3.1. Study Selection and Baseline Characteristics
The initial literature search yielded a total of 950 results. After the removal of duplicated records, 650 studies were evaluated based on their titles and abstracts according to the eligibility criteria. Among these, 27 met the criteria for full-text reading, as described in Figure 1. In conclusion, nine core studies were ultimately selected: four clinical trials and five observational cohorts, with a total of 590 patients involved. The studies population consisted of individuals with active or uncontrolled acromegaly who had undergone previous treatment in the first or second line, either with surgery, radiotherapy, or with medical treatment. In the pooled population, most patients (67.1%, 396/590) received medical treatment with first-generation SRL, DA and GH receptor antagonist, either alone or in combination, while 51.5% (304/590) underwent pituitary surgery. The median age of patients ranged from 43 to 56 years, with males comprising 48.8% of the population. 43.5% (180/414) of patients were diagnosed with diabetes before initiating pasireotide treatment. The baseline characteristics of the population in the included core studies are described in Table 1.
Moreover, six of the nine primary studies provided long-term results. Three clinical studies progressed into the extension phase and subsequently reported their findings. Three observational cohort studies also reported their long-term results within the same publication. Table 2 details the baseline characteristics of studies with long-term results.
Table 1. Study characteristics.
Study
|
Design
|
Follow-Up (mo)
|
N
|
Age, †
|
Male,
N (%)
|
Previous Treatments
|
Baseline mean IGF-1,
Baseline mean GH
|
PAS-LAR,
Dosage ‡
|
Diabetes status, N (%)
|
Chiloiro 2022[14]
|
Retrospective cohort
|
12
|
31
|
44
|
18 (58.1)
|
Surgery: 31 pts
First gen-SSA: 31 pts
|
IGF-I x ULN: 1.4
GH: 4.2 μg/L
|
40 mg or 60 mg/4w
|
10 (35.4)
|
Colao 2014[21]
NCT00600886
|
Phase III RCT
|
12
|
176
|
46
|
85 (48.3)
|
Surgery: 71 pts
Medically naïve: 176 pts
|
IGF-I x ULN: 3.1
GH: 21.9 μg/L
|
40 mg/4w
|
N/A
|
Corica 2023[15]
|
Retrospective
cohort
|
6
|
21*
|
56
|
8 (38)
|
Surgery: 13 pts
First gen-SSA: 7 pts
Combination therapy: 14 pts
Radiotherapy: 2 pts
|
IGF-I x ULN: 1.3
GH: 3.81μg/L
|
20 mg or 40 mg/4w
|
3 (14)
|
Gadelha 2019[22]
NCT02354508
|
Phase IIIb
non-RCT
|
9
|
123
|
43
|
61 (49.6)
|
First gen-SSA: 123 pts
|
IGF-I x ULN: 2.7
GH: 10.2 μg/L
|
40 mg/4w
|
52 (42.3)
|
Lasolle 2019[23]
|
Prospective
cohort
|
3
|
15
|
50
|
5 (33.3)
|
Surgery: 14 pts
Combination therapy: 15 pts
Radiotherapy: 4 pts
|
IGF-I x ULN: 1.4
GH: N/A
|
40 mg or 60 mg/4w
|
5 (33.3)
|
PAOLA 2014[8]
NCT01137682
|
Phase III RCT
|
6
|
130
|
45
|
57 (43.8)
|
Surgery: 91 pts
First gen-SSA + Peg-V: 37 pts
First gen-SSA + DA: 85 pts
Radiotherapy: 5 pts
|
IGF-I x ULN: 2.7
GH: 14.8 μg/L
|
40 mg or 60 mg/4w
|
86 (66)
|
Shimon 2018[24]
|
Retrospective cohort
|
12
|
35
|
46
|
20 (57.1)
|
Surgery: 30 pts
First gen-SSA: 18 pts
Combination therapy: 13 pts
Others: 2 pts
Radiotherapy: 6 pts
|
IGF-I x ULN: 1.7
GH: N/A
|
40 mg or 60 mg/4w
|
11 (31.4)
|
Stelmachowska 2022[25]
|
Prospective
cohort
|
12
|
26
|
N/A
|
14 (53.8)
|
Surgery: 25 pts
First gen-SSA: 26 pts
Radiotherapy:3 pts
|
IGF-1 x ULN: 2.3
GH: 3.9 μg/L
|
40 mg/4w
|
4 (15.4)
|
Tahara 2017[26]
NCT01673646
|
Phase II
Randomized
|
12
|
33
|
52
|
20 (60.6)
|
Surgery: 29 pts
First gen-SSA: 22 pts
Others: 21 pts
Medically naïve: 8 pts
|
IGF-1 x ULN: 2.7
GH: 28.8 μg/L
|
20 mg,
40 mg or 60 mg/4w
|
9 (27.3)
|
†, median; mo, months; d, days; w, weeks; N/A, Not available; SSA, somatostatin analogues; PEG-V, pegvisomant; DA, dopamine agonist; PAS- LAR, pasireotide-long active release; GH, growth hormone; IGF-1, insulin-like growth factor-1; ULN, upper limit of normality; pts, patients; ‡, Dose increases were permitted for patients who were uncontrolled, and the dose could be decreased for tolerability issues;*, Only nine uncontrolled acromegaly patients were included in meta-analysis; Combination therapy refers to combination of fgSRL with PEG-V or DA; Others, Peg-V or DA or combination of PEG-V and DA.
Table 2. Baseline characters of studies with long term results.
Study
|
Design
|
Treatment duration,
months (range), †
|
No. of
Patients
|
Akirov 2021[27]
|
Extension study of Shimon et al. 2018
|
50 ± 36 (12-135) *
|
19
|
Gadelha 2017[28]
|
Extension study of PAOLA 2014
|
30 (N/A)
|
111
|
Corica 2023[15]
|
Extension of the same study
|
35 (7.5-47)
|
9
|
Gadelha 2019[22]
|
Extension of the same study
|
18 (3-19)
|
88
|
Lasolle 2019[23]
|
Extension of the same study
|
29 (17-34)
|
8
|
Sheppard 2015[29]
|
Extension study of Colao et al. 2014
|
17.6 (N/A) *
|
74
|
†, median; *mean.
3.2. Biochemical Control
The Biochemical Control rate was 22% (95% confidence interval (CI): 13.48-33.80) for less strict control group patients and 31.68% (95% CI: 11.56-62.18) for more strict control group patients, without a significant difference between groups (p=0.49). The overall population biochemical control rate was 26.50% (95% CI: 14.87-42.66, I2 = 86%), as described in Figure 2A. The prevalence of normalized IGF1, presented in Figure 2B, was 36.27% (95% CI 29.15-43.39) with significant inter-study heterogeneity (I2 = 58%). In Figure 2C, the prevalence of Low GH levels was 34.76% (95% CI 24.58-44.95, I2 = 86%).
3.3 Long term efficiacy of Pasireotide
In a pooled analysis including four studies[22], [23], [28], [29], the prevalence of biochemical control rate in the overall population was 29.03% (95% CI: 11.49-46.58, I2 = 91%). Exploring the prevalence of biochemical control further in a subgroup analysis revealed no significant differences between studies with less strict control and studies with more strict control. The Biochemical response rate was 36.13% versus 19.05%, respectively (p = 0.32), as illustrated in Figure 3A. The overall population's normalized IGF1 rate was 53.32% (95% CI: 35.79-70.84, I2 = 86%) with 128 events out of 309 patients, as shown Figure 3B. The prevalence of low levels of GH was 46.98% (95% CI: 23.78–70.18, I2 = 95%), with 120 events out of 281 patients included in the analyses, as described in Figure 3C.
3.4 Adverse Events
Regarding safety, the most reported adverse events were hyperglycemia and diabetes mellitus. In the overall population, 29.55% (95% CI: 21.80–37.29, I2 = 67%) of patients experienced hyperglycemia, with 170 events out of 535 patients (Figure 4 A). New onset diabetes mellitus affected 23.36% (95% CI: 19.58-27.13, I2 = 35%) of the population, with a total of 139 adverse events out of 587 patients, as shown in Figure 4 B. Furthermore, 31.26% (95% CI: 7.44–72.01) of patients experienced gastrointestinal (GIS) related events, 15.23% (95% CI: 8.90–24.82) experienced biliary-related events, and 19.15% (95%CI: 13.46–26.52) experienced ≥ 3 AEs, indicating severe adverse events (Supplementary Figure1S A,B,C).
3.5 Quality Assessment and Sensitivity Analysis
Two trials, Colao et al. 2014[21] and PAOLA 2014[8], were considered to have a low risk of bias, whereas Tahara et al. 2017[26] was found to have some concerns as the risk classification. For the observational studies, the risk of bias assessment through ROBINS-I showed a serious risk in Chiloiro et al. 2022[14], and a moderate risk in Corica et al. 2023[15], Gadelha et al. 2019[22], Lasolle et al. 2019[23], Shimon et al. 2018[24], and Stelmachowska et al. 2022[25]. The tables reporting the results of RoB2 and ROBINS-I tools are available in Supplementary Tables S1 and S2.
Leave-one-out sensitivity analyses by systematically removing each study from the pooled estimates to evaluate the high heterogeneity in the prevalence of biochemical control, normal IGF1 levels, and low GH levels (Supplementary Figure S2A,B,C, respectively). In the leave-one-out analysis of the prevalence of normal IGF1 levels, excluding the PAOLA 2014 study significantly reduced the high heterogeneity. Other analyses did not substantially change the results.
In the visual inspection of the two funnel plots from the outcomes of biochemical control and low GH levels, we found a predominantly symmetrical pattern of the number of studies on each side and their disposition around the central axis. However, one study was notably located outside the plot in biochemical control analysis, which may represent differences in patient selection. To explore this further, we conducted Egger’s regression test, which showed no evidence of significant publication bias (z = 0.2687, p = 0.9229). The funnel plot for normalized IGF1 showed an asymmetrical pattern, but Egger’s regression test also indicated no significant publication bias (z = 1.9427, p = 0.1914). These findings are presented in Supplementary Figure S3 A, B, C, respectively. In the analysis of adverse events, only the funnel plot for diabetes mellitus showed a visually asymmetrical pattern, and Egger's regression test found significant asymmetry (z = 1.7928, p = 0.0455). Hyperglycemia (z = 0.7461, p = 0.7222), gastrointestinal related adverse events (z = 51.621, p = 0.0909), biliary related adverse events (z = 3.022, p = 0.5851), and adverse events with a grade greater than or equal to 3 (z = 3.446, p = 0.1776) did not exhibit significant asymmetry (Supplementary Figure S4A,B,C,D, E respectively)..