Monotherapy with mirabegron had a better tolerance than the anticholinergic agents on overactive bladder: A systematic review and meta-analysis.

BACKGROUND: We conducted this meta-analysis to explore the tolerance of monotherapy with mirabegron (50 mg) on an overactive bladder, compared with a common dosage of anticholinergic agents. MATERIALS AND METHODS: A comprehensive search for all randomized controlled trials that evaluated the safety of mirabegron and anticholinergic agents on overactive bladder was performed, and we searched the Cochrane Central Register of Controlled trials databases, Pubmed, Embase, and relevant trials from 2013.02 to 2019.10. RESULTS: Eight studies included 5500 patients with treatment of monotherapy on overactive bladder were identified. The total number of treatment-emergent adverse events had no significantly difference between two monotherapies (RR = 0.88 95%CI: 0.76-1.01; P = .08); however, patients would have a better tolerance with mirabegron (50 mg) in adverse events of dry mouth (RR = 0.42; 95%CI: 0.33-0.53; P < .01) and tachycardia (RR = 0.52; 95%CI: 0.29-0.94; P = .03); and there were no significant differences between two groups in hypertension (RR = 1.02; 95%CI: 0.80-1.30; P = .90), constipation (RR = 0.91; 95%CI: 0.65-1.26; P = 0.57), blurred vision (RR = 1.03; 95%CI: 0.60-1.77; P = 0.92), and urinary tract infection (RR = 0.90; 95%CI: 0.70-1.16; P = .41). CONCLUSIONS: Treatment-emergent adverse events in patients with overactive bladder who underwent monotherapy of mirabegron (50 mg) or the anticholinergic agents had no significant differences, but mirabegron has a better tolerance in the aspect of dry mouth and tachycardia.

Pharmacotherapy of patients with benign prostate enlargement and storage symptoms in everyday clinical practice.

OBJECTIVE: Storage symptoms significantly deteriorate the quality of life in men with benign prostate enlargement (BPE). Muscarinic receptor antagonists (MRAs) and ß3-adrenergic receptors agonists alone, or in combination with selective α1-alpha-antagonists, are considered the most effective medicines relieving storage symptoms. The aim of this study was to analyze the pharmacotherapy of storage symptoms in men with BPE, and their compliance with the European Association of Urology (EAU) guidelines. PATIENTS AND METHODS: The survey was conducted in 2018 by 261 urologists among 24,613 men with lower urinary tract symptoms (LUTS) and BPE treated pharmacologically. Data concerning recent severity of non-neurological LUTS, storage symptoms and pharmacotherapy were collected. RESULTS: Storage symptoms were reported by 12,356 patients (50.2%) with BPE, more frequently nocturia (75.8%), than urinary urgency (57.8%) and frequency (44.3%). Patients with storage symptoms were more frequently prescribed with MRAs and mirabegron (43.1% vs. 5.0% and 2.4% vs. 0.3%, respectively; p<0.001). Of note, 54.5% of patients with storage symptoms were treated neither with MRAs, nor ß3-adrenergic receptors agonists. In the subgroup with storage symptoms, the increasing severity of LUTS accounted for more frequent prescription of MRA (2.1% vs.  29.1% vs. 42.8% in patients with mild, moderate, and severe LUTS, respectively). Decision tree analysis revealed that patients with urinary urgency and urinary frequency, as well as younger ones with urinary urgency but without urinary frequency, were more frequently prescribed with MRAs. CONCLUSIONS: Urinary urgency and frequency are associated with increased utilization of MRAs in men with BPE in everyday clinical practice. The attitude of Polish urologists toward management of persistent storage symptoms in BPE patients is in line with the EAU guidelines.

Mirabegron: Pediatric First Approval.

Mirabegron (MYRBETRIQ®), a beta-3 adrenergic agonist developed by Astellas Pharma Inc., is well established as a treatment for overactive bladder in adults and is available as extended-release (ER) tablets administered once daily. More recently, mirabegron has been investigated in pediatric patients with neurogenic detrusor overactivity (NDO) and received its first approval in this indication in pediatric patients aged ≥ 3 years on 25 March 2021 in the USA. In addition to mirabegron ER tablets (which can be used in pediatric patients weighing ≥ 35 kg), mirabegron is available as an ER oral suspension (MYRBETRIQ® Granules) for pediatric patients; in those weighing < 35 kg, only the ER oral suspension formulation should be used. The ER tablet and ER oral suspension formulations are not substitutable on a mg-by-mg basis. This article summarizes the milestones in the development of mirabegron for NDO leading to this pediatric first approval.

Possible Involvement of Muscarinic Receptor Blockade in Mirabegron Therapy for Patients with Overactive Bladder.

The selective ß 3-adrenoceptor agonist mirabegron, an established alternative to antimuscarinic therapy for patients with overactive bladder, induces additional effects against receptors, transporters, and hepatic enzymes. The present study aimed to elucidate the effects of mirabegron on muscarinic receptors in the rat bladder using radioligand binding and functional assays. Mirabegron (0.1-100 µM) inhibited specific [N-methyl-3H]scopolamine methyl chloride binding in the bladder and other tissues of rats in a concentration-dependent manner. Binding affinity in the bladder was similar to that in the heart and significantly higher than those in the submaxillary gland and brain. Mirabegron induced the concentration-dependent relaxation of carbachol-induced contractions in the rat isolated bladder. Further analyses using a two-site model revealed that the relative quantities of high- and low-affinity components for mirabegron were 44.5% and 55.5%, respectively. Respective pEC50 values were 7.06 and 4.97. Based on the receptor binding affinity and pharmacokinetics of mirabegron, muscarinic receptor occupancy in the human bladder for 24 hours after the administration of a single oral dose of 50 mg mirabegron was 37%-76%. The present results demonstrate for the first time that mirabegron may relax the detrusor smooth muscle not only by ß 3-adrenoceptor activation but also muscarinic receptor blockade. SIGNIFICANCE STATEMENT: Mirabegron, the first selective ß 3-adrenoceptor agonist, represents an alternative to antimuscarinic agents for management of overactive bladder (OAB). The present study aimed to clarify whether mirabegron directly binds to muscarinic receptors and affects cholinergic agonist-induced contractions in rat urinary bladder and to predict muscarinic receptor occupancy in human bladder after oral administration of mirabegron. The results demonstrated that mirabegron therapy for patients with OAB may be due not only to ß 3-adrenoceptor activation but also muscarinic receptor blockade.

Systematic review and meta-analysis of the efficacy and safety of vibegron vs antimuscarinic monotherapy for overactive bladder.

BACKGROUND: Vibegron is a new ß3-adrenergic receptor agonist which has been demonstrated for the treatment of overactive bladder (OAB). We carried out meta-analysis to evaluate the efficiency of vibegron vs antimuscarinic monotherapy for treating OAB. METHODS: Randomized controlled trials (RCTs) of Vibegron vs antimuscarinic monotherapy for OAB were searched systematically by using EMBASE, MEDLINE, and the Cochrane Controlled Trials Register. The RevMan version 5.3.0. was used to analysis the data. RESULTS: Three RCTs involving a total of 1751 patients were studied in the Systematic review and Meta-analysis. Efficacy end points: the mean number of micturitions episodes/d (P = .16); the mean number of urgency episodes/d (P = .05); mean number of urgency incontinence episodes/d (P = .11) and mean number of incontinence episodes/d (P = .14) indicated that vibegron and antimuscarinic had no significant differences in terms of OAB treatment. Mean volume voided/micturition showed a distinct difference in the two groups (P = .009). With regard to dry mouth and drug related treatment-emergent adverse event (TEAE), vibegron showed better tolerance than antimuscarinic. Serious adverse event (SAE) and discontinuations due to adverse event (AE) did not show a significant difference between the two groups. CONCLUSIONS: The therapeutic effect of vibegron is similar to that of antimuscarinic, but vibegron does not increase the risk of AE.

B3 agonists or anticholinergics in the treatment of the lower urinary tract dysfunction in patients with multiple sclerosis?-A randomized study.

INTRODUCTION AND OBJECTIVE: Multiple sclerosis (MS) is the most frequent autoimmune demyelinating disease of the central nervous system. MS patients usually present with lower urinary tract dysfunction (LUTD). Objective of this study is to evaluate and compare the efficacy and safety of treating MS patients with LUTD with either a b3 agonist (mirabegron) or anticholinergics. The study's primary outcome is the LUTD symptom improvement. MATERIAL AND METHODS: This is a multi-center, single-blinded, comparative study including 91 MS patients with LUTD. At baseline, patients underwent thorough clinical examination, urine cultivation and abdominal ultrasound and completed urination diaries and specific, validated questionnaires (NBSS, MusiQoL). At second visit, patients were administered either mirabegron or anticholinergics. Treatment was always carried out alongside with MS treatment. Reevaluation was performed 3 months after first visit. Patients underwent the same clinical and imaging tests that were carried out at first visit. RESULTS: We compared several clinical and imaging parameters between the two groups at first visit and month 3 after treatment. Νo statistical difference was noted between the mirabegron group and the anticholinergic group in terms of LUTD improvement. In both groups, improvement from baseline regarding LUTD was recorded. Statistical analysis was performed using the paired and unpaired t test method. No patient discontinued either medication due to side effects. CONCLUSIONS: MS patients receiving either mirabegron or anticholinergic therapy for LUTD showed improvement. Nevertheless, no statistical difference was noted between the two cohorts at 3 months in terms of drug efficacy in all the statistically significant parameters.

Mirabegron, A Selective ß3-Adrenoceptor Agonist Causes an Improvement in Erectile Dysfunction in Diabetic Rats.

AIM: To investigate the possible beneficial effect of mirabegron [a selective ß3-adrenoceptor (AR) agonist] treatment on erectile dysfunction (ED) in streptozotocin-induced diabetic rats. METHODS: Sprague-Dawley rats (n=20) were divided into two groups: control group and streptozotocin-induced diabetic group. In vivo erectile responses were evaluated after intracavernosal injection of mirabegron (0.4 mg/kg) in rats. The relaxation responses to electrical field stimulation (EFS, 10 Hz), sodium nitroprusside (SNP, 10 nM) and sildenafil (1 µM) of corpus cavernosum (CC) strips were examined after the incubation with mirabegron (10 µM). ß3-ARs expression and localization were determined by Western blot and immunohistochemical analyses in CC tissue. RESULTS: In vivo erectile responses of diabetic rats [intracavernasal pressure (ICP) / mean arterial pressure, 0.17±0.01] were decreased, which were restored after administration of mirabegron (0.75±0.01, P<0.001). The basal ICP (7.1±0.6 mmHg) in diabetic rats was markedly increased after mirabegron (36.1 ±5.4 mmHg, P<0.01). Mirabegron caused markedly relaxation in diabetic rat CC after phenylephrine precontraction. The relaxation responses to EFS and sildenafil were reduced in diabetic CC, which were increased in the presence of mirabegron. Mirabegron enhanced SNP-induced relaxation response in both groups. The expression and immunoreactivity of ß3-ARs localized to CC smooth muscle were observed in control and diabetic rats. CONCLUSIONS: This is the first study to show that intracavernosal administration of mirabegron improved erectile function and neurogenic relaxation of CC in diabetic rats. These results may be supported by further studies using combinations of mirabegron and phosphodiesterase type 5 (PDE5) inhibitors for the treatment of diabetic ED, especially in patients who do not respond to PDE5 inhibitor therapy.

The metabolic effects of mirabegron are mediated primarily by ß3 -adrenoceptors.

The ß3 -adrenoceptor agonist mirabegron is approved for use for overactive bladder and has been purported to be useful in the treatment of obesity-related metabolic diseases in humans, including those involving disturbances of glucose homeostasis. We investigated the effect of mirabegron on glucose homeostasis with in vitro and in vivo models, focusing on its selectivity at ß-adrenoceptors, ability to cause browning of white adipocytes, and the role of UCP1 in glucose homeostasis. In mouse brown, white, and brite adipocytes, mirabegron-mediated effects were examined on cyclic AMP, UCP1 mRNA, [3 H]-2-deoxyglucose uptake, cellular glycolysis, and O2 consumption. Mirabegron increased cyclic AMP levels, UCP1 mRNA content, glucose uptake, and cellular glycolysis in brown adipocytes, and these effects were either absent or reduced in white adipocytes. In brite adipocytes, mirabegron increased cyclic AMP levels and UCP1 mRNA content resulting in increased UCP1-mediated oxygen consumption, glucose uptake, and cellular glycolysis. The metabolic effects of mirabegron in both brown and brite adipocytes were primarily due to actions at ß3 -adrenoceptors as they were largely absent in adipocytes derived from ß3 -adrenoceptor knockout mice. In vivo, mirabegron increased whole body oxygen consumption, glucose uptake into brown and inguinal white adipose tissue, and improved glucose tolerance, all effects that required the presence of the ß3 -adrenoceptor. Furthermore, in UCP1 knockout mice, the effects of mirabegron on glucose tolerance were attenuated. Thus, mirabegron had effects on cellular metabolism in adipocytes that improved glucose handling in vivo, and were primarily due to actions at the ß3 -adrenoceptor.

Safety and Tolerability Results from the PILLAR Study: A Phase IV, Double-Blind, Randomized, Placebo-Controlled Study of Mirabegron in Patients ≥ 65 years with Overactive Bladder-Wet.

BACKGROUND: In older patients with overactive bladder (OAB), mirabegron, a ß3-adrenoreceptor agonist, represents an alternative treatment that may have a favorable risk-benefit profile. OBJECTIVES: Our objective was to further examine the safety and tolerability of mirabegron versus placebo treatment in patients aged ≥ 65 years with OAB-wet. METHODS: We conducted a 12-week, double-blind, randomized, placebo-controlled phase IV study to compare mirabegron with placebo. Community-dwelling patients aged ≥ 65 years with OAB-wet (one or more incontinence episode and three or more urgency episodes, and an average of eight or more micturitions/24 h over a 3-day diary) were randomized to receive placebo or mirabegron 25 mg/day (optional dose escalation to 50 mg/day at week 4 or 8). Safety analyses were performed for adverse events (AEs) and vital signs on all randomized patients who received one or more dose of study drug. RESULTS: Treatment-emergent AEs (TEAEs), the majority mild or moderate in severity, were reported in 39.4% of placebo patients and 44.2 and 49.8% of those who received mirabegron 25 mg or 50 mg, respectively. The most common TEAEs in mirabegron-treated patients were urinary tract infection, headache, and diarrhea. The incidence of TEAEs was slightly higher in mirabegron patients aged ≥ 75 years than in those aged < 75 years. There were no clinically meaningful differences in changes in vital signs from baseline to end of treatment for any treatment group, and no differences were observed between mirabegron and placebo treatment groups. TEAEs tended to occur early post exposure and were not dose related. CONCLUSIONS: Mirabegron treatment was well-tolerated in older adults with OAB-wet. Safety and tolerability were consistent with the known mirabegron safety profile. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov: NCT02216214.

Efficacy of adding mirabegron to alpha-adrenoreceptor blocker in patients with benign prostatic hyperplasia with persistent overactive bladder symptoms: A prospective study.

Purpose: To compare the efficacies of mirabegron 50 mg addition after alpha-adrenoreceptor blocker in terms of reducing storage symptoms in patients with BPH. Materials and Methods: Fifty-eight patients that had been taking alpha-adrenoreceptor blocker for more than 8 weeks, but had an OABSS of greater than 3 points, were initially enrolled. One group added any alpha-adrenoreceptor blocker with mirabegron 50 mg (n=39; the mirabegron group) and the other group received alpha-adrenoreceptor blocker only (n=19; the control group) for 8 weeks. Results: In the control group, mean total IPSS decreased from 15.7 to 13.1 (p=0.298) and in mirabegron group, mean total IPSS decreased from 19.4 to 16.5 (p=0.024). Mean storage symptom scores reduced in the control and mirabegron groups from 8.5 to 7.9 (p=0.584) and from 9.1 to 7.6 (p=0.015), respectively, and mean QoL scores from 3.7 to 3.1 (p=0.052) and 3.6 to 3.2 (p=0.027), respectively. Mean overall OABSS in the control and mirabegron groups reduced from 8.4 to 7.2 (p=0.173) and from 8.8 to 7.3, respectively (p=0.005); mean OABSS Q3 from 3.6 to 2.9 (p=0.073) and from 3.5 to 2.7 (p=0.002), respectively; and mean OABSS Q4 from 2.4 to 2.0 (p=0.306) and from 2.7 to 2.0 (p=0.016), respectively. The change of mean Qmax and PVR was insignificant in 2 groups. Conclusions: IPSS total scores, storage symptom scores, QoL, overall OABSS, OABSS Q3 and Q4 were more improved significantly by alpha-adrenoreceptor blocker with mirabegron 50 mg in BPH patients with persistent overactive symptoms. Mirabegron 50 mg addition is considered to patients with persistent storage symptoms after alpha-adrenoreceptor blocker.

The clinical pharmacology of the medical treatment for overactive bladder in adults.

INTRODUCTION: Overactive bladder is a prevalent symptom complex that affects the patient's quality of life. Any disruption between the neuronal micturition pathway can lead to bladder overactivity. Neurogenic causes, myogenic causes, aging, bladder outlet obstruction, sex, and psychological factors are some of the factors contributing to bladder overactivity. The complaint of any symptoms of OAB, which is highly prevalent and affects overall QOL, often needs therapeutic interventions. When conservative therapy methods fail, the addition of medications is recommended. The most commonly used agents for the treatment of OAB are antimuscarinic drugs. New classes of drugs, such as beta-3 agonists, have enriched our pharmacologic armamentarium. AREAS COVERED: In this review, with a special focus on oral pharmacological treatments, we discussed the definition, etiology, symptoms, diagnosis, and management of OAB. EXPERT OPINION: OAB is a multifactorial condition with every patient presenting with a different collection of symptoms and signs. Medical therapies should be given in conjunction with behavioral therapies. Using high or low doses, flexible doses, and stopping or changing the medications are interchangeable strategies based on the level of treatment efficacy and patient satisfaction.

Additive effects of intravenous and intravesical application of vibegron, a ß3-adrenoceptor agonist, on bladder function in rats with bladder overactivity.

To examine the effects of intravenous and intravesical application of vibegron, a new ß3-adrenoceptor (ß3-AR) agonist, on bladder function in rats with oxotremorine methiodide (oxo-M: a nonselective muscarinic receptor agonist)-induced bladder overactivity. Cystometry was performed in conscious female rats with intravesical instillation of oxo-M (200 µM). In oxo-M-treated rats, vehicle or vibegron (1 and 10 mg/kg) was cumulatively applied intravenously at 30-min intervals. In other groups of rats, oxo-M + vehicle or oxo-M + vibegron (10, 100 µM, and 1 mM) was cumulatively instilled intravesically at 60-min intervals followed by intravenous application of vibegron (10 mg/kg). Expression of ß3-ARs in the bladder was also evaluated using immunohistochemical staining. Intravenous application of vibegron (10 mg/kg) significantly increased bladder capacity (1.3 times) and decreased baseline, threshold, and maximal voiding pressure compared with vehicle. Next, intravesical application of vibegron (1 mM) significantly increased threshold pressure and bladder capacity (1.2 times) compared with vehicle. Combined treatments of intravesical (1 mM) and intravenous (10 mg/kg) application of vibegron induced a significantly larger degree of increases in bladder capacity (1.4 times) compared with vehicle. In addition, ß3-ARs were expressed throughout the rat bladder, mainly in the urothelium. These results suggest that vibegron excreted in urine as an unchanged compound can induce the additive inhibitory effects on bladder overactivity possibly through urothelial ß3-AR activation, which inhibits the afferent limb of micturition reflex rather than the efferent function as evidenced by the increases in threshold pressure and bladder capacity without affecting bladder contractile function after intravesical vibegron application.

The efficacy and safety of Vibegron in treating overactive bladder: A systematic review and pooled analysis of randomized controlled trials.

OBJECTIVE: Vibegron is a new kind of ß3-adrenergic receptor agonist. We performed a systematic review and pooled analysis to assess the efficacy, safety, and tolerability of Vibegron for treating overactive bladder (OAB). METHODS: MEDLINE, the Cochrane Controlled Trial Register and EMBASE were used to pick out randomized controlled trials (RCTs) of Vibegron in treating OAB. The reference lists of the retrieved articles were also studied. We used RevMan version 5.3.0. to analyze the data. RESULTS: Three high-quality RCTs involving a total of 2120 OAB patients were adopted in the systematic review and pooled analysis. The mean number of micturitions episodes/d (mean difference [MD] = -0.77; 95% confidence interval [CI] = -1.0 to -0.55; P < .00001); the mean number of urgency episodes/d (MD = -0.77; 95% CI = -1.03 to -0.52; P < .00001); mean number of urgency incontinence episodes/d (MD = -0.50; 95% CI = -0.64 to -0.35; P < .00001); mean number of incontinence episodes/d (MD = -0.45; 95% CI = -0.66 to -0.25; P < .0001); and mean volume voided/micturition (MD = 22.22; 95% CI = 17.36 to 27.07, P < .00001) showed that Vibegron was more efficacy in treating OAB than placebo. Dry mouth, drug-related treatment-emergent adverse event (TEAE), serious adverse event (SAE), and discontinuations due to adverse event (AE) suggested that Vibegron was well tolerated. CONCLUSIONS: Our systematic review and pooled analysis demonstrate that Vibegron 75 mg or 100 mg/d statistically significant improved OAB symptoms. The treatment was well-tolerated, with a favorable safety profile.

Potential of Mirabegron and its Extended-release Formulations for the Treatment of Overactive Bladder Syndrome.

BACKGROUND: Overactive bladder syndrome is a broadly occurring urological disorder with a distressing impact on the quality of life. The commonly used antimuscarinic drugs show poor patient compliance because of unsatisfactory potency, tolerability and high occurrence of adverse effects such as dry mouth, blurred vision, constipation, dizziness etc. Mirabegron is the first approved ß3-adrenoreceptor agonist, used as mono or in combination therapies for overactive bladder syndrome. OBJECTIVE: The present review provides an insight into the mechanism, pharmacokinetics, toxicokinetics, clinical trials and the development of various conventional and modified-release dosage forms of mirabegron for the treatment of overactive bladder syndrome. RESULTS: The clinical trials of phase II and phase III of mirabegron demonstrated symptomatic relief from the overactive bladder without disturbing the micturition cycle. To date, mirabegron showed promising results for safety, tolerability and efficacy in patients with overactive bladder syndrome. The modified-release tablet dosage form of mirabegron appear to be a proficient and suitable replacement for antimuscarinics and revealed the tremendous potential to overcome the adverse effects of conventional antimuscarinic drugs like Oxybutyline chloride ER, Detrol LA, VESIcare, etc. Conclusion: Mirabegron shows a distinct mode of action, i.e., targeting ß3-adrenoreceptors and improving bladder storage without altering void contractions. The limited side effects, high safety, efficacy and tolerability of mirabegron present an adequate substitute to antimuscarinics. However, long-term analysis and clinical studies are prerequisites for assessing the safety, tolerability and efficacy profile of mirabegron.

The Efficacy of Mirabegron for the Relief of Ureteral Stent-Related Symptoms.

To investigate the efficacy of mirabegron for lower urinary tract symptoms in patients with an indwelling ureteral stent after ureterorenoscopic lithotripsy. This was a prospective follow-up study of 76 patients with stent-related symptoms (SRSs). Patients with upper urinary calculi who were pre-stented for > 2 weeks before lithotripsy were examined for the presence of SRSs by tests including the International Prostate Symptom Score (IPSS), OAB Symptom Score (OABSS), and urinary bother and pain measured by a Visual Analogue Scale (VAS) before lithotripsy. Mirabegron (50 mg/day) was prescribed post-lithotripsy for 2 weeks. SRSs were assessed at the time of stent removal. The IPSS scores improved significantly from 16.2 to 14.3 (p<0.001) and the IPSS-QoL scores decreased significantly from 5.0 to 4.6 (p=0.012). The OABSS scores improved significantly from 7.7 to 6.8 (p=0.006), and the urinary urgency scores (OABSS-Q3) decreased significantly from 3.24 to 2.68 (p<0.001). The number of nocturia episodes decreased significantly from 2.5 to 2.2 (p=0.045). Urinary bother and pain assessed by the VAS declined from 4.2 and 3.1 to 3.8 (p=0.15) and 2.5 (p=0.075), respectively. Mirabegron significantly improved SRSs and the number of nocturia episodes due to a ureteral stent.

The ß3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans.

BACKGROUNDBeige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains ß3-adrenergic receptors (ß3-ARs), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the ß3-AR agonist mirabegron, which stimulates beige adipose formation in subcutaneous white adipose tissue (SC WAT), would induce other beneficial changes in fat and muscle and improve metabolic homeostasis.METHODSBefore and after ß3-AR agonist treatment, oral glucose tolerance tests and euglycemic clamps were performed, and histochemical analysis and gene expression profiling were performed on fat and muscle biopsies. PET-CT scans quantified brown adipose tissue volume and activity, and we conducted in vitro studies with primary cultures of differentiated human adipocytes and muscle.RESULTSThe clinical effects of mirabegron treatment included improved oral glucose tolerance (P < 0.01), reduced hemoglobin A1c levels (P = 0.01), and improved insulin sensitivity (P = 0.03) and ß cell function (P = 0.01). In SC WAT, mirabegron treatment stimulated lipolysis, reduced fibrotic gene expression, and increased alternatively activated macrophages. Subjects with the most SC WAT beiging showed the greatest improvement in ß cell function. In skeletal muscle, mirabegron reduced triglycerides, increased the expression of PPARγ coactivator 1 α (PGC1A) (P < 0.05), and increased type I fibers (P < 0.01). Conditioned media from adipocytes treated with mirabegron stimulated muscle fiber PGC1A expression in vitro (P < 0.001).CONCLUSIONMirabegron treatment substantially improved multiple measures of glucose homeostasis in obese, insulin-resistant humans. Since ß cells and skeletal muscle do not express ß3-ARs, these data suggest that the beiging of SC WAT by mirabegron reduces adipose tissue dysfunction, which enhances muscle oxidative capacity and improves ß cell function.TRIAL REGISTRATIONClinicaltrials.gov NCT02919176.FUNDINGNIH: DK112282, P30GM127211, DK 71349, and Clinical and Translational science Awards (CTSA) grant UL1TR001998.

Mirabegron Add-on Therapy to Tamsulosin for the Treatment of Overactive Bladder in Men with Lower Urinary Tract Symptoms: A Randomized, Placebo-controlled Study (MATCH).

BACKGROUND: Men with lower urinary tract symptoms (LUTS) treated with α-blockers (eg, tamsulosin) may experience overactive bladder (OAB) symptoms and receive add-on antimuscarinics. Mirabegron (a ß3-adrenoreceptor agonist) is an alternative add-on therapy. OBJECTIVE: To evaluate the efficacy of mirabegron versus placebo in men with OAB symptoms receiving tamsulosin for LUTS. DESIGN, SETTING, AND PARTICIPANTS: Japanese and Korean men with OAB treated with tamsulosin for LUTS (January 2016-July 2017). INTERVENTION: Single-blind, 4-wk screening: tamsulosin plus placebo orally once daily; double-blind, 12-wk treatment: patients randomized (n=568) to mirabegron 50mg or placebo, as add-on to tamsulosin. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary endpoint: baseline to end of treatment (EoT) change in the mean number of micturitions/24h, based on a 3-d voiding diary. Secondary endpoints: change in other diary variables and patient-reported outcomes from baseline to EoT. The primary endpoint was analyzed by analysis of covariance, including treatment group and region as fixed factors and baseline as a covariate. RESULTS AND LIMITATIONS: Mirabegron add-on therapy was superior to placebo in improving the primary endpoint (adjusted mean difference [95% confidence interval] vs placebo -0.52 [-0.82 to -0.21]) and secondary endpoints, including mean volume voided/micturition (12.08 [6.33-17.84]), OAB symptom score (-0.65 [-1.04 to -0.26]), International Prostate Symptom Score total (-1.19 [-1.94 to -0.44]), storage (-0.78 [-1.13 to -0.43]), quality of life scores (-0.29 [-0.51 to -0.07]), OAB symptom bother (-4.52 [-6.91 to -2.13]), and total health-related quality of life (2.79 [1.13 to 4.44]). Differences, compared with placebo, in urgency, urgency urinary incontinence, and nocturia were not statistically significant. Mirabegron was well tolerated, with no major safety concerns. Limitations included a lack of antimuscarinic comparison. CONCLUSIONS: The mirabegron add-on therapy to tamsulosin for 12 wk in men with LUTS and OAB symptoms demonstrated superior efficacy to placebo and was well tolerated. PATIENT SUMMARY: We looked at the efficacy and safety of mirabegron compared with placebo in men being treated with tamsulosin but who still had overactive bladder symptoms. Mirabegron improved overactive bladder symptoms and patient-reported outcomes compared with placebo, and was well tolerated.

Overactive bladder - pharmacological treatment.

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.