Efficacy, safety, quality of life, adherence and cost-effectiveness of long-acting growth hormone replacement therapy compared to daily growth hormone in children with growth hormone deficiency: A systematic review and meta-analysis.

We evaluated the efficacy, safety, adherence, quality of life (QoL) and cost-effectiveness of long-acting growth hormone (LAGH) vs daily growth hormone (GH) preparations in the treatment of growth hormone deficiency (GHD) in children. Systematic searches were performed in PubMed, Embase and Web of Science up to July 2022 on randomized and non-randomized studies involving children with GHD receiving LAGH as compared to daily GH. Meta-analyses for efficacy and safety were performed comparing different LAGH/daily GH formulations. From the initial 1393 records, we included 16 studies for efficacy and safety, 8 studies for adherence and 2 studies for QoL. No studies reporting cost-effectiveness were found. Pooled mean differences of mean annualized height velocity (cm/year) showed no difference between LAGH and daily GH: Eutropin Plus® vs Eutropin® [- 0.14 (-0.43, 0.15)], Eutropin Plus® vs Genotropin® [- 0.74 (-1.83, 0.34)], Jintrolong® vs Jintropin AQ® [0.05 (-0.54, 0.65)], Somatrogon vs Genotropin® [- 1.40 (-2.91, 0.10)], TransCon vs Genotropin® [0.93 (0.26, 1.61)]. Also, other efficacy and safety outcomes, QoL and adherence were comparable for LAGH and daily GH. Our results showed that, although most of the included studies had some concerns for risk of bias, regarding efficacy and safety all the LAGH formulations were similar to daily GH. Future high quality studies are needed to confirm these data. Adherence and QoL should be addressed from real-world data studies for both the mid and long term and in a larger population. Cost-effectiveness studies are needed to measure the economic impact of LAGH from the healthcare payer's perspective.

Cost-Utility of Acromegaly Pharmacological Treatments in a French Context.

Objective: Efficacy of pharmacological treatments for acromegaly has been assessed in many clinical or real-world studies but no study was interested in economics evaluation of these treatments in France. Therefore, the objective of this study was to estimate the cost-utility of second-line pharmacological treatments in acromegaly patients. Methods: A Markov model was developed to follow a cohort of 1,000 patients for a lifetime horizon. First-generation somatostatin analogues (FGSA), pegvisomant, pasireotide and pegvisomant combined with FGSA (off label) were compared. Efficacy was defined as the normalization of insulin-like growth factor-1 (IGF-1) concentration and was obtained from pivotal trials and adjusted by a network meta-analysis. Costs data were obtained from French databases and literature. Utilities from the literature were used to estimate quality-adjusted life year (QALY). Results: The incremental cost-utility ratios (ICUR) of treatments compared to FGSA were estimated to be 562,463 € per QALY gained for pasireotide, 171,332 € per QALY gained for pegvisomant, and 186,242 € per QALY gained for pegvisomant + FGSA. Pasireotide seems to be the least cost-efficient treatment. Sensitivity analyses showed the robustness of the results. Conclusion: FGSA, pegvisomant and pegvisomant + FGSA were on the cost-effective frontier, therefore, depending on the willingness-to-pay for an additional QALY, they are the most cost-effective treatments. This medico-economic analysis highlighted the consistency of the efficiency results with the efficacy results assessed in the pivotal trials. However, most recent treatment guidelines recommend an individualized treatment strategy based on the patient and disease profile.

Cost-Effectiveness and Efficacy of a Novel Combination Regimen in Acromegaly: A Prospective, Randomized Trial.

CONTEXT: Combination therapy with somatostatin receptor ligand (SRL) plus pegvisomant for patients with acromegaly is recommended after a maximizing dose on monotherapy. Lower-dose combination regimens are not well studied. OBJECTIVE: To compare cost-effectiveness and efficacy of 3 lower-dose combination regimens in controlled and uncontrolled acromegaly. DESIGN AND SETTING: Prospective, randomized, open-label, parallel arm study at a tertiary referral pituitary center. PATIENTS: Adults with acromegaly regardless of response to prior SRL and biochemical control status at baseline, stratified by an SRL dose required for insulin-like growth factor (IGF)-I normalization during any 3-month period within 12 months preceding enrollment. INTERVENTION: Combination therapy for 24 to 32 weeks on arm A, high-dose SRL (lanreotide 120 mg/octreotide long-acting release [LAR] 30 mg) plus weekly pegvisomant (40-160 mg/week); arm B, low-dose SRL (lanreotide 60 mg/octreotide LAR 10 mg) plus weekly pegvisomant; or arm C, low-dose SRL plus daily pegvisomant (15-60 mg/day). MAIN OUTCOME MEASURE: Monthly treatment cost in each arm in participants completing ≥ 24 weeks of therapy. RESULTS: Sixty patients were enrolled and 52 were evaluable. Fifty of 52 (96%) demonstrated IGF-I control regardless of prior SRL responsiveness (arm A, 14/15 [93.3%]; arm B, 22/23 [95.7%]; arm C, 14/14 [100%]). Arm B was least costly (mean, $9837 ±â€…1375 per month), arm C was most expensive (mean, $22543 ±â€…11158 per month), and arm A had an intermediate cost (mean, $14261 ±â€…1645 per month). Approximately 30% of patients required pegvisomant dose uptitration. Rates of adverse events were all < 10%. CONCLUSIONS: Low-dose SRL plus weekly pegvisomant represents a novel dosing option for achieving cost-effective, optimal biochemical control in patients with uncontrolled acromegaly requiring combination therapy.

Interchangeability of Biosimilars: A European Perspective.

Many of the best-selling 'blockbuster' biological medicinal products are, or will soon be, facing competition from similar biological medicinal products (biosimilars) in the EU. Biosimilarity is based on the comparability concept, which has been used successfully for several decades to ensure close similarity of a biological product before and after a manufacturing change. Over the last 10 years, experience with biosimilars has shown that even complex biotechnology-derived proteins can be copied successfully. Most best-selling biologicals are used for chronic treatment. This has triggered intensive discussion on the interchangeability of a biosimilar with its reference product, with the main concern being immunogenicity. We explore the theoretical basis of the presumed risks of switching between a biosimilar and its reference product and the available data on switches. Our conclusion is that a switch between comparable versions of the same active substance approved in accordance with EU legislation is not expected to trigger or enhance immunogenicity. On the basis of current knowledge, it is unlikely and very difficult to substantiate that two products, comparable on a population level, would have different safety or efficacy in individual patients upon a switch. Our conclusion is that biosimilars licensed in the EU are interchangeable.

Assessment of Primary Cancer Incidence in Growth Hormone-Treated Children: Comparison of a Multinational Prospective Observational Study with Population Databases.

BACKGROUND/AIMS: Although results of the majority of clinical studies have shown no association between growth hormone (GH) treatment in childhood and risk of primary cancer, concerns remain regarding the potential influence of GH therapy on neoplastic cell growth. This study evaluated the incidence of primary malignancies in a large observational study of paediatric GH treatment. METHODS: Primary cancer incidence was assessed in a cohort of 19,054 GH-treated children without a reported prestudy history of malignancy in the observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). The standardised incidence ratio (SIR) for primary cancer in GH-treated children was determined by comparing cancer incidence in the GeNeSIS study population with incidence rates for country-, age-, and sex-matched cohorts of the general population. RESULTS: During a mean follow-up of 3.4 years in GeNeSIS (64,705 person-years), 13 incident potential primary cancers were identified in GH-treated patients. The SIR (95% confidence interval) for all observed cancers was 1.02 (0.54-1.75), and the crude incidence was 20.1 (10.7-34.4) cases per 100,000 person-years. CONCLUSION: Acknowledging the relatively short follow-up in our study, GH-treated children without a history of previous malignancy did not have a higher risk of all-site primary cancer during the study when compared to general-population cancer registries.

Impact of adult growth hormone deficiency on metabolic profile and cardiovascular risk [Review].

Adult growth hormone deficiency (GHD) is a well defined clinical condition, which is characterized by abnormal body composition, impaired physical activity and decreased quality of life. In addition, in recent years, growing interest has been shown towards cardiovascular risks in adult patients affected by GHD. In this regard, GHD is widely known to be associated with increased mortality, likely due to the increase of risk factors, such as central obesity, impaired lipid and glucose profiles and other less-known risk factors, such as inflammatory cytokines, endothelial dysfunction and oxidative stress. However, very few papers have recently discussed this topic. In this review, the aim is to clarify this issue by discussing evidence regarding the effects of adult GHD on metabolic and cardiovascular profiles.

A 4-Year, Open-Label, Multicenter, Randomized Trial of Genotropin® Growth Hormone in Patients with Idiopathic Short Stature: Analysis of 4-Year Data Comparing Efficacy, Efficiency, and Safety between an Individualized, Target-Driven Regimen and Standard Dosing.

BACKGROUND/AIMS: Growth hormone (GH) treatment regimens for children with non-GH-deficient, idiopathic short stature (ISS) have not been optimized. To compare the efficacy, efficiency, and safety of an individualized, target-driven GH regimen with standard weight-based dosing after 4 years of treatment. METHODS: This is a 4-year, open-label, multicenter, randomized trial comparing individualized, formula-based dosing of Genotropin® versus a widely used ISS dose of Genotropin®. Subjects were prepubertal, had a bone age of 3-10 years for males and 3-9 years for females, were naive to GH treatment, and had a height standard deviation score (Ht SDS) of -3 to -2.25, a height velocity <25th percentile for their bone age, and peak stimulated GH >10 ng/ml. After the first 2 years, the individualized-dosing group was further randomized to either 0.18 or 0.24 mg/kg/week. RESULTS: At 4 years, subjects in all treatment regimens achieved similar average height gains of +1.3 SDS; however, the individualized dosing regimen utilized less GH to achieve an equivalent height gain. CONCLUSION: Individualized, formula-based GH dosing, followed by a dose reduction after 2 years, provides a more cost-effective growth improvement in patients with ISS than currently employed weight-based regimens.

Consequences of brand switches during the course of pediatric growth hormone treatment.

OBJECTIVE: To explore the effects of insurance-mandated brand switches during the course of pediatric recombinant human growth hormone (rhGH) treatment on clinical practice. METHODS: We e-mailed a 9-question, anonymous, Internet-based survey to active members of the Pediatric Endocrine Society. The survey consisted of multiple-choice and yes/no answers. Free-text comments were solicited for further explanation of responses. Quantitative answers were tabulated. Each investigator independently coded the free-text responses; themes based on codes identified by all 3 investigators in a minimum of 5 different respondents' comments were compiled and organized. RESULTS: Of the 812 active members of the Pediatric Endocrine Society who were e-mailed the survey, 231 responded. Two hundred eight respondents reported switching a patient's regimen from one rhGH product to another, and of these, 50% experienced repeated switches. Switches occurred for each commercially available rhGH brand. Frequent concerns noted by respondents involved dosing errors and treatment lapses from having to learn a new device and impaired adherence related to patient-family frustration and anxiety. Anti-GH antibodies, measured by only 3 endocrinologists when switching a patient's regimen from one brand to another, were negative before and after the product switch. When a patient switched rhGH brands, the most frequently reported time involvement for endocrine office staff was 2 hours for paperwork, 1 hour for device instruction, and 1 hour for "other" (mostly related to telephone reassurance). CONCLUSION: GH brand switches may adversely affect patient care and burden pediatric endocrinology practices.

Assessment of primary cancers in GH-treated adult hypopituitary patients: an analysis from the Hypopituitary Control and Complications Study.

OBJECTIVE: GH and IGFs have mitogenic properties, causing speculation that GH treatment could increase risk of malignancy. While studies in GH-treated childhood cancer survivors have suggested a slight increase in second neoplasms, studies in GH-treated adults have been equivocal. Design Incidence of de novo and second cancers was evaluated in 6840 GH-treated and 940 non GH-treated adult patients in the Hypopituitary Control and Complications Study pharmacoepidemiological database. METHODS: Evident cancer cases were evaluated in the main analysis, with sensitivity analyses including probable and possible cancers. Standardized incidence ratios (SIRs) for cancers were calculated using Surveillance, Epidemiology and End Results for the USA and GLOBOCAN for all other countries. RESULTS: During the mean follow-up of 3.7 years/GH-treated patient, 142 evident cancer cases were identified, giving an overall SIR of 0.88 (95% confidence interval (CI) 0.74-1.04); 95% CIs included the value of 1.0 for each country examined. The SIR for GH-treated patients from the USA (71 cases) was 0.94 (95% CI 0.73-1.18), and for non GH-treated patients from the USA (27 cases) was 1.16 (95% CI 0.76-1.69). For GH-treated patients from the USA aged <35 years, the SIR (six cases) was 3.79 (1.39-8.26), with SIR not elevated for all other age categories; SIR for patients from the USA with childhood onset (CO) GH deficiency (GHD) was 2.74 (95% CI 1.18-5.41). The SIR for colorectal cancer in GH-treated patients (11 cases) was 0.60 (95% CI 0.30-1.08). CONCLUSIONS: With relatively short follow-up, the overall primary cancer risk in 6840 patients receiving GH as adults was not increased. Elevated SIRs were found for subgroups in the USA cohort defined by age <35 years or CO GHD.

[GH treatment in patients with idiopathic short stature]. / Uso de GH em pacientes com baixa estatura idiopática.

Growth hormone has been used in the treatment of patients with idiopathic short stature. Clinical and laboratory criteria are discussed, taking into consideration the indication of GH and the evaluation of its efficacy and individual responsiveness. Anthropometric, psychosocial, ethical, and also cost/benefit aspects must be considered before GH prescription in idiopathic short stature patients.

Uso de GH em pacientes com baixa estatura idiopática: [revisão] / GH treatment in patients with idiopathic short stature: [review]

Pacientes com baixa estatura idiopática podem ser tratados com GH. Os critérios clínicos e laboratoriais utilizados na decisão do uso do GH, bem como no reconhecimento da responsividade dos indivíduos ao tratamento, são discutidos. Não apenas os resultados antropométricos, mas também os aspectos éticos e psicossociais devem ser considerados na avaliação dos custos/benefícios envolvidos no tratamento com GH em pacientes com baixa estatura idiopática.

Growth hormone has been used in the treatment of patients with idiopathic short stature. Clinical and laboratorial criteria are discussed, taking into consideration the indication of GH and the evaluation of its efficacy and individual responsiveness. Anthropometric, psychosocial, ethical, and also cost/benefit aspects must be considered before GH prescription in idiopathic short stature patients.

The public health impact of prion diseases.

Several prion disease-related human health risks from an exogenous source can be identified in the United States, including the iatrogenic transmission of Creutzfeldt-Jakob disease (CJD), the possible occurrence of variant CJD (vCJD), and potential zoonotic transmission of chronic wasting disease (CWD). Although cross-species transmission of prion diseases seems to be limited by an apparent "species barrier," the occurrence of bovine spongiform encephalopathy (BSE) and its transmission to humans indicate that animal prion diseases can pose a significant public health risk. Recent reports of secondary person-to-person spread of vCJD via blood products and detection of vCJD transmission in a patient heterozygous at codon 129 further illustrate the potential public health impacts of BSE.

Human growth hormone and the temptations of biomedical enhancement.

It is likely that humans have sought enhancements for themselves or their children for as long as they have recognised that improvements in individuals are a possibility. One genre of self-improvement in modern society can be called 'biomedical enhancements'. These include drugs, surgery and other medical interventions aimed at improving the mind, body or performance. This paper uses the case of human growth hormone (hGH) to examine the social nature of enhancements. Synthetic hGH was developed in 1985 by the pharmaceutical industry and was approved by the FDA for very specific uses, particularly treatment of growth hormone deficiency. However, it has also been promoted for a number of 'off label' uses, most of which can be deemed enhancements. Drugs approved for one treatment pave the way for use as enhancements for other problems. Claims have been made for hGH as a treatment for idiopathic shortness, as an anti-ageing agent and to improve athletic performance. Using the hGH case, we are able to distinguish three faces of biomedical enhancement: normalisation, repair and performance edge. Given deeply ingrained social and individual goals in American society, the temptations of biomedical enhancements provide inducement for individuals and groups to modify their situation. We examine the temptations of enhancement in terms of issues such as unnaturalness, fairness, risk and permanence, and shifting social meanings. In our conclusions, we outline the potentials and pitfalls of biomedical enhancement.

The many faces of human growth hormone.

The story of human growth hormone (hGH) is colorful by drug industry standards. HGH, also known as somatropin, was first used to treat stunted growth in children. Later is was used in people with HIV disease to treatment the gauntness of AIDS-related wasting and, more recently, the fat accumulations associated with lipodystrophy. HGH also may play a role in immune reconstitution. Outside the field of HIV, this very expensive therapy has multiple indications. Unapproved uses for hGH run the gamut from muscle enhancer to purported cure-all. Not surprisingly, the man-made hormone does not always perform as desired. Yet new research into how hGH may fit into the future of HIV disease management warrants another look at this unusual drug.

Shouldn't adults with growth hormone deficiency be offered growth hormone replacement therapy?

Growth hormone as therapy for adults with growth hormone deficiency has not been universally accepted by endocrinologists who treat adult patients. The following are addressed in this commentary: the evidence on safety and efficacy in the literature supporting the idea that growth hormone should be offered as replacement therapy to adults who are growth hormone deficient; common concerns of the average prescribing endocrinologist, including the purported association between insulin-like growth factor-I and malignant neoplasms and quality-of-life issues with long-term therapy; and controversial subjects, such as differences in dosing for adults versus children and diagnostic issues. This analysis should encourage reluctant practitioners to at least consider growth hormone replacement therapy for patients with definite growth hormone deficiency--that is, patients with symptomatic panhypopituitarism.

Metabolic effects of stopping growth hormone: body composition and energy expenditure.

Discontinuation of growth hormone (GH) treatment at the end of childhood growth in individuals with GH deficiency has been shown to be associated with markedly increasing fat mass and decreasing metabolic rate. The association of these findings with increased abdominal fat and adverse changes in lipid biochemistry suggests that without longer-term GH therapy into adult life, these individuals will be at increased risk for cardiovascular morbidity and mortality. However, the evidence that these adverse events do not arise in those shown to be GH sufficient on retesting emphasizes the principle that all individuals who received GH therapy for childhood-onset GH deficiency require careful re-evaluation of their GH secretion when growth is completed.