Prader–Willi Syndrome (PWS) is a rare genetic disorder (OMIM#176270) with an estimated incidence of 1 in 21,000 live births. It results from the lack of expression of paternally inherited genes on chromosome 15q11–q13 and is characterized by hypothalamic dysfunction, hyperphagia, obesity, intellectual disability, and endocrine abnormalities (1).

PWS is an indication for growth hormone therapy (GHT), as its clinical features, such as impaired growth, abnormal body composition, hypotonia, and low energy expenditure, closely resemble those seen in growth hormone deficiency (GHD) unrelated to PWS. Studies have shown that nearly all individuals with PWS exhibit reduced spontaneous growth hormone (GH) secretion and low insulin-like growth factor-1 (IGF)-1 levels, primarily due to hypothalamic dysfunction and potential defects in neuroendocrine convertase 1 (2, 3). In many countries, including the United States, United Kingdom, and European nations, GHT is initiated in patients with PWS during infancy or early childhood to maximize benefits. In South Korea, GHT for PWS has been covered by the national insurance system starting at age 2, recognizing its critical role in managing this condition (4). These include improvements in growth, body composition, motor and cognitive development, and overall quality of life. The long-term benefits of GHT include reduced fat accumulation, increased lean body mass, and improved metabolic and cardiovascular health.

However, GH exerts counter-regulatory effects on insulin action by stimulating hepatic glucose production and reducing peripheral glucose uptake, thereby raising concerns regarding its long-term metabolic safety. In prepubertal children with PWS, GHT has been associated with increases in insulin resistance, with occasional cases of impaired glucose tolerance reported after approximately two years of treatment (5). Data from KIGS registry have documented rare instances of hyperglycemia and type 2 diabetes mellitus (T2DM) in GH-treated PWS (6). In adults, a longitudinal study of 12 GH-treated patients showed a statistically significant rise in fasting glucose and a modest increase in HbA1c (from 5.6% to 5.8%) (7). A meta-analysis focusing on adult GHT further identified a small increase in fasting glucose and trends toward higher insulin resistance (8). By contrast, an Italian cohort study found that disorders of glucose metabolism in PWS were more strongly associated with age and obesity than with GH exposure (9). A recent systematic review similarly reported that GHT improves body composition without significantly impairing glucose homeostasis (10).

However, GH exerts counter-regulatory effects on insulin action by stimulating hepatic glucose production and reducing peripheral glucose uptake, raising concerns about its long-term metabolic safety. In prepubertal children with PWS, GHT has been associated with increased insulin resistance, with occasional cases of impaired glucose tolerance reported after approximately two years of treatment (5). Data from the KIGS registry have documented rare instances of hyperglycemia and type 2 diabetes mellitus (T2DM) in GH-treated individuals with PWS (6). In adults, a longitudinal study of 12 GH-treated patients showed a statistically significant rise in fasting glucose and a modest increase in HbA1c (from 5.6% to 5.8%) (7). A meta-analysis of GH therapy in adults further reported small increases in fasting glucose and a trend toward greater insulin resistance (8). Conversely, an Italian cohort study suggested that glucose metabolism disorders in PWS are more strongly related to age and obesity than to GH exposure (9). A recent systematic review also concluded that GHT improves body composition without significantly impairing glucose homeostasis (10).

These findings suggest that while GH clearly benefits body composition, its long−term metabolic safety and impact on serious outcomes such as all-cause mortality and T2DM remain limited. In addition, how factors such as timing of diagnosis or duration of therapy influence these outcomes is not well understood.

We hypothesized that prolonged exposure to GHT may be associated with altered risks of mortality and T2DM in individuals with PWS. To address this, we conducted a nationwide population-based study to examine the associations between GHT duration and these long-term outcomes, aiming to inform risk stratification and long-term management in this population.

This study investigated long-term outcomes of GHT on mortality and T2DM in patients with PWS using a nationwide cohort. Our analysis suggests that mortality in this population is more closely associated with comorbidities—especially peripheral vascular disease, renal disease, behavioral disorders, and adrenal insufficiency—than with GHT itself.

The impact of GHT on mortality in PWS remains unclear. Some studies have suggested that early GHT may improve survival (15), others report no significant effect (16–18). Research in patients with idiopathic short stature (ISS), isolated GHD, and small-for-gestational-age (SGA) highlights that GHT may increase long-term mortality related to cardiovascular and hematologic diseases, necessitating ongoing surveillance (19). Studies on PWS have reported adverse events and deaths during GHT, though no direct causal relationship has been established (6, 10). Our findings align with the prevailing consensus that GHT itself does not directly influence mortality rates (20). Instead, early diagnosis of PWS and effective management of comorbidities are crucial in improving survival outcomes.

Among the comorbidities observed, adrenal insufficiency, a common but often underrecognized complication in PWS, may have contributed to stress-related mortality from acute adrenal crisis in some cases (21–23). Although we could not distinguish central from primary adrenal insufficiency using claims data, the observed association with mortality emphasizes the importance of early detection and appropriate hydrocortisone coverage during acute illness or surgery (24). Behavioral disorders were also more common among non-survivors. While not traditionally considered direct mortality drivers, these conditions may increase the risk of choking, gastric perforation, and obesity-related morbidity (25, 26). Consistent with previous studies, respiratory failure remains the leading cause of mortality in PWS (31%–70%) (15, 26). Although no direct link has been confirmed, GHT may exacerbate respiratory dysfunction due to hypothalamic impairment (25), underscoring the need for respiratory assessment in those receiving GHT.

In contrast to mortality, GHT duration was independently associated with a higher risk of T2DM, even after adjusting for age, timing of diagnosis, and comorbid conditions. While GHT improves body composition and reduces visceral adiposity, it may also reduce insulin sensitivity through counter-regulatory mechanisms (27).

Clinical evidence regarding the metabolic effects of GHT has been mixed. Some observational studies have reported no significant deterioration in glucose metabolism during GHT, including in GH-treated children followed into adulthood (28), adults receiving long-term biosimilar GHT (29), and children born SGA (30).

However, other studies in SGA children (31) and adults with GHD (27, 32) have demonstrated impaired insulin action following GH administration. GH-induced lipolysis increases circulating free fatty acids, which interfere with skeletal muscle glucose uptake via the glucose–fatty acid cycle (27), and may promote intramyocellular lipid accumulation that disrupts insulin signaling (33).

In our PWS cohort, older age was independently associated with T2DM, independent of other metabolic factors. Moreover, certain comorbidities, including peptic ulcer disease, mild liver disease, and diabetes insipidus, were associated with an increased risk of T2DM, though their clinical significance in the context of PWS requires further investigation.

A later PWS diagnosis was independently linked to T2DM risk, likely due to prolonged exposure to metabolic risk factors such as obesity and insulin resistance. Early recognition and intervention, including lifestyle modifications and timely GHT initiation, may help reduce long-term metabolic complications.

In other conditions, such as Turner syndrome, GH-related insulin resistance may normalize after discontinuation (34), though large retrospective studies in pediatric populations have reported persistent T2DM (35, 36) and cardiovascular risks post-treatment (37).

The association between GHT and T2DM in PWS remains uncertain due to mixed findings. Several studies have reported low diabetes incidence during GHT (9, 10), including one involving 235 patients with only a single case attributed to preexisting obesity (38). In contrast, other studies have identified abnormal glucose metabolism and insulin resistance, particularly in prepubertal children or those with obesity (5, 6), and slightly impaired glucose homeostasis in adults receiving long-term GHT (8, 39). Thus, it has been established by expert consensus to include a diabetes risk assessment in patients with PWS receiving GHT, especially those who are obese, older than 12 years, or on antipsychotic medications (2, 5, 40).

This study has several strengths, including its large, nationally representative sample and linkage with mortality records. Use of validated diagnostic and treatment codes allowed for reliable cohort construction and longitudinal follow-up. However, several limitations merit consideration. Residual confounding due to unmeasured variables such as body mass index, laboratory data, or family history could not be fully addressed. In addition, the left-skewed distribution of age at PWS diagnosis, particularly among patients without T2DM, may have influenced group comparisons. Although age at diagnosis was included as a covariate in multivariate models, the potential for bias remains. Furthermore, the inability to differentiate PWS genetic subtypes may have limited our ability to explore phenotype–treatment interactions. Lastly, as with all observational studies, the associations observed cannot establish causality. Prospective studies are needed to validate our findings, explore alternative explanations, and inform risk stratification in the management of PWS.

This nationwide study found that while GHT was not directly associated with increased mortality in patients with PWS, it was linked to a higher likelihood of T2DM with longer treatment duration. These findings highlight the need for long-term, multidisciplinary monitoring of both endocrine and non-endocrine complications in this population. A multidisciplinary approach—including endocrinology, nutrition, behavioral management, and psychosocial support—remains essential to optimizing outcomes in patients receiving GHT.