominant MUI as exclusion criteria for participation in clinical trials. Considering that current treatment options focus almost exclusively on treating the predominant symptom of MUI and that emerging pharmacological treatments exclude patients with stress‐predominant MUI during the development phase, effective treatments for MUI are lacking both in standard and emerging practice. Ideally, agents with dual mechanisms of action could provide symptom benefit for both the stress and urgency components of MUI.

1. INTRODUCTION

Because urinary symptoms generally, and urinary incontinence (UI) specifically, can be stigmatizing for patients, ¹ obtaining accurate prevalence data can be problematic; the prevalence of UI varies widely between studies, populations, and countries, ² , ³ , ⁴ although most studies report a prevalence in the range of 25%–45%. ⁴ Although UI affects both men and women, ⁵ the prevalence is generally higher in women than men and increases with patient age. ² , ⁶ Some studies estimate approximately 10% of adult women are affected, ⁶ although ranges from 5% to 72% have been reported. ⁵

UI has a negative impact on quality of life, ⁷ mental health, and social activities. ⁵ Of the three most common UI subtypes (stress, urgency, and mixed UI), ⁴ urgency UI (UUI) and mixed UI (MUI) are generally considered more bothersome than stress UI (SUI). ⁸ , ⁹ While there is no distinctive definition of MUI in terms of frequency ratio between the stress and urge component, all components of the MUI presentation have a summative impact on the patient who suffers from this condition. UI also imposes an economic burden on both patients and society at large. Associated costs vary between countries ⁵ and UI type, with USD 65.9 billion estimated for UUI in 2007, which the same study projected to USD 82.6 billion for 2020. ¹⁰

SUI and UUI are caused by different physiological mechanisms ⁵ and therefore have different treatment options. In general, treatment options include behavioral and lifestyle changes, pharmacologic intervention, and surgery. Behavioral programs, which are noninvasive and therefore often a first line of therapy, ⁸ , ¹¹ can cost USD 150 to USD 344 (2015), but whether these programs provide value remains unclear considering that not all participants fully adhere to the program. ⁵ Several pharmacological interventions are available for UUI, but options are limited for SUI. Pharmacological treatments for UUI have been considered cost‐effective in some analyses, but the cost‐effectiveness decreased for less severe UUI. ⁵ Surgical interventions are more expensive, but the cost‐effectiveness is harder to measure. ⁵ Treatment options for MUI, which comprises both stress and urgency UI, ¹¹ are usually limited to treating the predominant symptom (stress OR urgency) ⁸ , ¹¹ , ¹² rather than treating MUI directly.

The purpose of this debate article is to discuss whether there are effective treatments for MUI specifically. To this end, how a diagnosis of MUI is made is presented briefly, followed by a description of patient population characteristics and risk factors. The article then focuses on current treatments, their effectiveness, and their drawbacks, as well as emerging treatments and their target indication and patient populations. The article ends with a discussion on whether the current and emerging treatments fulfill the treatment needs of patients with MUI.

2. DIAGNOSIS

Multiple sources and guidelines describe the diagnostic process and assessments used to diagnose UI and UI subtypes. ⁸ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ Patients presenting with symptoms of UI are usually assessed by their doctors to record the type and duration of symptoms. Diagnostic assessments can include medical history, physical examinations, completion of bladder diaries, urinalysis, postvoid residual volume calculations, and patient‐reported outcomes. The aims of these initial assessments are to determine the UI subtype (or other underlying cause that may require specialist referral), the frequency and severity of the symptoms, the impact on the patient's quality of life, and the degree of treatment need. Medical history is used to determine whether a patient has any other conditions that affect UI, such as diabetes, as improvement in the associated condition may improve UI severity, ¹¹ although the evidence is not conclusive. Validated questionnaires allow for a subjective differential diagnosis of UI subtype ¹⁵ , ¹⁷ while invasive urodynamic testing is not recommended for diagnostic purposes. ¹¹

Establishing the type of UI is important; although some treatments, such as lifestyle and behavioral modifications, do not vary by UI subtypes, others are subtype‐specific. ¹⁵ Most women present with a degree of MUI, ⁵ and the phenotype (stress or urge predominant symptomatology as determined by patient history and questionnaires) directs the initial treatment. ⁸ , ¹¹ , ¹² Absent standardized objective methodology to determine the predominant symptom, the patient history is critical. Furthermore, establishing the quality of life and social impact of the condition for the unique individual is critical for the determination of outcome and overall benefit of therapy. ⁸

3. PATIENT POPULATION

Gender, age, and medical history are all factors that affect UI. Women are more commonly affected than men, although the epidemiology in men is less well‐established than in women. ⁴ Predominant UI subtypes also very between the genders: women are more likely to suffer SUI or MUI than UUI whereas men are more likely to suffer UUI or MUI than SUI. ⁴

Multiple UI risk factors that relate to bladder or pelvic floor muscle dysfunction have been identified in women. In young and middle‐aged women, age, BMI, pregnancy, and vaginal birth are all established risk factors for UI. For all of these, the association is stronger for SUI than MUI.

Summary of UI risk factors in women:

• Age: most studies agree that UI prevalence in women increases with age and the incidence of UI peaks around menopause. ⁴ However, the causal relationship between age and UI has not been proven; other comorbidities associated with age also affect UI, such as obesity.

• Obesity, which doubles the risk of UI, is one of the most well‐established UI risk factors regardless of patient age. Obesity is positively correlated to increased UI severity for all three main UI subtypes, but the effect is more pronounced in SUI and MUI than UUI. ⁴

• Pregnancy and vaginal delivery are both causally related to UI, and SUI in particular. ⁴ Although many women return to full continence postpartum, women who develop UI during pregnancy or childbirth remain at increased risk of UI in later life. ⁴

• UI in postmenopausal women has been linked to reduced estrogen levels; however, systemic menopausal replacement therapy may be associated with iatrogenic UI ⁴ and worsening of UI outcomes. ¹⁸

• Hysterectomy has been associated with ensuing UI, particularly SUI, with loss of pelvic floor support hypothesized as a cause. ⁴

• Diabetes is associated with a higher prevalence of UI, ¹¹ and there are pathophysiological mechanisms that could explain a causal relationship even though this has not been proven explicitly. ⁴

• In older women, dementia is strongly associated with both prevalent and incident UI and considering that improvement in reversible dementia has also been shown to improve UI symptoms, causality seems likely. ⁴

UI in men often arises from damage to continence mechanisms following prostatectomy. ⁴ , ⁷ Prostatectomy in general is a known iatrogenic cause of UI, but risk varies with the type of procedure performed and reporting study. Although different studies report different risk factors, other established risk factors in men include increasing age, other lower urinary tract symptoms, functional and cognitive impairment, and neurological disorders. Diabetes has also been associated with UI, but the evidence is not yet conclusive. ⁴ , ¹⁹

Although the most common UI subtype is SUI in women and UUI in men, MUI is the second most commonly reported UI subtype in both genders. ⁴ Patients presenting with MUI have both stress and urge events, but the stress‐to‐urge ratio varies with patients having stress‐predominant, urge‐predominant, or equal stress and urge MUI. ²⁰

4. STANDARD TREATMENTS

Different mechanisms cause SUI and UUI: SUI results from urethral hypermobility and/or intrinsic sphincter deficiency, whereas UUI results from detrusor overactivity and/or poor detrusor compliance. ⁷ As such, different treatment pathways are followed for SUI and UUI, with MUI generally treated by treating the predominant symptom. Urethral failure has also recently been identified as critical to female UI and is believed to play a role in both SUI and UUI. As the exact role and mechanism of urethral failure in UI has yet to be discovered, there are no currently available treatments targeting urethral failure. ²¹

Containment products, including absorbent pads, urinary catheters, external collection devices, penile clamps for men, and intravaginal devices such as continence pessaries for women, are costly and uncomfortable and therefore offered as temporary coping strategies rather than long‐term solutions. ¹¹ , ¹³ Regardless of UI subtype, current guidelines recommend starting with conservative management, ¹¹ , ¹² , ¹³ , ¹⁴ including pelvic floor muscle training (PFMT), weight loss if the patient is obese, fluid intake adjustment, and timed voiding. ⁷ , ²² , ²³ Although such measures can be beneficial in milder forms of UI, long‐term effectiveness of these approaches have not been demonstrated ²⁴ , ²⁵ and various studies present conflicting results. ²⁶ , ²⁷

Beyond conservative management, the treatment of SUI and UUI diverges. Pharmacologic interventions have been developed to treat UI, however, there are currently more interventions aimed at UUI than SUI, and no approved pharmacological treatments that simultaneously target both the stress and the urge component that results in MUI. For example, antimuscarinic (anticholinergic) drugs block muscarinic receptors on the detrusor thereby inhibiting bladder contraction and improving UUI ⁵ , ²⁴ and several, such as tolterodine, fesoterodine, trospium, solifenacin, and darifenacin, have proven efficacy in treating UUI. ²⁴ Patient adherence, however, tends to be poor given that anticholinergic drugs have dry mouth, constipation, somnolence, drowsiness and blurred vision as adverse effects, ¹¹ , ²⁸ and prolonged use has been associated with a risk of dementia in elderly patients. ²⁹ , ³⁰ The beta‐3‐adrenoceptor agonist mirabegron, which is better tolerated than anticholinergic drugs with a comparable overall efficacy, acts to induce detrusor relaxation ¹¹ but may affect the cardiovascular system and has pharmacokinetic interactions with other drugs. ³¹ , ³² Antimuscarinics and beta‐3‐adrenoreceptor agonizts are the most commonly administered treatments for overactive bladder and UUI; these can be administered as combination therapies to increase efficacy and tolerability, and other pharmacologic options with alternative action mechanisms also exist. ²⁴ , ³³ , ³⁴

Duloxetine, a serotonin and noradrenaline reuptake inhibitor that increases striated urethral sphincter activity, ³⁵ is approved for the treatment of SUI in Europe; it is currently the only pharmacological option for SUI, although the reported side effects of nausea and suicidality likely prevented its approval in the US. ³⁶ , ³⁷ , ³⁸

Surgical procedures are often standard treatment options for SUI in both men and women, but the specific surgical options vary between the genders. ³⁹ , ⁴⁰ Surgical procedures in women, including the use of bulking agents, mid‐urethral slings, autologous fascia pubovaginal slings, and Burch colposuspensions, ¹⁶ are more invasive than pharmacological treatment but remain standard options for SUI despite known complications and controversies. ¹⁶ , ⁴¹ In general, surgical procedures can relieve UI symptoms, but some procedures (e.g., bulking agents and mid‐urethral slings) have limited long‐term efficacy. ¹⁶ , ²⁰ , ⁴² Some surgical procedures to treat SUI also result in new or worsening UUI symptoms. ²⁰

There are very few treatment options that specifically target MUI; treatment is usually initiated with conservative management including lifestyle changes and PFMT, although these have been shown to be less effective in patients with MUI than in patients with SUI. ¹¹ , ⁴³ Pharmacological agents developed to treat UUI can also help patients with MUI where UUI is the predominant symptom, but this has no effect on the stress component. ⁴⁴ SUI surgery remains a treatment option for MUI in patients who have stress incontinence as the predominant symptom ⁷ , ¹⁶ , ²⁰ ; however, this can result in worsening of the urgency component and overall cure rates after surgery are lower for women with MUI than with pure SUI. ¹¹ , ⁴⁵ As such there remains a large unmet medical need for UI treatments generally and MUI treatments specifically acting simultaneously on the urge (detrusor) and the stress (sphincter) component.

5. EMERGING TREATMENTS

At the time of writing, there were over 350 interventional trials in UI (both recruiting trials and completed trials were included in the search) listed on ClinicalTrials.gov, the vast majority (321/353) of which are Phase 2 or later. Refining the search from “urinary incontinence” to “mixed urinary incontinence” left only 21 interventional studies, compared to 112 trials for “stress urinary incontinence,” and 22 trials for “urgency urinary incontinence” plus 77 trials for “urge urinary incontinence” (some of which may overlap with the 22 trials for “urgency urinary incontinence”). This search does not show all research being conducted in finding treatments for UI, but it gives a snapshot idea of the distribution of effort between the three main UI subtypes.

The interventions listed range from surgical interventions to acupuncture and from pharmacological agents to physical exercise regimens. In discussing emerging treatments, we will focus the discussion on pharmacological interventions in at least Phase 2 of development.

A recent review article by Gandi and Sacco summarized emerging treatments for UI. Novel antimuscarinics are being developed with the hope of retaining the efficacy demonstrated by standard treatments while reducing the number and severity of side effects. ²⁸ The review specifically discussed imidafenacin, which has an efficacy comparable to tolterodine and other antimuscarinics but a milder side effect profile that may improve patient adherence to treatment, and tarafenacin, which versus placebo in a Phase 2 trial demonstrated an improvement in overactive bladder symptoms but a higher rate of dry mouth than other antimuscarinics. ²⁸ DA‐8010 is another recent antimuscarinic agent recently evaluated against both solifenacin and placebo in a Phase 2 trial in patients with overactive bladder symptoms. The results suggested that both the 2.5 and 5 mg doses had efficacies comparable to solifenacin while the 2.5 mg dose had fewer adverse drug reactions. ⁴⁶ However, SUI or stress‐predominant MUI were exclusion criteria in the trials evaluating imidafenacin, ⁴⁷ , ⁴⁸ tarafenacin ⁴⁹ (NCT01458197), and DA‐8010 (NCT03566134). DA‐8010 is currently being evaluated in a Phase 3 trial that also had SUI and stress‐predominant MUI as exclusion criteria (NCT05282069). While more effective or tolerable pharmacologics would be beneficial to patients with UUI, neither of these novel antimuscarinics is currently being assessed to address the treatment need of patients with MUI.

While novel beta‐3‐adrenoreceptor agonizts continue being developed, ²⁸ the most recently developed compound, vibegron, was approved by the FDA in 2020. ⁵⁰ This development program, consisting of two Phase 3 trials preceding approval, found that vibegron reduced micturition frequency, urgency episodes, and urgency incontinence with statistical significance compared to placebo ⁵¹ , ⁵² and had a favorable safety profile with a smaller percentage of patients discontinuing treatment due to adverse events compared to the tolterodine ⁵¹ or imidafenacin ⁵² control groups. Solabegron is another beta‐3‐adrenoreceptor agonizts currently in development; a clinical proof‐of‐concept trial revealed preliminary evidence of efficacy for solabegron over placebo and promising tolerability, ⁵³ but the data from the Phase 2 trials completed in 2019 (NCT03594058 and NCT03475706) have not been published yet. Although these novel beta‐3‐adrenoreceptor agonizts also target overactive bladder and UUI, the solabegron trials did not actively list SUI or MUI as exclusion criteria on their ClinicalTrials.gov registrations.

Various other pharmacologic treatments targeting other mechanisms of action are in development for overactive bladder and UUI, but these have, for the most part, not proceeded to clinical stages of development yet. ³³ Some that have reached clinical phases of development include phosphodiesterase‐5 inhibitors, such as tadalafil, and purinergic P2X₃ receptor agonizts, such as eliapixant. ³⁴ Tadalafil, which prevents the degradation of mediators including cGMP and cAMP that help maintain smooth muscle tone, showed preliminary evidence of efficacy in treating overactive bladder in men ⁵⁴ and in women. ³⁴ , ⁵⁵ Eliapixant blocks P2X receptors involved in sensing volume changes, which may affect the micturition reflex. ³⁴ Eliapixant is currently being investigated in a Phase 2 trial into overactive bladder and UUI (NCT04545580), but SUI and MUI are again exclusion criteria. At the time of writing, efficacy and safety results were not yet available. Whether a combination of these treatment modalities may provide further synergistic effect remains a research hypothesis to be tested.

Our literature searches have only revealed one emerging treatment for SUI, by continuing investigations into duloxetine. ⁵⁶ , ⁵⁷ Meanwhile, litoxetine, a highly specific and selective serotonin reuptake inhibitor and multifunctional serotonin agonist and antagonist with a dual effect to exert excitation of the external urethra sphincter and relaxation on the bladder detrusor has been investigated as a pharmacological treatment for patients with MUI specifically, hypothesizing activity on both the stress and the urge component. Although the primary analysis did not find a statistically significant difference between litoxetine and placebo most endpoints observed a greater numerical effect in treated subjects. A post hoc analysis confirmed that the effect of litoxetine was clinically meaningful, statistically significant and more evidenced compared to placebo in subjects with severe MUI. ⁵⁸

6. DISCUSSION

This debate article has summarized data establishing that UI is a large‐scale issue affecting millions of people worldwide, with an economic burden in the billions of US dollars and a negative impact on the quality of life of individual patients. A systematic review and meta‐analysis by Pizzol et al. ⁷ recently showed that UI is associated with a poor quality of life in patients, but standard treatments have not been shown to significantly improve patients' quality of life overall. In fact, a systematic review and network meta‐analysis of clinical outcomes published as late as 2019 concluded that “behavioral therapy, alone or in combination with other interventions, is often more effective than pharmacologic therapies alone in treating both stress and urgency UI,” ⁵⁹ even though other reports have concluded that behavioral therapies do not always achieve desired treatment outcomes and tend to be less effective in MUI than SUI.

Conservative management is often used as a first‐line treatment regardless of UI subtype, but when conservative options are insufficient a discrepancy arises between options available for UUI and SUI. There are significantly more pharmacological options available for UUI than for SUI; treatments for SUI are almost exclusively surgical, and therefore by nature more invasive and with a different risk profile than the treatment options available for UUI. As there are very few treatments targeting MUI directly, it is difficult to discuss the discrepancy between UUI, SUI, and MUI in terms of invasiveness of procedures. Meanwhile it is telling that MUI has not been targeted as necessitating its own treatment despite the fact that treating the urgency component does not relieve the stress component and surgical procedures to relieve the stress component can cause a worsening of urgency symptoms. Ideally, future treatment options for MUI would target both the stress and urgency component rather than only the predominant symptom.

Interestingly, the fact that stress‐predominant MUI is more common in women while urge‐predominant MUI is more common in men implies that there is a gender‐based difference in how patients with MUI are treated. Given that UUI has more effective treatment options than SUI, the difference in UI prevalence in men and women could potentially be partially explained by the relative effectiveness of available treatments, especially as surgery for SUI in women is more likely to worsen UUI or overactive bladder symptoms. The picture is, however, complicated by how relatively recent the endeavor to identify MUI and its prevalence in men is compared to those in women, and the fact that the majority of men have not had a prostatectomy and therefore are dealing with outlet obstruction caused by the resident prostate.

The lack of comparability between studies and definitions used makes it difficult to establish accurate and precise prevalence data and to determine the percentage of patients of any UI subtype who achieve their desired treatment outcomes. As discussed, SUI surgeries do relieve stress symptoms, but considering that many women need repeat treatments and/or suffer de novo or worsening urgency symptoms suggests that there is room for improvement in these procedures. Pharmacological interventions available for UUI are less invasive than surgery, but they still have many reported side effects.

Emerging pharmacological interventions continue to target UUI to the exclusion of SUI and MUI. While safe and effective UUI treatments are still necessary, there seems to be a discrepancy in the amount of research put towards noninvasive options for UUI compared to SUI and MUI.

7. CONCLUSION

Although standard treatments for UI benefit some patients, a large unmet medical need remains. Emerging pharmacological treatments seem to offer better risk‐benefit profiles than current options, but they are still mainly targeting UUI and overactive bladder and actively excluding patients with MUI from the development phase. While the development of safe and effective UUI treatments are a worthy endeavor, it does not address the current unmet need of patients with MUI, for whom adequate treatment remains a challenge.

CONFLICTS OF INTEREST

Xavier Gamé is a consultant to Pierre Fabre Medicament, Coloplast, Hollister and Medtronic. Roger Dmochowski is a consultant to Ixaltis SA. Dudley Robinson is a researcher at Ixaltis SA, and a speaker for Allergan plc, Astellas Pharma, Ferring Pharmaceuticals, and Laborie.

Game X, Dmochowski R, Robinson D. Mixed urinary incontinence: are there effective treatments? Neurourol Urodyn. 2023;42:401‐408. 10.1002/nau.25065

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.