To date, numerous large-scale, internationally registered rhGH databases have been established to investigate the long-term safety and efficacy of rhGH therapies and emphasize the advantages of daily rhGH injections for GHD [5, 16, 17]. The CGLS database is the first large-scale growth hormone database developed in China, distinguished by its significant number of participants who received the LAGH.

Despite the consensus statement on LAGH therapy in PGHD [18], there remains a significant gap in large-sample, long term data across globally approved and marketed LAGH formulations. This study addresses this unmet need by providing a comprehensive, long-term dataset focused on the use of a PEGylated LAGH, offering valuable real-world evidence. The safety and efficacy outcomes captured here could serve as a foundational resource for both national-level clinical guidance and cross-national benchmarking of LAGH therapies. Notably, the study contributes to the consensus-driven call for long-term safety evaluations of LAGH molecules with diverse mechanisms of action—an area identified as a core research priority in the 2024 consensus. By addressing the data gaps emphasised in the consensus, this study represents a critical step toward evidence-based harmonization of paediatric GHD management, fostering more nuanced understanding of LAGH use in diverse clinical settings.

The overall incidence of AEs was 563 (46.6%), which is lower than the previously reported safety profile of PEG-rhGH over a 3-year period (53.6%) [12]. In this study, the three most common AEs were upper respiratory tract infection (23.8%, n = 287), fever (9.2%, n = 111), and cough (4.7%, n = 57). In the KIGS study, upper respiratory tract infection and cough were reported at rates of 0.6% and 0.2%, respectively. The overall incidence of these three AEs was higher than that observed in the KIGS, while treatment-related AEs were comparable to those reported by KIGS [17]. This may be attributed to the impact of the coronavirus disease 2019 (COVID-19) on the respiratory tract. In addition, LAGH has also become the preferred treatment option during the COVID-19 pandemic due to its convenient weekly administration. The main purpose of the CGLS database is to capture AEs, which has led to the collection of more AEs due to the stringent collection process. This further emphasizes the need to pay attention to comorbidities during growth hormone (GH) treatment. In terms of SAEs, although there were 12 SAEs recorded in both the 5-year or the 3-year outcomes reported before [12], none were related to PEG-rhGH treatment, but with differences in the disease spectrum of SAEs.

In this study, incidence of TRAEs was 8.5% with no severe adverse reactions. Scoliosis is a relatively high clinical concern, which was observed in 8 participants (0.7%). All children with scoliosis were referred to the pediatric orthopedics department for specialized care. It is reported that the use of rhGH in participants with GHD may not directly cause scoliosis; it may exacerbate the condition, particularly in those with preexisting scoliosis [19]. This may manifest as an increased Cobb angle or greater translation of the apical vertebra in imaging studies. The prevailing hypothesis suggests that the progression of scoliosis linked to rhGH treatment may result from accelerated growth [20]. Due to retrospective nature of current research, the baseline spinal x-ray examinations were unavailable. Therefore, updating the CGLS database with more baseline spinal x-ray data would help to assess the incidence or progression of scoliosis in PEG-rhGH recipients.

Hypothyroidism is one of the commonly observed outcomes of GH treatment, potentially due to central hypothyroidism in patients with multihormonal hypopituitarism or effects of GH on thyroid hormone metabolism. The lack of the cause of GHD in this study hinders the determination of the proportion of multihormonal hypopituitarism, Since baseline thyroid screening is a routine practice in China, and patients who developed thyroid dysfunction during treatment had normal baseline results, we cautiously conclude that thyroid abnormalities were treatment-related (n = 15 [1.2%]). Abnormal glucose metabolism is a frequent AE during rhGH therapy. In this study, two participants exhibited abnormal glucose metabolism (one with elevated glycosylated hemoglobin and the other with increased fasting insulin) without any cases of type 1 or 2 diabetes (data not shown).

In both KIGS and GeNeSIS studies, headache was primarily reported as a treatment-emergent AE (TEAE) (0.4% in KIGS) [17, 21]. The GeNeSIS database showed varied incidence across countries, with 2.8% in the United States, 3.0% in Germany, and 6.3% in France [21]. In this study, the incidence of treatment-related headaches was 0.2% (2 cases), which was even lower than those reported in the previous databases.

The long-term safety risks of GH therapy focus on tumors, cardiovascular events, and death. LAGH is expected to become the preferred therapy, due to its reduced injection frequency compared to daily GH, making long-term monitoring and follow-up necessary. Existing clinical evidence does not indicate the association between rhGH treatment and tumor development [20]. Despite the five-year duration of drug exposure in the current study, no new or recurrent tumor occurrence was observed. Additionally, there were no serious cardiovascular events (such as vascular rupture), or deaths noted. However, the KIGS study which followed patients for 8.2 years reported 24 deaths possibly due to drug-related causes, with tumors being the most common cause, followed by cerebral hemorrhage [17]. Therefore, continued long-term monitoring of the CGLS database is necessary, with particular attention to the aforementioned AEs.

The frequency of AEs in this study is consistent with previous findings from KIGS [17] and NordiNet [5], where most events were reported within the first year of treatment. Significantly, no cases of malignancy or fatal outcomes were observed in this study, suggesting that PEG-rhGH may not pose significant life-threatening risks.

Over five years of use, continuous improvement was observed in height, with the Ht SDS reaching − 0.3 ± 0.8 by the fifth year. Studies have indicated that the growth response of rhGH tends to be higher in the first year, tapering off in the subsequent years [22]. In the current study, the improvement in height was most significant in the first year, accounting for 47.4% of the total height gain observed during the five years. The “first-year effect” was also documented in other real-world registry studies [19]. Improvement in growth response at an early age is necessary, as it allows the participants to attain proper adult height post-puberty [23]. Further research suggests that height gain is affected by many factors, including age at the start of GH treatment and the initial deficit in target height [24,25,26].

HV has significantly improved from baseline during the five-year treatment. HV peaked in the first year and exhibited a downward trend in the following years (Fig. 2C, Table 3). Fifth-year HV was analyzed by Tanner stage, showing that boys in stages 3–4 and girls in stage 2 had faster growth, possibly due to combined effects of sex hormones and PEG-rhGH.

Another significant finding from this study was the assessment of the ratio of ∆Ht-SDS to the cumulative medication dose. The findings indicate that initiating treatment at a younger age resulted in a more substantial increase in height per unit dose (Table 4). Long-term studies are essential to understand if the PEG-rhGH produces an accurate dose–response effect, which can be achieved by utilizing growth databases such as CGLS, aiding in better understanding of a longer follow-up and also address questions related to growth responses.

This study demonstrates the five-year safety and growth response outcomes of PEG-rhGH, but has limitations. The five-year observation period may miss long-term malignancy, cardiovascular, or metabolic risks, necessitating continued follow-up. The final adult height (FAH) was not analyzed due to limited data. In future follow-up studies, with the accumulation of CGLS data, it is expected to address the long-term therapeutic effect of GH treatment based on FAH.

CGLS represents the first and largest real-world registry of GH usage conducted in China, involving over 1000 participating centers. Data on the use of GH has been accumulated for many indications, including but not limited to GHD, TS, and ISS. Extensive data collection in future could enhance our understanding of long-term safety and efficacy.