Highlights
- Long-acting growth hormone (LAGH) therapy is associated with a significant increase in Body Mass Index (BMI) Standard Deviation Scores (SDS) (+0.41) during the first 12 months of use.
- Compared to daily recombinant human growth hormone (rhGH), LAGH treated patients showed a mean difference of 0.66 SDS in BMI at the 12-month mark.
- Switching from daily rhGH to LAGH results in a pronounced BMI SDS increase (+0.75), while continuing LAGH maintains a steady BMI profile after the initial year.
- Evidence suggests that lonapegsomatropin, somatrogon, and somapacitan share this metabolic trend, necessitating longitudinal anthropometric monitoring beyond height velocity.
Background
Growth hormone deficiency (GHD) in children has traditionally been managed with daily subcutaneous injections of recombinant human growth hormone (rhGH) for nearly four decades. While highly effective in increasing linear growth and improving body composition, the burden of daily administration often leads to poor adherence, which subsequently compromises final adult height outcomes. To address this challenge, the pharmaceutical industry has developed several long-acting growth hormone (LAGH) formulations designed for once-weekly administration.
As these LAGH products, including lonapegsomatropin, somatrogon, and somapacitan, have entered clinical practice following pivotal Phase 3 trials, the focus has predominantly remained on their non-inferiority regarding annualized height velocity (AHV). However, growth hormone (GH) is a potent metabolic regulator, influencing lipolysis, protein synthesis, and carbohydrate metabolism. Emerging data suggest that the pharmacokinetics (PK) and pharmacodynamics (PD) of LAGH, characterized by different IGF-1 profiles compared to daily injections, may exert unique effects on body mass and composition. Given the global rise in pediatric obesity, understanding the impact of these new therapies on Body Mass Index (BMI) is critical for clinical decision-making and long-term patient health.
Key Content
The Evolution of Long-Acting Growth Hormone Preparations
The development of LAGH has utilized diverse molecular strategies to extend the half-life of the GH molecule. Lonapegsomatropin utilizes a prodrug technology where the GH molecule is transiently attached to a methoxy-polyethylene glycol carrier via a proprietary linker, releasing unmodified GH. Somatrogon is a fusion protein consisting of the amino acid sequence of GH and three copies of the C-terminal peptide of human chorionic gonadotropin. Somapacitan, on the other hand, involves a single amino acid substitution in the GH backbone to allow for non-covalent binding to endogenous albumin. Each of these strategies results in a unique PK/PD profile, typically involving a more sustained elevation of insulin-like growth factor 1 (IGF-1) compared to the transient peaks observed with daily rhGH.
Meta-Analysis Methodology and Patient Population
A comprehensive systematic review and meta-analysis were conducted to synthesize evidence from randomized controlled trials (RCTs) that tracked BMI changes over at least six months. The analysis identified three major RCTs providing longitudinal data for lonapegsomatropin, somatrogon, and somapacitan. The study population comprised 585 children with GHD, with 346 receiving LAGH and 239 receiving daily rhGH. Data were extracted from seven original peer-reviewed articles and supplemental reports (abstracts/ePosters), ensuring a robust dataset for the 12-month and 24-month (extension phase) periods.
Primary Outcomes: 12-Month BMI SDS Changes
At the 12-month primary endpoint, the meta-analysis revealed a statistically significant divergence in BMI SDS between the two treatment modalities. Children treated with LAGH experienced a significant increase in BMI SDS, with a mean change of +0.41 SDS (95% CI 0.04; 0.77). Conversely, the daily rhGH group showed a slight, non-significant decrease in BMI SDS (-0.35 SDS; 95% CI -0.76; +0.07). The resulting mean difference (MD) between LAGH and daily GH was 0.66 SDS (95% CI 0.04; 1.29), favoring a higher BMI in the LAGH cohorts. This finding suggests that LAGH therapy may induce a ‘catch-up’ in weight or a shift in body composition that is more pronounced than that seen with traditional therapy.
Longitudinal Dynamics and Switching Effects
One of the most striking findings of the analysis pertains to the transition period between 12 and 24 months. In many RCT extension phases, patients previously on daily rhGH were switched to the LAGH arm (daily GH/LAGH). In this switching group, BMI SDS increased significantly by +0.75 SDS (95% CI 0.24; 1.27). In contrast, patients who had been on LAGH from the start (LAGH/LAGH) maintained a steady BMI SDS during the second year, suggesting that the BMI-elevating effect primarily occurs during the first 12 months of exposure to the long-acting molecule. This plateau effect indicates that while LAGH promotes an initial increase in BMI, it does not necessarily lead to progressive, uncontrolled weight gain over time.
Molecular Subgroup Insights
The study specifically noted that BMI data were consistent across lonapegsomatropin, somatrogon, and somapacitan. However, data were notably absent for polyethylene glycol (PEGylated) LAGH formulations, highlighting a gap in the current literature regarding whether all long-acting technologies share the same metabolic footprint. The consistency among the three included molecules suggests a class effect likely related to the sustained GH/IGF-1 signaling inherent to weekly dosing schedules.
Expert Commentary
The observation of increased BMI SDS with LAGH use raises several physiological and clinical questions. From a mechanistic perspective, the pharmacokinetics of LAGH differ fundamentally from daily GH. Daily injections produce a peak in GH levels followed by a rapid decline, whereas LAGH provides a more continuous presence of the hormone or its IGF-1 mediator. GH is known to be lipolytic; therefore, an increase in BMI might seem counterintuitive. However, BMI does not distinguish between adipose tissue and lean body mass. It is highly plausible that the observed increase in BMI SDS reflects a significant gain in muscle mass or total body water, which are known effects of GH therapy, rather than an increase in adiposity.
Furthermore, the ‘catch-up’ growth phenomenon in children with GHD often involves a rapid normalization of both height and weight. The fact that BMI SDS increases more significantly with LAGH suggests that these formulations may be more ‘potent’ in their metabolic signaling or that the improved adherence associated with weekly dosing leads to a more consistent therapeutic effect. However, clinicians must remain vigilant. While an increase in BMI SDS might represent healthy catch-up growth in a previously growth-restricted child, if the increase is driven by fat mass, it could carry long-term cardiovascular or metabolic risks.
A limitation of the current meta-analysis is the lack of body composition data (e.g., DXA scans or bioelectrical impedance) in the primary studies. Without these data, we cannot definitively conclude whether the BMI increase is ‘metabolically healthy.’ Additionally, the exclusion of PEGylated GH from the results means we cannot yet generalize these findings to all long-acting technologies.
Conclusion
In conclusion, this meta-analysis provides the first comprehensive evidence that LAGH therapy is associated with a distinct increase in BMI SDS during the first year of treatment and upon switching from daily GH. While height velocity remains the primary metric for GH efficacy, these findings underscore the importance of comprehensive anthropometric monitoring. Pediatric endocrinologists should be aware of this trend when counseling families and transitioning patients to long-acting regimens. Future research should prioritize body composition analysis and long-term metabolic follow-up to ensure that the convenience of LAGH does not come at the cost of unfavorable metabolic shifts. As the therapeutic landscape for GHD continues to evolve, the integration of both linear growth and metabolic health data will be paramount for optimizing patient outcomes.
References
- Levaillant L, Bouhours-Nouet N, Emeriau F, et al. Long-Acting Growth Hormone for Treating Growth Hormone Deficiency in Children: A Meta-Analysis of Randomized Controlled Trials Focusing on Changes in Body Mass Index. J Clin Endocrinol Metab. 2026; PMID: 41787735.
- Thornton PS, Silverman LA, Geffner ME, et al. Once-weekly Lonapegsomatropin in Children with Growth Hormone Deficiency: The Phase 3 heiGHt Trial. J Clin Endocrinol Metab. 2021;106(8):2284-2295. PMID: 33831154.
- Deal CL, Steelman J, Vlachopapadopoulou E, et al. Once-weekly Somatrogon vs Daily Somatropin in Children with Growth Hormone Deficiency: A Phase 3 Study. J Clin Endocrinol Metab. 2022;107(7):e2717-e2728. PMID: 35134947.
- Miller BS, Velazquez E, Yuen KCJ, et al. Once-Weekly Somapacitan is Effective and Well Tolerated in Children with GH Deficiency: The Randomized Phase 3 REAL 4 Trial. J Clin Endocrinol Metab. 2022;107(12):3378-3388. PMID: 36043510.
