Urolithiasis is a common condition affecting the human urinary system, with a prevalence of approximately 2%–3% across all populations (Cui et al., 2014). Ureteral stones, which make up about 20% of all urolithiasis cases, are particularly troublesome, with around 70% of these stones located in the distal ureter (Ahmed and Al-Sayed, 2010; Raheem et al., 2017). If untreated, ureteral stones can cause severe pain and lead to serious complications, such as acute kidney injury, infections, and septic shock, posing significant health risks and economic burdens for patients (Thongprayoon et al., 2020; Türk et al., 2016).

The main treatment options for ureteral stones include medical expulsion therapy (MET), extracorporeal shockwave lithotripsy (ESWL), and endoscopic surgery (Paffenholz and Heidenreich, 2021). MET is commonly recommended for distal ureteral stones, as it helps relax smooth muscles in the urinary tract, facilitating the passage of stones (Segura et al., 1997). The most widely used medications for MET are α-adrenergic antagonist, such as tamsulosin (Raheem et al., 2017).

Recently, mirabegron, a β3-adrenergic receptor agonist, has gained attention for its ability to relax bladder smooth muscle and alleviate overactive bladder symptoms (Solakhan et al., 2019; Wanajo et al., 2004). Emerging research indicates that β3-adrenergic receptors are also expressed in the smooth muscle and urothelium of the ureter, suggesting that mirabegron could be a novel option for MET in treating ureteral stones (Kaya et al., 2018; Kelleher et al., 2018). Activation of β3-adrenergic receptors can reduce the excitability of smooth muscle cells by inhibiting the release of intracellular calcium ions (Ca²⁺) and enhancing the efflux of potassium ions (K⁺), which may contribute to the relaxation of ureteral smooth muscle and facilitate stone passage (Dey et al., 2024). However, the current evidence regarding its effectiveness remains inconclusive and has yet to be thoroughly evaluated. This study aims to systematically review and compare the effectiveness and safety of mirabegron versus α-adrenergic receptor antagonist in the treatment of distal ureteral stones.

The review protocol was registered with PROSPERO (CRD42024599866; https://www.crd.york.ac.uk/PROSPERO/) following the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Current clinical guidelines indicate that MET is a viable treatment option for distal ureteral stones (Beach and Mauro, 2006). α-adrenergic receptor blockers, such as tamsulosin, are commonly utilized in MET. Additionally, other medications, including calcium channel blockers, phosphodiesterase type 5 inhibitors, and corticosteroids, have also demonstrated efficacy in facilitating the passage of ureteral stones (Itoh et al., 2011). Recently, studies have explored the potential of mirabegron, a β3-adrenergic receptor agonist, in promoting stone expulsion (Shen et al., 2017). A meta-analysis by Song et al. concluded that mirabegron significantly increased the SER of distal ureteral stones and reduced the frequency of pain episodes (Song et al., 2023).However, the effectiveness of mirabegron remains a subject of debate. While some randomized controlled trials have reported benefits of mirabegron in stone expulsion, others have not confirmed these findings (Van Asseldonk and Elterman, 2015; Ye et al., 2011). For instance, Tang et al. demonstrated that mirabegron significantly improved SER in patients with stones measuring ≤5 mm but had no effect on those with larger stones (Tang et al., 2021). In this meta-analysis, we systematically evaluated the efficacy and safety of mirabegron compared to α-adrenergic receptor blockers for the treatment of distal ureteral stones.

Our findings indicated no significant differences in SER or SEI between the mirabegron and α-adrenergic receptor antagonist groups. This suggests that mirabegron may have comparable overall efficacy to tamsulosin and silodosin regarding stone passage and expulsion time. Notably, our analysis revealed that mirabegron significantly reduced the frequency of pain episodes during stone expulsion, particularly in comparison to silodosin. Although pain perception is a subjective outcome measure—unlike objective metrics such as SER or SEI—it remains a critical endpoint in urolithiasis management. Patient-reported pain relief directly reflects therapeutic success from the patient’s perspective, as uncontrolled colic not only diminishes quality of life but also drives healthcare resource utilization (Cabo and Miller, 2024). This reduction in pain frequency holds direct clinical relevance: fewer pain episodes may translate into improved quality of life by reducing dependence on analgesics (e.g., opioids or NSAIDs), decreasing emergency department visits for uncontrolled colic, and enabling earlier resumption of daily activities or occupational duties. The result underscores the potential advantage of mirabegron in pain management during MET.

The use of β3-adrenergic receptor agonists, such as mirabegron, is primarily associated with the management of overactive bladder (Lipkin and Shah, 2009). However, recent research has identified the presence of β-adrenergic receptors in the smooth muscle of the human ureter (Taylor et al., 2004). The activation of β3-adrenergic receptors is believed to relax ureteral smooth muscle, facilitating stone passage by reducing the frequency of peristaltic contractions (Tomiyama et al., 2007). This mechanism may account for the observed reduction in pain frequency in our analysis, as fewer ureteral contractions can lead to less discomfort during stone expulsion.

In terms of adverse effects, the analysis revealed that mirabegron had a significantly lower incidence of headache and orthostatic hypotension compared to α-adrenergic receptor antagonists, suggesting that mirabegron may have a more favorable safety profile. However, there were no significant differences between the two groups in terms of dizziness or ejaculation dysfunction, further supporting the potential suitability of mirabegron for certain patients. It is important to note that the safety assessment was based on only two included studies. While meta-analyses can be conducted with as few as two studies, the low heterogeneity observed here should be interpreted cautiously. A low I² value does not necessarily indicate the absence of true heterogeneity; it may instead reflect limited statistical power due to the small number of trials or insufficient variability in study designs. The reduced side effects of mirabegron, particularly in relation to headache and hypotension, are likely due to its targeted action on β3 receptors in the bladder, with minimal influence on the vascular system (Shen et al., 2017). In contrast, α1-adrenergic receptor antagonists act by blocking α1 receptors in vascular smooth muscle, leading to vasodilation and lower blood pressure, which increases the risk of orthostatic hypotension and headache (Itoh et al., 2011; Tomiyama et al., 2007). Overall, both mirabegron and α-adrenergic receptor antagonists were generally well tolerated by patients, with mild side effects commonly reported. Nevertheless, the limited scope of safety data underscores the need for future trials to prioritize standardized reporting of adverse events across larger cohorts, which would enhance the reliability of safety comparisons. This suggests that mirabegron may serve as an alternative treatment option for patients with contraindications to α-adrenergic receptor antagonists or for those who do not respond well to initial therapy.

In our subgroup analysis, we compared mirabegron with both tamsulosin and silodosin. Interestingly, while mirabegron showed a significant improvement in pain relief compared to silodosin, no significant differences were noted between mirabegron and tamsulosin across any of the studied parameters, including SER, SEI, or pain episodes. This suggests that the therapeutic effects of mirabegron may be more comparable to tamsulosin but could offer superior pain relief compared to silodosin. However, further studies are required to confirm these findings and explore the underlying mechanisms.

Our study has several limitations. Firstly, the small number of studies and limited sample size reduce the statistical power of the analysis. Secondly, the high heterogeneity in some endpoints, potentially due to variations in study design, sample size, and inclusion criteria, weakens the overall reliability of our findings. Additionally, most of the included studies were conducted in specific regions, limiting the generalizability of the results to broader populations.

Mirabegron may offer advantages in managing pain during medical expulsive therapy for distal ureteral stones, especially when compared to silodosin, even though no significant differences were observed in SER or SEI. Furthermore, mirabegron demonstrated a favorable safety profile, showing reduced rates of headache and orthostatic hypotension relative to α-adrenergic receptor antagonists. To validate these results and explore the mechanisms behind the different impacts on pain relief and safety, additional well-structured randomized controlled trials are necessary.