Selection and inclusion of studies

A total of 283 articles were yielded based on the initial search strategy, then 158 duplicates were removed during title screening. 125 potentially relevant studies remained. Of these, 6 articles were reviewed in the full text, and 4 RCTs involved in phase II – III (2813 participants) were considered eligible and were taken into this analysis [13, 14, 23, 24], which included an additional 2 RCTs with 1064 patients on the basis of previous meta-analysis [11, 12]. A flow chart outlining the literature search is shown in Fig. 1.

Fig. 1

Process of identifying eligible studies for the meta-analysis

All studies involved a placebo comparator, the agents studied were different doses of atogepant. The baseline demographics, specifically age and gender, did not differ widely among the included studies. Participants were adults (≥ 18 years) with a mean age of 41.34 years in the atogepant group and 41.47 years in the placebo group, and reported gender was 2472 females and 341 males with female-to-male ratio of 7.25:1. Almost all migraine sufferers with or without aura had been diagnosed according to the International Classification of Headache Disorders (ICHD) 3/3-beta [25, 26]. Patients in the atogepant group had suffered from migraine with a mean frequency of 10.7 days per month, while those in the placebo group reported a mean frequency of 11.5 migraine days per month. Details of the study characteristics were shown in Table 1.

Table 1 Characteristics of the included studiesRisk of bias and quality of evidence

Figure 2 displays the results from the risk of bias assessment based on the 7-item criteria in RevMan 5.3. Four studies evaluating the efficacy and safety of atogepant for migraine prevention were included [13, 14, 23, 24], all of which were randomized, double-blind, placebo-controlled trials. These RCTs described the randomization procedure in enough detail, and were considered as having a low risk of bias, whereas the risks for detection bias were unclear in two studies [23, 24], and the Goadsby P J et al. 2020 study was also assessed as having a unclear risk. In addition, the quality of the evidence for the effectiveness and safety outcomes was summarized in Fig. 3 and Supplementary Table 1.

Fig. 2

Risk of bias for included trials

Fig. 3

Summary of GRADE results for each outcomes

Effectiveness of atogepant for the treatment of migraine preventionThe reduction of monthly migraine days (MMDs)

All four trials (2732 subjects) included in this meta-analysis were evaluated for the reduction of MMDs. As shown in Fig. 4, compared with placebo, patients receiving atogepant treatment achieved a significant decrease in the numbers of MMDs (SMD − 0.40, 95% CI -0.46 to -0.34, P˂0.00001), with statistically significant differences observed across all dosage groups. However, there were no significant differences among the various dosage groups (P = 1.00, I2 = 0%). Furthermore, the results showed similar trends over different time periods from baseline to week 4, 8, and 12 (week 4: SMD − 0.47, 95% CI -0.53 to -0.41, P˂0.00001; week 8: SMD − 0.28, 95% CI -0.35 to -0.22, P˂0.00001; and week 12: SMD − 0.27, 95% CI -0.33 to -0.21, P˂0.00001; Figs. 5, 6 and 7), but notably, greater mean decreases in MMDs were observed with atogepant from baseline to week 4. The total I2 value (χ2 = 7.97, P = 0.63, I2 = 0%) revealed non-significant heterogeneity among the included trials.

Fig. 4

Meta-analysis of the reduction of MMDs in different doses compared with placebo. The diamond indicates the estimated standardized mean difference with 95% confidence interval for the pooled patients. MMDs, Monthly migraine days; M-H, Mantel-Haenszel; CI, confidence interval

Fig. 5

Meta-analysis of the reduction of MMDs in different doses at week 4. The diamond indicates the estimated standardized mean difference with 95% confidence interval for the pooled patients. MMDs, Monthly migraine days; M-H, Mantel-Haenszel; CI, confidence interval

Fig. 6

Meta-analysis of the reduction of MMDs in different doses at week 8. The diamond indicates the estimated standardized mean difference with 95% confidence interval for the pooled patients. MMDs, Monthly migraine days; M-H, Mantel-Haenszel; CI, confidence interval

Fig. 7

Meta-analysis of the reduction of MMDs in different doses at week 12. The diamond indicates the estimated standardized mean difference with 95% confidence interval for the pooled patients. MMDs, Monthly migraine days; M-H, Mantel-Haenszel; CI, confidence interval

The reduction of monthly headache days (MHDs)

Four trials of 2732 subjects were included in this meta-analysis and evaluated for the reduction of MHDs. The SMD after treatment favored atogepant over placebo (SMD − 0.39, 95% CI -0.46 to -0.33, P˂0.00001; Fig. 8), and the subgroup analysis didn’t show a remarkable difference in the reduction of MHDs from different dosage of atogepant over control therapy (χ2 = 0.75, P = 0.95, I2 = 0%). Furthermore, the total(χ2 = 9.46, P = 0.49, I2 = 0%) or subgroup I2 value on the reduction of MHDs revealed a non-significant heterogeneity among the included trials except for the atogepant 60 mg QD group (χ2 = 6.50, P = 0.09, I2 = 54%).

Fig. 8

Meta-analysis of the reduction of MHDs in different doses compared with placebo. The diamond indicates the estimated standardized mean difference with 95% confidence interval for the pooled patients. MHDs, Monthly headache days; M-H, Mantel-Haenszel; CI, confidence interval

The reduction of acute medication use days

Four trials with a total of 2732 subjects included for the outcomes. As shown in Fig. 9, atogepant also showed benefits with over placebo at the reduction of acute medication use days (SMD − 0.45, 95% CI -0.51 to -0.39, P˂0.00001), while no dose-related improvements were found in different dosage groups (χ2 = 0.46, P = 0.98, I2 = 0%), and continuing to increase the dose of the medication did not further improve the efficacy. The total or subgroup I2 value revealed non-significant heterogeneity among the included trials.

Fig. 9

Meta-analysis of the reduction of acute medication use days in different doses compared with placebo. The diamond indicates the estimated standardized mean difference with 95% confidence interval for the pooled patients. M-H, Mantel-Haenszel; CI, confidence interval

50% responder rate in monthly migraine days

The 50% reduction rate, when the MMDs were reduced by 50% or more over a period of 12 weeks, was counted in four included trials with a total of 2732 subjects. As shown in Fig. 10, the data showed a significant decrease in 50% responder rates of atogepant compared with placebo (RR 1.66, 95% CI 1.46 to 1.89, P = 0.002), and the statistical differences observed across all dosage groups. The total I2 value revealed a moderate heterogeneity among the included trials (χ2 = 28.12, P = 0.002, I2 = 64%), and a high level of heterogeneity in two dosage groups (30 mg QD: χ2 = 6.77, P = 0.009, I2 = 85%; 60 mg QD: χ2 = 16.42, P = 0.0009, I2 = 82%).

Fig. 10

Meta-analysis of the 50% responder rates in diferent doses compared with placebo. The diamond indicates the estimated relative risk with 95% confidence interval for the pooled patients. M-H, Mantel-Haenszel; CI, confidence interval

Safety of atogepant for the treatment of migraine prevention

Safety outcomes were reported in four trials for adverse events (AEs). As shown in Table 2, the atogepant group and two dosage groups (atogepant 30 mg BID or 60 mg BID) showed a significantly higher risk of any treatment-emergent adverse events (TEAEs) and treatment-related TEAEs (TEAEs: all [RR 1.11, 95% CI 1.02–1.21, P = 0.02], atogepant 30 mg BID [RR 1.17, 95% CI 1.02–1.34, P = 0.02]; treatment-related TEAEs: atogepant 60 mg BID [RR 1.64, 95% CI 1.02–2.63, P = 0.04]). Furthermore, there were remarkable differences between atogepant and placebo in the incidence of constipation, nausea, fatigue and urinary tract infection (constipation: all [RR 2.55, 95% CI 1.91–3.41, P < 0.00001], atogepant 30 mg QD [RR 2.14, 95% CI 1.10–4.18, P = 0.03], atogepant 60 mg QD [RR 2.74, 95% CI 1.74–4.32, P < 0.0001], atogepant 30 mg BID [RR 3.03, 95% CI 1.54–5.95, P = 0.001]; nausea: all [RR 2.19, 95% CI 1.67–2.87, P < 0.00001], atogepant 60 mg QD [RR 2.63, 95% CI 1.71–4.05, P < 0.0001], atogepant 30 mg BID [RR 2.10, 95% CI 1.16–3.78, P = 0.01]; fatigue: atogepant 60 mg BID [RR 3.07, 95% CI 1.13–8.35, P = 0.03], urinary tract infection: all [RR 1.05, 95% CI 1.05–2.11, P = 0.03]), some statistically significant differences between the various dosage groups were detected regarding the aforementioned AEs. In addition, there were no significant differences in the incidence of nasopharyngitis and upper respiratory tract infection, serious TEAEs were reported in 22 of the participants in the atogepant or placebo group. Most of the I2 value revealed a low heterogeneity among the included studies.

Table 2 Comparison of main TEAEs between atogepant and placebo