Cotreatment of Acromegaly with a Somatostatin Analog and a Growth Hormone Receptor Antagonist

Introduction: The GH/IGF1 axis may modulate inflammatory processes. However, the relationship seems complicated as both pro-and anti-inflammatory effects have been demonstrated. Methods/design: Twelve healthy volunteers (mean age 36, range 27-49 years) were treated in random order with increasing doses of GH for 3 weeks (first week 0.01 mg/kg per day, second week 0.02 mg/kg per day, and third week 0.03 mg/kg per day) or a GH receptor antagonist (pegvisomant; first week 10 mg/day and last two weeks 15 mg/day), separated by 8 weeks of washout. Circulating levels of the pro-inflammatory cytokines tumor necrosis factor a (TNFa (TNFA)), interleukin 6 (IL6), and IL1b (IL1B) and the acute phase proteins (APPs) C-reactive protein (CRP), haptoglobin, orosomucoid, YKL40 (CHI3L1), and fibrinogen were measured. Conclusions: GH/IGF1 action appears to modulate the initial stage of the inflammatory response as well as downstream processes elucidated by levels of APPs. The data suggest a complicated relationship not allowing any simple conclusions as to whether GH/IGF1 actions have mainly pro-or antiinflammatory effects in vivo.

Section: Discussionsupporting

confidence: 55%

“…During GH receptor blockage we aimed to mimic severe GHD. The 15 mg/day dose was chosen based on the experiences with treatment of acromegalic patients with severe GH hypersecretion (27). The two treatment regimens were separated by an 8-week washout period.…”

Section: Methodsmentioning

confidence: 99%

GH activity and markers of inflammation: a crossover study in healthy volunteers treated with GH and a GH receptor antagonist

Andreassen

Frystyk

Faber

et al. 2012

“…However, since a remarkable 83% of those acromegalic patients treated with pegvisomant in this country are monitored and documented in this German Database, one strength of the study is the nationwide reflection of clinical practice under field conditions, which frequently differ from clinical studies. Over the years between 2004 and 2008, an increasing use of combination therapies was recognized (14,15). Another strength of this observational study was the careful observation of side effects.…”

Section: Discussionmentioning

confidence: 99%

The German ACROSTUDY: past and present

Buchfelder

Schlaffer²,

Droste³

et al. 2009

Pivotal studies have demonstrated that pharmacotherapy with pegvisomant (Somavert) is a highly effective treatment for acromegaly. Since clinical experience with the drug was very limited, the Pegvisomant Observational Study was launched in Germany immediately with the drug becoming commercially available to patients early in 2004. Its purpose was to record safety and efficacy data on as many patients as possible.As of 12th August 2008 a total of 371 patients (185 males, 186 females) had been included in the study. They were on pegvisomant therapy for an average of 118 weeks. Median and mean doses of pegvisomant were 15 and 16.4 mg/day respectively. Treatment efficacy was monitored by IGF1 levels and the patients symptoms were evaluated by completion of a questionnaire (patient-assessed acromegaly symptom questionnaire). Safety data included liver function tests, fasting glucose, HbA1c measurements, and tumor size monitoring by repeated magnetic resonance imaging.Normalization of IGF1 ranged from 55.7% of the 273 patients assessed after 6 months to 71.3% of 202 patients assessed after 24 months of treatment. It was 70.7% after 36 months (133 patients), 64.8% at 48 months (71 patients), and 58.4% after 60 months (24 patients). In 39 patients (10.9%) treatment was discontinued due to serious adverse events or adverse events with 25 (6.7%) of these patients having a potential causal relationship with the pegvisomant treatment. Liver function tests became abnormal in 20 patients and another three patients were recorded to have hepatobiliary disorders. Tumor size increase was reported in 20 patients, but only confirmed in nine patients by careful revision of all available images. Local injection site reactions were observed in 12 patients.In conclusion, in this large group of pegvisomant-treated patients, long-term data for up to 5 years of treatment are now available. In 71.3% of patients with previously not sufficiently treatable acromegaly, IGF1 levels were normalized by pegvisomant therapy. Elevated transaminases usually normalized after discontinuation but in half of the affected patients also despite continuation of treatment without dose alteration. Tumor progression was a rare event. It did not exceed the expected rate in patients with acromegaly not treated with pegvisomant. As from this presently largest database of acromegalic patients treated with pegvisomant, long-term results are encouraging. The German data are now merged into the global ACROSTUDY and will constitute a major portion of the international ACROSTUDY project as a continuing global web-based observational study.

“…These undetectable PEGV serum levels could be explained by a false negative error of the assay, noncompliance of the patient in taking the drug or the absence of PEGV due to the half-life of the drug (T 1/2el Z 74-172 h (27)). Although the half-life of the drug is probably increased during combination treatment, since PEGV serum levels increase by 20% (24,28), in our opinion it is the loss of PEGV from the circulation that is the most likely explanation for the undetectable PEGV serum levels. The majority of patients with undetectable PEGV serum levels were using a low PEGV dose, between 10 and 60 mg once weekly.…”

Section: European Journal Of Endocrinologymentioning

confidence: 70%

“…The IGF1 age-adjusted reference ranges were used in accordance with earlier reports (23). PEGV serum levels were assessed in Aarhus, as described previously (24). Assessments of side effects included serum concentrations of alanine aminotransferase (ALT), aspartate aminotransaminase (AST), alkaline phosphatase, g-glutamyltranspeptidase and total bilirubin.…”

Section: Hormone Assaysmentioning

confidence: 99%

Pegvisomant in combination with long-acting somatostatin analogues in acromegaly: the role of the GH receptor deletion of exon 3

Franck

Lely

Delhanty

et al. 2015

Background: Doses of the GH receptor (GHR) antagonist pegvisomant (PEGV) that normalize insulin-like growth factor 1 (IGF1) levels vary widely among acromegaly patients. Predictors for PEGV response are baseline IGF1 levels, sex, body weight and previous radiotherapy. A GHR polymorphism lacking exon 3 (d3-GHR) is frequent in the general population. The influence of d3-GHR on PEGV responsiveness in acromegaly is unclear. Objective: To assess the influence of d3-GHR on IGF1 levels and PEGV responsiveness in acromegaly patients using combined PEGV and long-acting somatostatin receptor ligand (LA-SRIF) treatment. Design: Data were collected at the Rotterdam Pituitary Centre between 2004 and 2013. Patients with elevated IGF1 levels (O1.2 upper limit of normal; nZ112) and over 6 months of high-dose LA-SRIF treatment were co-treated with PEGV. GHR genotype was assessed using genomic DNA in 104 patients. Results: D3-GHR was observed in 51 (49.0%) of the patients (7.7% homozygous, 41.3% heterozygous) and was in Hardy-Weinberg equilibrium (PZ0.859). Baseline characteristics were similar in d3-GHR and full-length (fl)-GHR genotypes. During PEGV/LA-SRIF treatment IGF1 levels were not different between d3-carriers and non-carriers. Similarly, no difference in PEGV dose required to normalize IGF1 (PZ0.337) or PEGV serum levels (PZ0.433) was observed between the two groups. However, adenoma size decreased significantly (O20% of largest diameter) in 25.6% of the fl-GHR genotype but only in 7.5% of d3-carriers (PZ0.034, OR: 4.6 (CI: 1.1-18.9)). Conclusions: GHR genotype does not predict the IGF1 normalizing dose of PEGV in acromegaly patients using combination PEGV/LA-SRIF treatment. However, fewer d3-carriers showed significant reductions in adenoma size. IntroductionDisease activity and phenotype is diverse among patients with acromegaly. Comorbidities such as hypertension, cardiomyopathy, type 2 diabetes, sleep apnea and osteoarthritis are influenced by the severity and the duration of growth hormone (GH) hypersecretion (1). Pegvisomant (PEGV) is a competitive GH receptor (GHR) antagonist that is used in the treatment of acromegaly (2). The required dose of PEGV to achieve disease control as assessed by the normalization of insulin-like growth factor 1 (IGF1) levels differs significantly between individual patients (2). Baseline IGF1 appears to be a predictor for the required dose (3). Other factors known to influence the required dose are sex, body weight and previous radiotherapy (4). However, GHR polymorphisms seem to have an influence as well (5, 6). A polymorphism of the GHR that lacks exon 3 (d3-GHR) during splicing is common in the general population. About half of the population is homozygous for the full-length GHR (fl-GHR), 30-40% is heterozygous for d3-GHR and 10-20% is homozygous for this deletion (7,8,9). It has been reported that the d3-GHR polymorphism shows a comparable distribution between different cohorts of acromegalic patients (6,10,11,12). Multiple studies show that the fl-GHR and d3-GHR have co...