Pegvisomant Therapy Research Articles

Control of acromegaly in more than 90% of patients after 10 years of pegvisomant therapy: an European referral centre real-life experience

PurposePegvisomant (PEG) efficaciously controls IGF-I excess in acromegaly and possesses a positive impact on glucose metabolism. Data on very prolonged PEG treatment are still limited, therefore, we investigated the effects of 10-years PEG on disease control, maximal tumour diameter (MTD), and metabolic profile in consecutive patients resistant to somatostatin analogues (SRLs) followed in an European referral centre for acromegaly.MethodsSince the 2000s, we collected data on anthropometric, hormonal and metabolic parameters, and MTD of patients receiving PEG. In the current study, we included 45 patients (19 men, 26 women, 46.8 ± 11 years) treated for at least 5 years with PEG mono or combined therapy, analyzing data before, after 5- and 10-years PEG.ResultsAfter10 years, 91% of patients showed full disease control and in 37% a significant decrease in MTD was found. Diabetes prevalence was slightly increased, whereas HbA1c remained stable over the decade. Transaminases remained stable and no case of cutaneous lipohypertrophy was recorded. A different metabolic impact between mono- or combined therapy was found. Patients in monotherapy showed significantly lower fasting glucose (p = 0.01), fasting insulin (p = 0.008), HbA1c (p = 0.007), HOMA-IR (p = 0.001), and significantly higher ISI0 (p = 0.002), whereas patients under combined therapy showed significantly lower total (p = 0.03), and LDL cholesterol (p = 0.007). Acromegaly duration before PEG was inversely related to ΔFG (r = − 0.46, p = 0.03) and ΔFI (r = − 0.54, p = 0.05).ConclusionsPEG is effective and safe in long term. In patients resistant to SRLs, early beginning of PEG allows a wider gluco-insulinemic improvement.

Experiense of treatment with a growth hormone receptor antagonist in patients with hereditary form of acromegaly: clinical cases

Acromegaly is a severe neuroendocrine disease caused by chronic excessive production of somatotropic hormone (STH), characterized by specific changes in appearance, metabolic disorders. In 95% of cases, the cause of pathology is STH-producing pituitary adenomas. The priority method of treatment for acromegaly is transnasal transsphenoidal adenomectomy. If it is impossible to carry out neurosurgical intervention, in order to prevent the progression of the disease and the development of complications, patients are recommended drug therapy with long-acting somatostatin analogues, and if their effectiveness is low, additional radiation therapy may be applied to the neoplasm area. The usage of a relatively new group of drugs, antagonists of STH receptors, namely Pegvisomant for the purpose of drug treatment of acromegaly demonstrates high efficacy even in cases of aggressive forms resistant to other types of treatment. In this article we present two clinical cases of hereditary acromegaly, when the initiation of Pegvisomant therapy led to the achievement of clinical and laboratory remission of acromegaly in patients with an aggressive form of the disease, accompanied by continued growth of residual neoplasm tissue and preservation of its secreting ability even after surgical interventions, radiatiotherapy and long-term drug treatment with somatostatin analogues. The results of the above clinical cases confirm the success of mono- or combined (in cases with continued growth of the neoplasm) therapy with a growth hormone receptor antagonist, Pegvisomant, especially in the case of aggressive acromegaly.

Pegvisomant therapy in acromegalic patient resistant to other treatment: case report

Introduction: Acromegaly is a chronic, rare disorder resulting from growth hormone (GH) hypersecretion, usually caused by a pituitary adenoma. GH stimulates synthesis of insulin-like growth factor 1 (IGF-1), whom assay should be used as a screening test whenever acromegaly is suspected. Patients with acromegaly normally take from 5 to 10 years to receive a correct diagnosis, leading to complications such as cardiovascuar, respiratory, and endocrine problems that are responsible for an increase mortality. Late diagnosis of the disease also impact the effectiveness of surgical, pharmacological and radiotherapy treatment. 
 
 Case report: A 33-year-old acromegalic man with pituitary macroadenoma resistant to therapy of somastatin analogue (octreotide, lanreotide) and dopamine agonist (cabergoline). The patient underwent transsphenoidal adenomectomy, after wich high level of GH and IGF-1 were still measured. Due to the lack of the effect of the current treatment, the patient was qualified for pegvisomant therapy, as a result of which biochemical control was achieved without adverse events and with a good compliance of treatment. 
 
 Conclusions: Treatment with pegvisomant is now an important therapeutic strategy to achieve full disease control in acromegalic patients resistant or poorly responders to first generation somatostatin receptor ligands and in patients who do not respond adequately to selective excision of pituitary adenoma and /or for whom surgery is not possible.

Efficacy, safety and metabolic impact of long-term pegvisomant therapy in acromegaly: results from a 10-year single center experience

Efficacy, safety and metabolic impact of long-term pegvisomant therapy in acromegaly: results from a 10-year single center experience

Body Composition Changes with Long-term Pegvisomant Therapy of Acromegaly.

ContextIn active acromegaly, the lipolytic and insulin antagonistic effects of growth hormone (GH) excess alter adipose tissue (AT) deposition, reduce body fat, and increase insulin resistance. This pattern reverses with surgical therapy. Pegvisomant treats acromegaly by blocking GH receptor (GHR) signal transduction and lowering insulin-like growth factor 1 (IGF-1) levels. The long-term effects of GHR antagonist treatment of acromegaly on body composition have not been studied.MethodsWe prospectively studied 21 patients with active acromegaly who were starting pegvisomant. Body composition was examined by whole body magnetic resonance imaging, proton magnetic resonance spectroscopy of liver and muscle and dual-energy x-ray absorptiometry, and endocrine and metabolic markers were measured before and serially during 1.0 to 13.4 years of pegvisomant therapy. The data of patients with acromegaly were compared with predicted and to matched controls.ResultsMass of visceral AT (VAT) increased to a peak of 187% (1.56-229%) (P < .001) and subcutaneous AT (SAT) to 109% (–17% to 57%) (P = .04) of baseline. These remained persistently and stably increased, but did not differ from predicted during long-term pegvisomant therapy. Intrahepatic lipid rose from 1.75% to 3.04 % (P = .04). Although lean tissue mass decreased significantly, skeletal muscle (SM) did not change. IGF-1 levels normalized, and homeostasis model assessment insulin resistance and HbA1C were lowered.ConclusionLong-term pegvisomant therapy is accompanied by increases in VAT and SAT mass that do not differ from predicted, stable SM mass and improvements in glucose metabolism. Long-term pegvisomant therapy does not produce a GH deficiency-like pattern of body composition change.

All-cause mortality in patients with acromegaly treated with pegvisomant: an ACROSTUDY analysis.

To examine all-cause mortality rates in patients with acromegaly on pegvisomant and identify pertinent risk factors, including insulin-like growth factor I (IGF-I). Retrospective cohort analysis of data from ACROSTUDY (global surveillance study of patients with acromegaly treated with pegvisomant). Kaplan-Meier analyses and Cox regression techniques were used to examine survival rates. Standardized mortality ratios (SMR) with reference to general population (WHO GBD 2016) were estimated. Multiplicative multiple Poisson regression models were used to characterize the association between SMR, IGF-I, and other risk factors associated with mortality risk. The study consisted of 2077 subjects who were followed for a median interval of 4.1 years, contributing to 8957 patient-years. Higher on-treatment IGF-I (P = 0.0035), older attained age (P < 0.0001), and longer duration of acromegaly (>10 years) before starting pegvisomant (P = 0.05) were associated with higher mortality rates. In reference to general population rates, higher SMR (1.10, 1.42, and 2.62, at attained age 55 years) were observed with higher serum IGF-I category (SMR trend: 1.44 (44%)/per fold level of IGF-I/ULN (95% CI: 1.10, 1.87), P = 0.0075). SMR increased per year of younger attained age (1.04 (1.02-1.04), P < 0.0001) and were higher for longer disease duration (>10 years) before starting pegvisomant (1.57 (1.02, 2.43), P = 0.042). Serum IGF-I levels within the normal range during pegvisomant therapy were associated with all-cause mortality rates that were indistinguishable from the general population. Higher on-treatment IGF-I, older attained age, and longer duration of acromegaly before starting pegvisomant are associated with higher all-cause mortality rates. Younger patients with uncontrolled acromegaly have higher excess all-cause mortality rates in comparison with older patients.

Plasma Agouti-Related Protein Levels in Acromegaly and Effects of Surgical or Pegvisomant Therapy.

GH activates agouti-related protein (AgRP) neurons, leading to orexigenic responses in mice. The relationship between serum GH and plasma AgRP, which has been shown to reflect hypothalamic AgRP, has not been evaluated in humans. To test the hypothesis that central stimulatory actions of GH on hypothalamic AgRP could be reflected in plasma AgRP in acromegaly. We studied 23 patients with active acromegaly before and for ≤2 years after surgical (n = 13) or GH receptor antagonist therapy with pegvisomant (n = 10), and 100 healthy subjects with morning fasting blood samples for AgRP, leptin, GH, and IGF-1 and anthropometric measurements. The plasma AgRP levels were higher in those with active acromegaly than in the matched healthy subjects [median, 100 pg/mL; interquartile range (IQR), 78 to 139 pg/mL vs median, 63 pg/mL; IQR, 58 to 67 pg/mL; P < 0.0001]. Plasma AgRP decreased from before to after surgery (median, 102 pg/mL; IQR, 82 to 124 pg/mL vs median, 63 pg/mL; IQR, 55.6 to 83 pg/mL; P = 0.0024) and from before to during pegvisomant therapy (median, 97 pg/mL; IQR, 77 to 175 pg/mL vs median, 63; IQR, 61 to 109 pg/mL; P = 0.006). The plasma AgRP level correlated with GH (r = 0.319; P = 0.011) and IGF-1 (r = 0.292; P = 0.002). In repeated measure analysis, AgRP was significantly associated with IGF-1. Our data have provided evidence of a stimulatory effect of GH on plasma AgRP in humans. The levels were greater in active acromegaly and decreased in parallel with GH and IGF-1 decreases with acromegaly treatment. Data from mice suggest that AgRP may mediate some of the known effects of GH on energy metabolism. This warrants further study in patients with acromegaly and other populations.

OR16-6 Cardiometabolic Abnormalities in Patients with Acromegaly with Elevated Plasma IGF-1 Concentrations but GH Concentrations &lt;2ng/ml

The increased cardiovascular mortality in acromegaly can be reversed by achieving plasma GH concentrations to a target of <2ng/ml and normalizing IGF-1 concentrations to within the age-related reference range. However, in approximately 30% of patients, plasma GH concentrations which are on target are associated with discordantly elevated plasma IGF-1 concentrations. It is not known whether this discordance confers excess morbidity. The aim of this study was to determine whether discordance of plasma GH and IGF-1 negatively affects parameters which predict cardiovascular morbidity. Methods: Group 1 (Concordant): 28 patients (15F,13M) with plasma GH <2ng/ml and IGF-1 concentrations within the age and sex matched reference range. Group 2 (Discordant): 27 patients (5F, 22M) with plasma GH <2ng/ml and elevated plasma IGF-1 concentrations above the age and sex-matched reference range. IGF-1 and GH concentrations were analysed in one laboratory using IDS-iSYS assay. Patients were excluded if they were receiving Pegvisomant therapy, if they had a change in therapy in the preceding 6 months or if the random GH was >2ng/ml. Parameters Measured: OGTT with GH, fasting lipid profile, HOMA-IR, Carotid Intima Thickness (CIMT), pulse wave velocity (PWV), flow mediated dilatation (FMD) and 24-hour ambulatory blood pressure. All tests were completed with a standardised protocol over one day. IGF-1 concentrations were calculated as % Upper limit of normal (%ULN) to allow comparison across different age matched reference ranges. Results: The median age (range) was similar in the two groups; 54 (32-78) years in the concordant group and 61 (34-83) years in the discordant group, p=0.45. There were no significant between group differences in BMI, smoking, hypertension, diabetes mellitus or obstructive sleep apnoea. GH nadir during OGTT (p=0.03) and basal plasma GH (p=0.03) were higher in the discordant group. HOMA-IR was also higher in the discordant group (median = 1.75, range 0.73 - 4.88) compared to the concordant group (median = 1.123, range 0.27-4.63), p=0.01. However, there were no significant differences in HbA1c and fasting glucose between the two groups. Furthermore, there were no significant differences between IMT (p=0.63), PWV (p=0.3), mean daytime (p=0.48) or night-time systolic blood pressure (p=0.54) between the two groups. Conclusion: Elevated plasma IGF-1, with controlled GH concentrations, was associated with higher basal GH, higher nadir GH on OGTT and higher markers of insulin resistance in comparison to patients with controlled GH and IGF-1 concentrations. However, we found no difference in other predictors of future cardiovascular risk between the two groups. Further investigation of these findings is warranted to determine if the differences in HOMA-IR and GH dynamics between the two groups requires intervention.

MON-415 Pituitary Carcinoma With Sequential Hormone Hypersecretion And A Novel Renal Complication Of Hormone Excess

Background: Pituitary carcinoma is a rare diagnosis, occurring in <1% of pituitary tumours. Most are hormonally active and resistant to conventional treatment. We present a rare case of a malignant lactotroph tumour whose extreme and evolving secretory phenotype has induced an unprecedented form of nephropathy. Case: A 55 year old man presented to ophthalmology with painful right third nerve palsy. Subsequent imaging revealed a 24 x 26 mm sellar mass extending into the right cavernous sinus and encroaching upon the optic chiasm. Endocrine evaluation demonstrated prolactin (PRL) of 68,000 mIU/L and accompanying hypogonadism (testosterone 1.3 nmol/L, FSH 1.8 IU/L, LH 1.4 IU/L), hypoadrenalism (peak cortisol 272 nmol/L after 250 mcg synacthen) and hypothyroidism (TSH 2.9 mIU/L, T4 8 pmol/L). IGF1-1 was also at the lower end of the reference range (10 nmol/L). He made an initial good response to cabergoline with PRL falling to 1570 mIU/L, resolution of visual symptoms, tumour shrinkage to 7 x 16 mm and restoration of HPA axis function. Five years later he demonstrated escape from hormone control with PRL rising to 32,000 mIU/L and return of the ophthalmoplegia, despite escalation of cabergoline to 3.5mg weekly. Unexpectedly, he also developed acute ketotic diabetes mellitus secondary to new onset acromegaly (GH >100 ug/L, IGF-1 97 nmol/L). The tumour remnant had expanded into the cavernous sinus on MRI. Biopsy of the lesion showed a tumour with strong PRL staining, micro-vacuolation, sparse GH staining and Ki-67 of 15-20% suggesting an aggressive nature and potentially in keeping with the rare acidophilic stem cell tumour subtype. He underwent stereotactic pituitary radiotherapy and later commenced pegvisomant therapy after a failed octreotide trial. Following this, prolactin levels continued to rise. Unfortunately, subsequent investigations for back pain with bilateral hand paraesthesia (at first considered secondary to acromegaly) revealed metastatic lesions in spine, lung and stomach - the latter confirmed to be of PRL-secreting neuroendocrine origin on biopsy. There was no uptake on octreotide scan. In response to new renal dysfunction (creatinine 463 umol/L with microscopic haematuria and proteinuria), a renal biopsy was also performed and revealed changes compatible with interstitial nephritis with cast nephropathy. The tubular casts stained positive for PRL, and serum PRL at this time reached a peak of 3.7 million mIU/L. Temolozamide has been commenced, and the patient may later be considered for immunotherapy . Conclusion: This is the first documented case of prolactin cast nephropathy and a rare example of a changing tumour secretion pattern, with intractable acute on chronic hyperprolactinaemia and acute acromegaly, in a case of metastatic pituitary carcinoma.

SUN-LB080 ACROSTUDY - Safety and Efficacy of a Cohort of 110 Naïve Patients with Acromegaly Treated with Pegvisomant

Background: ACROSTUDY is an open-label, non-interventional post-authorization safety study that began in 2004 to evaluate safety in at least 1000 acromegaly patients treated with the GH receptor antagonist pegvisomant (PEGV). This commitment was fulfilled in Jan 2013. ACROSTUDY was later amended to enroll an additional 110 patients that were naïve/semi-naive to PEGV treatment. Semi-naïve patients are defined as not having received PEGV therapy for at least 6 months prior to enrollment. Objectives: The primary objectives were to: 1) assess the long-term safety of PEGV in real world practice; 2) assess the effect of IGF-I normalization on treatment outcomes, including safety, glucose control and patient-reported outcomes (PROs). Patients & Methods: 110 patients with Acromegaly 53.6% male, 81.8% Caucasian, median age 42.4 years at diagnosis; median age 48.9 years at PEGV start. Patients were considered ‘IGF-I Controlled’ if the most temporally-related IGF-I measurement was normal for that laboratory. Safety data including adverse events and liver tests were collected. IGF-I and HbA1C were measured; PROs were evaluated using the Acromegaly Quality of Life Questionnaire (AcroQoL) and PatientAssessed Acromegaly Symptom Questionnaire (PASQ), stratified by IGF-I control. Results: No new safety signals were identified in this sub-study. IGF-I SDS >2 decreased from 87% of patients at baseline to 31% at year 2 at a mean dose(±SD) of 10.4(±7.45) mg/day; patients with IGF-I SDS <2 had a mean dose of 14.8(±6.7). Among IGF-I controlled patients, median (range) HbA1C levels were 5.8% (5.4-6.1) at baseline and 5.6% (4.5-7.2) at year 2; in IGF-I uncontrolled patients, HbA1C was 6.1% (4.9-6.6) at baseline and 6.3% (2.9-10.6) at year 2. Among IGF-I controlled patients, median (range) global AcroQoL scores were 54.6 (24-73) at baseline and 61.4 (13-86) at year 2; while in IGF-I uncontrolled patients, median global AcroQoL score was 59.7 (8-92) at baseline and 63.6 (25-76) at year 2. Among IGF-I controlled patients, median (range) total PASQ score was 20 (3-38) at baseline and 17.5 (1-40) at year 2; in IGF-I uncontrolled patients, median total PASQ score was 17 (0-44) at baseline and 14 (3-39) at year 2. A greater number of the six individual symptoms of the PASQ score showed a positive trend for improvement from baseline to year 2 in the IGF-I controlled patients than in the uncontrolled patients. Summary: In this real-life world international study, overall biochemical control (i.e. normal IGF-I) was achieved with pegvisomant in 64.3% patients by year 2. Improved IGF-I control was associated with improved HbA1C, QoL and symptoms of acromegaly. One limitation of the study was that the PEGV dose may not have been adequately titrated to achieve IGF-I normalization. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

How to Position Pasireotide LAR Treatment in Acromegaly.

Pasireotide long-acting release (LAR) is a somatostatin multireceptor ligand, and in the current consensus criteria pasireotide LAR is considered the second-line medical treatment for acromegaly. We present in this article our recommendations to define the position of pasireotide LAR in the treatment of acromegaly and provide recommendations for the management of pasireotide-induced hyperglycemia. Our recommendations are based on our experiences with the pasireotide LAR and pegvisomant (PEGV) combination study and the available basic or clinical articles published in peer-reviewed international journals on pasireotide LAR and acromegaly. In accordance with the current consensus criteria, we recommend pasireotide LAR monotherapy as a second-line therapy in young patients who show tumor growth during first-generation somatostatin receptor ligand (SRL) therapy and in patients who show tumor growth during PEGV therapy. In addition, we recommend pasireotide LAR monotherapy in patients with headache not responsive to first-generation SRL therapy and in patients who experience side effects or are intolerant to PEGV monotherapy. In contrast to the current consensus criteria, we recommend considering combination therapy with pasireotide LAR and PEGV as third-line treatment in patients without diabetes at low PEGV dosages (≤80 mg/week) and in patients with tumor growth or symptoms of active acromegaly during first-generation SRL and PEGV combination therapy. With respect to pasireotide-induced hyperglycemia, we recommend a more liberal strategy of blood glucose monitoring during pasireotide treatment. In contrast to the current consensus criteria, we recommend a more reluctant use of pasireotide LAR therapy for the treatment of acromegaly.

Prevalence of morphometric vertebral fractures in "difficult" patients with acromegaly with different biochemical outcomes after multimodal treatment.

Skeletal fragility with high risk of vertebral fractures is an emerging complication of acromegaly in close relationship with duration of active disease. The aim of this cross-sectional study was to evaluate the prevalence and determinants of vertebral fractures in males and females with a history of long-standing active acromegaly undergoing treatment with Pegvisomant. Thirty-eight patients (25 females, 13 males) with acromegaly under Pegvisomant therapy were evaluated for vertebral fractures and bone mineral density at lumbar spine and femoral neck. Gonadal status, serum IGF1 levels and growth hormone receptor genotype were also assessed. Vertebral fractures were detected in 12 patients (31.6%). Fractured patients had longer duration of active disease (p = 0.01) with higher frequency of active acromegaly (p = 0.04), received higher dose of Pegvisomant (p = 0.008), and were more frequently hypogonadic (p = 0.02) as compared to patients who did not fracture. Stratifying the patients for gender, vertebral fractures were significantly associated with Pegvisomant dose (p = 0.02) and untreated hypogonadism (p = 0.02) in males and with activity of disease (p = 0.03), serum insulin-like growth factor-I values (p = 0.01) and d3GHR polymorphism (p = 0.005) in females. No significant association was found between vertebral fractures and bone mineral density at either skeletal site. Vertebral fractures are a frequent complication of long-standing active acromegaly. When patients are treated with Pegvisomant, vertebral fractures may occur in close relationship with active acromegaly and coexistent untreated hypogonadism.

Growth hormone receptor antagonism with pegvisomant in insulin resistant non-diabetic men: A phase II pilot study

Background: Growth hormone (GH) is known to affect insulin and glucose metabolism. Blocking its effects in acromegalic patients improves diabetes and glucose metabolism. We aimed to determine the effect of pegvisomant, a GH receptor antagonist, on insulin resistance, endogenous glucose production (EGP) and lipolysis in insulin resistant non-diabetic men. Methods: Four men between the ages of 18-62 with a BMI of 18-35kg/m 2, with insulin resistance as defined by a HOMA-IR > 2.77, were treated for four weeks with pegvisomant 20 mg daily. Inpatient metabolic assessments were performed before and after treatment. The main outcome measurements were: change after pegvisomant therapy in insulin sensitivity as measured by hyperinsulinemic euglycemic clamp; and EGP and lipolysis assessed by stable isotope tracer techniques. Results: Insulin like growth factor-1 (IGF-1) concentrations decreased from 134.0 ± 41.5 (mean ± SD) to 72.0 ± 11.7 ng/mL (p = 0.04) after 4 weeks of therapy. Whole body insulin sensitivity index (M/I 3.2 ± 1.3 vs. 3.4 ± 2.4; P = 0.82), as well as suppression of EGP (89.7 ± 26.9 vs. 83.5 ± 21.6%; p = 0.10) and Ra glycerol (59.4 ± 22.1% vs. 61.2 ± 14.4%; p = 0.67) during the clamp were not changed significantly with pegvisomant treatment. Conclusions: Blockade of the GH receptor with pegvisomant for four weeks had no significant effect on insulin/glucose metabolism in a small phase II pilot study of non-diabetic insulin resistant participants without acromegaly.

Growth hormone receptor antagonism with pegvisomant in insulin resistant non-diabetic men: A phase II pilot study.

Background: Growth hormone (GH) is known to affect insulin and glucose metabolism. Blocking its effects in acromegalic patients improves diabetes and glucose metabolism. We aimed to determine the effect of pegvisomant, a GH receptor antagonist, on insulin resistance, endogenous glucose production (EGP) and lipolysis in insulin resistant non-diabetic men. Methods: Four men between the ages of 18-62 with a BMI of 18-35kg/m 2, with insulin resistance as defined by a HOMA-IR > 2.77, were treated for four weeks with pegvisomant 20 mg daily. Inpatient metabolic assessments were performed before and after treatment. The main outcome measurements were: change after pegvisomant therapy in insulin sensitivity as measured by hyperinsulinemic euglycemic clamp; and EGP and lipolysis assessed by stable isotope tracer techniques. Results: Insulin like growth factor-1 (IGF-1) concentrations decreased from 134.0 ± 41.5 (mean ± SD) to 72.0 ± 11.7 ng/mL (p = 0.04) after 4 weeks of therapy. Whole body insulin sensitivity index (M/I 3.2 ± 1.3 vs. 3.4 ± 2.4; P = 0.82), as well as suppression of EGP (89.7 ± 26.9 vs. 83.5 ± 21.6%; p = 0.10) and Ra glycerol (59.4 ± 22.1% vs. 61.2 ± 14.4%; p = 0.67) during the clamp were not changed significantly with pegvisomant treatment. Conclusions: Blockade of the GH receptor with pegvisomant for four weeks had no significant effect on insulin/glucose metabolism in a small phase II pilot study of non-diabetic insulin resistant participants without acromegaly.

Effectiveness of first-line pegvisomant monotherapy in acromegaly: an ACROSTUDY analysis.

To examine the effectiveness and safety of primary pegvisomant monotherapy. Retrospective analysis of data extracted from ACROSTUDY (global observational outcomes study of patients with acromegaly treated with pegvisomant). The earliest time to insulin-like growth factor 1 (IGF-1) normalization on pegvisomant monotherapy was determined. Both the proportion of patients who achieved IGF-1 normalization and the time to IGF-1 normalization on pegvisomant monotherapy were assessed. Eligible patients included 28 subjects on primary medical therapy (PT) and 176 controls on adjunctive pegvisomant therapy treated postoperatively, including 43 who were naïve to medical therapy (NMT) and 133 who were previously treated medically and were washed out (WASH). IGF-1 normalization occurred in 76.9% (PT), 85.2% (NMT) and 78.3% (WASH) patients (P = NS). Median times to IGF-1 normalization were 0.5 year (PT), 0.7 year (NMT) and 0.6 year (WASH), P = NS. On survival analysis, the fraction of patients controlled on pegvisomant monotherapy was not different between groups. Higher baseline IGF-1 levels, obtained at study entry, predicted a lower likelihood of IGF-1 normalization on monotherapy (P = 0.012). Safety data include low prevalence of skin rashes, injection site reactions and reversible transaminase elevations. There was one patient (NMT) with a verified increase in tumor size. Pegvisomant monotherapy, administered either as primary medical therapy or as adjunctive therapy according to local practice, led to IGF-1 normalization in >75% of patients. Pegvisomant monotherapy had a favorable safety profile, consistent with previous observations. Prospective data are needed to further evaluate the role of primary pegvisomant monotherapy in acromegaly.

Experience with pegvisomant treatment in acromegaly in a single Brazilian tertiary reference center: efficacy, safety and predictors of response.

To describe the safety and efficacy of pegvisomant therapy and the predictors of treatment response in acromegaly patients at a single tertiary reference center in Brazil. We retrospectively reviewed the clinical, hormonal and radiological data of acromegaly patients treated with pegvisomant in our center. We also evaluated the presence of the d3 isoform of the growth hormone receptor (d3GHR). Twenty-seven patients were included (17 women). Pegvisomant was used in combination with octreotide LAR in 20 patients (74%), in combination with cabergoline in one (4%) and as monotherapy in six (22%). IGF-I normalization was achieved in 23 patients (85%). Mild and transitory elevation of liver enzymes was observed in two patients (7.4%), tumor growth in one (3.4%) and lipodystrophy in two (7.4%). One patient stopped the drug due to headaches. The GHR isoforms were evaluated in 14 patients, and the presence of at least one d3GHR allele was observed in 43% of them, but it was not a predictor of treatment response. Only pre-treatment IGF-I level was a predictor of treatment response. Pegvisomant treatment was highly effective and safe in our series of Brazilian patients. A better chance of disease control can be expected in those with lower pre-pegvisomant IGF-I levels.

Pegvisomant: a growth hormone receptor antagonist used in the treatment of acromegaly.

To review published data on pegvisomant and its therapeutic role in acromegaly. Electronic searches of the published literature were conducted using the keywords: acromegaly, growth hormone (GH) receptor (antagonist), pegvisomant, therapy. Relevant articles (n=141) were retrieved and considered for inclusion in this manuscript. Pegvisomant is a genetically engineered, recombinant growth hormone receptor antagonist, which is effective in normalizing serum insulin-like growth factor 1 (IGF-1) levels in the majority of patients with acromegaly and ameliorating symptoms and signs associated with GH excess. Pegvisomant does not have direct antiproliferative effects on the underlying somatotroph pituitary adenoma, which is the etiology of GH excess in the vast majority of patients with acromegaly. Therefore, patients receiving pegvisomant monotherapy require regular pituitary imaging in order to monitor for possible increase in tumor size. Adverse events in patients on pegvisomant therapy include skin rashes, lipohypertrophy at injection sites, and idiosyncratic liver toxicity (generally asymptomatic transaminitis that is reversible upon drug discontinuation), thus necessitating regular patient monitoring. Pegvisomant is an effective therapeutic agent in patients with acromegaly who are not in remission after undergoing pituitary surgery. It mitigates excess GH action, as demonstrated by IGF-1 normalization, but has no direct effects on pituitary tumors causing acromegaly. Regular surveillance for possible tumor growth and adverse effects (hepatotoxicity, skin manifestations) is warranted.

Long-term effects of pegvisomant on comorbidities in patients with acromegaly: a retrospective single-center study.

ContextThe effect of pegvisomant on IGF1 levels in patients with acromegaly is well documented, but little is known of its long-term impact on comorbidity.AimThe aim of this retrospective study was to evaluate the effects of long-term pegvisomant therapy on cardiorespiratory and metabolic comorbidity in patients with acromegaly.Patients and methodsWe analyzed the long-term (up to 10 years) effect of pegvisomant therapy given alone (n=19, 45%) or in addition to somatostatin analogues and/or cabergoline (n=23, 55%) on echocardiographic, polysomnographic and metabolic parameters in respectively 42, 12 and 26 patients with acromegaly followed in Bicêtre hospital.ResultsAt the first cardiac evaluation, 20±16 months after pegvisomant introduction, IGF1 levels normalized in 29 (69%) of the 42 patients. The left ventricular ejection fraction (LVEF) improved significantly in patients whose basal LVEF was ≤60% and decreased in those whose LVEF was >70%. The left ventricular mass index (LVMi) decreased from 123±25 to 101±21 g/m2 (P<0.05) in the 17 patients with a basal LVMi higher than the median (91 g/m2), while it remained stable in the other patients. Pegvisomant reduced the apnoea–hypopnea index and cured obstructive sleep apnea (OSA) in four of the eight patients concerned. Long-term follow-up of 22 patients showed continuing improvements in cardiac parameters. The BMI and LDL cholesterol level increased minimally during pegvisomant therapy, and other lipid parameters were not modified.ConclusionsLong-term pegvisomant therapy not only normalizes IGF1 in a large proportion of patients but also improves cardiac and respiratory comorbidity.

Prediction of therapy response in acromegalic patients under pegvisomant therapy within the German ACROSTUDY cohort.

This study aimed at investigating predicting factors for therapy response under growth hormone receptor antagonist therapy with a focus on subjective and patient-oriented measures. Observational, multicenter nested-cohort study including 271 selected patients with the diagnosis of acromegaly and a minimum of one-year follow-up period within the German ACROSTUDY cohort (total cohort: n=514). Outcome measures were the change of the biomarker IGF-1 (IGF-1 change and IGF-1 normalisation) between baseline and after 1year of pegvisomant therapy (12±6months). Main predictors were patient-assessed subjective measures according to the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) in conjugation with age, gender, BMI, max. dosage of pegvisomant at follow-up and IGF-1 before the start of pegvisomant therapy. The mean age of the study population was 51.2 (13.9) years and the mean BMI was 29.5 (5.1)kg/m(2). In adjusted analyses, none of the individual perceived health (PASQ) scores, but age, BMI and IGF-1 at baseline were predictive for an IGF-1 decrease after 1year of pegvisomant therapy and BMI and IGF-1, but equally none of the PASQ items, were predicting IGF-1 normalisation. Age, BMI and baseline IGF-1 but not subjective perceived health measures predict therapy response under second line medical therapy with pegvisomant.

Does pegvisomant treatment expertise improve control of resistant acromegaly? The Italian ACROSTUDY experience.

GH receptor antagonist pegvisomant is indicated for treatment of patients with resistant acromegaly. We compared safety and treatment outcomes of pegvisomant therapy in patients managed by Italian centers enrolling less or more than 15 cases in ACROSTUDY, a safety surveillance study of long-term pegvisomant treatment of patients with acromegaly. A noninterventional safety surveillance study in which safety and treatment outcomes of pegvisomant were evaluated on the basis of data collected during a 7-year period. A total of 204 acromegaly patients treated by seven centers enrolling 16-49 patients each (group A) and 137 subjects by 18 centers following 3-14 cases ( group B). Patients of group A and B were treated for 4.4±2.7 and 4.2±2.2years, respectively. IGF-1 ULN normalized in 64.4% (n=56) and 54.4% (n=31) in group A and B, respectively, after 1-year treatment, and in 57.3% (n=106) and 72.5% (n=87) at last visit. Starting doses were significantly higher in group A. They were progressively increased during treatment in both groups, but were higher in uncontrolled patients than in controlled ones only in group A. Reported adverse events were more frequent, and the prevalence of patients with adverse events was higher in group B. On the basis of this original study approach, we could speculate that in the centers in which more patients are treated with pegvisomant, less adverse events are reported, but the long-term effectiveness is lower than in centers with less cases, perhaps because of an inadequate patient's selection.