Growth hormone (GH), a pulsatile peptide hormone secreted by the somatotroph cells in the anterior pituitary gland, plays a pivotal role in mediating linear growth during childhood and adolescence, while also regulating critical metabolic processes, body composition homeostasis, and skeletal integrity in adults (1, 2). The advent of recombinant human GH (rhGH) in the 1980s marked a therapeutic revolution, providing an effective treatment for growth hormone deficiency (GHD) (3). Despite the clinical success of rhGH, the management of GHD has long been hindered by the inherent pharmacokinetic (PK) limitations of conventional daily rhGH therapy. The recombinant hormone exhibits a short plasma half-life of approximately 2–4 hours due to rapid renal clearance and proteolytic degradation. Consequently, patients are burdened with a rigorous regimen of daily subcutaneous injections (4, 5). This demanding schedule is a well-documented primary cause of suboptimal treatment adherence. Real-world evidence indicates that a substantial number of patients (particularly pediatric and adolescent populations) frequently miss dose; this non-adherence directly compromises growth velocity in children and undermines the metabolic benefits in adults (6, 7). Beyond the clinical consequences of non-adherence, the psychological burden of daily injections—encompassing injection-related anxiety, persistent “needle fatigue,” and diminished treatment satisfaction—exerts a significant negative impact on the quality of life of both patients and their caregivers, further exacerbating the challenges of long-term GHD management (8, 9).

Against this backdrop of unmet clinical needs, the development of long-acting GH (LAGH) formulations has emerged as a major focus in endocrine therapeutics over the past two decades. The core goal of LAGH development is to retain the well-established efficacy of rhGH while fundamentally transforming the treatment experience by drastically reducing injection frequency (10, 11). This review is dedicated to a comprehensive analysis of how this goal has been progressively achieved. We first delve into the molecular engineering strategies underpinning the extended half-life of LAGH formulations, then synthesize pivotal evidence on clinical efficacy and safety, integrating data from randomized controlled trials and real-world studies. Next, we outline evidence-based frameworks for the practical application of LAGH in clinical practice. Finally, we discuss emerging trends and future directions in this rapidly evolving therapeutic field.

The principal challenge in developing LAGH formulations lies in delaying the systemic elimination of the GH molecule without compromising its intrinsic bioactivity at the GH receptor. To address this, researchers have developed multiple innovative technological platforms (Figure 1), each leveraging distinct molecular mechanisms to extend circulating half-life while maintaining therapeutic efficacy.

The transition from daily to weekly GH administration fundamentally alters the drug’s exposure profile. A thorough understanding of its PK and pharmacodynamic (PD) characteristics is therefore crucial for both safety and efficacy (22, 23). In contrast to endogenous pulsatile secretion, LAGH formulations generate a sustained, supra-physiological concentration-time profile. This profile is characterized by a peak concentration following injection, which subsequently declines gradually over the dosing interval (24, 25).

This distinct PK pattern has driven a paradigm shift in PD monitoring strategies. For daily rhGH, serum GH concentrations themselves could be used to approximate exposure. However, LAGH’s prolonged half-life renders direct GH measurement less informative for assessing sustained biological activity. Instead, serum insulin-like growth factor-I (IGF-I) has emerged as the primary and most clinically validated PD biomarker for LAGH. As a downstream mediator of GH’s biological effects (e.g., cell proliferation, linear growth, metabolic regulation), IGF-I exhibits a longer half-life than native GH and correlates tightly with LAGH’s sustained exposure, making it ideal for evaluating biological activity and guiding dose titration (26). This established shift from GH to IGF-I monitoring underscores the fundamental change in exposure dynamics introduced by long-acting formulations.

The efficacy and safety profiles of the leading LAGH formulations—lonapegsomatropin, somapacitan, and somatrogon—have been rigorously validated through multinational, randomized controlled Phase III trials. These trials form the cornerstone of their global regulatory approvals. Table 1 provides a comparative summary of these studies, highlighting key differences in trial design, endpoints, and outcomes that inform clinical decision-making. A critical distinction across these trials lies in their methodological design, which directly influences the interpretability of efficacy results.

The heiGHt trial for lonapegsomatropin employed an open-label design with standardized objective assessment procedures to minimize potential bias. In this 52-week study of 161 treatment-naive pediatric patients with GHD, lonapegsomatropin (once-weekly) not only met the primary endpoint of non-inferiority to daily rhGH but also demonstrated statistical superiority in annualized height velocity (AHV) (11.2 cm/yr vs. 10.3 cm/yr; p<0.01) (21). This superiority is hypothesized to stem from its TransCon™ technology, which enables steady, physiological release of native GH—avoiding the supraphysiological peaks and subtherapeutic troughs associated with daily injections, and thereby optimizing IGF-I exposure for growth. The REAL 4 trial for somapacitan and the NCT02968004 trial for somatrogon were also conducted with an open-label design, both trials robustly met their primary endpoints of non-inferiority to daily rhGH in AHV. The REAL 4 trial reported an AHV of 11.2 cm/yr for once-weekly somapacitan versus 11.7 cm/yr for daily rhGH, while the somatrogon trial (n=224) observed an AHV of 10.1 cm/yr for once-weekly somatrogon compared to 9.8 cm/yr for daily rhGH (27, 28).

Recent international consensus statements have established crucial frameworks for the standardized implementation of LAGH therapies. A foundational principle is the necessity for clinicians to acquire a thorough understanding of the distinct PK and PD profiles of each LAGH agent to ensure appropriate selection, dosing, and monitoring. While the core principles outlined in these documents—such as patient selection criteria, the standardized approach to IGF-I-based monitoring, and dose titration protocols—are universally applicable, their real-world execution is inevitably shaped by local contexts. Factors including national drug formularies, reimbursement policies, and regional clinical guidelines (e.g., those issued by the Chinese Society of Pediatric Endocrinology and Genetics) play a decisive role in determining the accessibility and practical adoption of specific LAGH therapies across different healthcare systems (37).

A cornerstone of this modernized management paradigm is the novel strategy for monitoring IGF-I. International consensus recommends that serum IGF-I levels be measured at a standardized trough point—typically on day 4 or day 4.5 following injection, depending on the specific product—as this timing strategically corresponds to the agent’s average weekly exposure (37). Strict adherence to this sampling schedule is critical for accurate interpretation. Deviations necessitate the application of product-specific correction factors to derive a reliable estimate of the average IGF-I standard deviation score (SDS). The overarching therapeutic goal is to maintain this estimated average IGF-I SDS within the normal physiological range (typically -2 to +2), balancing the aims of optimizing efficacy and minimizing potential safety concerns related to over-exposure (37, 38).

Within this evolving therapeutic landscape, shared decision-making emerges as an indispensable element for successful therapy initiation and long-term adherence (39). This collaborative process engages clinicians, patients, and their families in a comprehensive discussion that balances the potential benefits of LAGH—primarily the reduced injection frequency and its positive impact on quality of life—against product-specific considerations, such as cost, reimbursement, delivery device design, and storage requirements. This patient-centered approach is particularly vital for populations at higher risk of non-adherence, such as adolescents and individuals experiencing significant needle anxiety, ensuring that treatment choices align with patient preferences and lifestyle to foster optimal long-term outcomes.

Despite the robust efficacy and safety data established in pivotal clinical trials, international consensus groups have pinpointed several critical knowledge gaps that must be addressed to fully integrate LAGH into long-term clinical practice. Table 3 systematically outlines these unresolved questions and proposes essential avenues for future research.

As detailed in Table 3 below, the evidence base for LAGH continues to mature. A paramount need is for long-term, real-world evidence (RWE) collected from diverse populations beyond the controlled setting of clinical trials. Such data are crucial for elucidating the true effectiveness, real-world adherence patterns, and long-term safety profiles of these therapies.

A major and interrelated set of gaps concerns the long-term safety of sustained GH exposure in specific populations. Pivotal trials have largely excluded vulnerable groups such as survivors of childhood cancer due to theoretical safety concerns. While conventional daily rhGH has a well-established long-term safety profile in this population, including no significant increase in cancer recurrence risk (40), the unique pharmacokinetic profile of LAGH characterized by continuous, non-pulsatile GH exposure precludes direct extrapolation. This distinct exposure pattern differs from both endogenous physiology and daily rhGH therapy, raising unanswered questions about its long-term effects. Consequently, there is a paucity of clinical data on LAGH use in cancer survivors, creating a significant evidence gap that necessitates prospective studies focused on long-term safety, particularly regarding cancer recurrence risk and metabolic outcomes.

More broadly, the long-term implications of this continuous exposure profile remain undefined for all patients. While available short- to medium-term data demonstrate comparable safety to daily rhGH and efficacy in maintaining serum IGF-I within the target range (4), critical questions persist. These include the metabolic implications for glucose homeostasis and insulin sensitivity, the potential impact on cardiovascular and neoplastic risk over decades, and whether non-pulsatile delivery influences pubertal timing or final height attainment in children (5, 11).

Regarding non-GHD indications, emerging evidence has laid the groundwork for LAGH application, though data remain preliminary. For children born small for gestational age (SGA), a randomized, multi-center phase 2 study of somapacitan (NCT03878446) showed dose-dependent height velocity improvements in treatment-naive prepubertal patients after 26 weeks, with the highest dose demonstrating efficacy comparable to higher daily GH doses and consistent safety (40, 41). For Turner syndrome, the most robust preliminary evidence comes from Jintrolong, the first global LAGH approved in China for growth disorders caused by gonadal dysgenesis. Critical gaps persist across both indications: no large-scale phase III trials have specifically validated LAGH efficacy in these populations, optimal dosing regimens remain undefined, and long-term impacts on final adult height and metabolic outcomes are uncharacterized. Extending LAGH benefits to non-GHD indications thus represents a major future direction, given their distinct therapeutic requirements and safety considerations.

Addressing these gaps will require coordinated global efforts through international patient registries [e.g., the Global LAGH Registry, GloBE-Reg (42)] and targeted clinical studies. The rapid and dynamic progress of the LAGH landscape in China is uniquely positioned to contribute substantially to filling these knowledge gaps. The extensive clinical use of earlier approved agents (e.g., Jintrolong, Yipaisheng) is generating a wealth of real-world evidence. When combined with the superior efficacy data from newly approved, this will provide invaluable insights into long-term outcomes and enable a unique, direct comparison of the effectiveness of different technological platforms within a single, large healthcare system.

In conclusion, LAGH formulations represent a transformative advancement in the management of GHD. By leveraging innovative bioengineering strategies, these therapies have successfully decoupled dosing frequency from efficacy. With robust clinical data confirming their safety and effectiveness, LAGH agents have moved from scientific curiosity to mainstream therapeutics. As clinical experience deepens and future innovations materialize, LAGH is set to become the new global standard of care, significantly improving the lives of patients with growth hormone deficiency.