Hyperglycemia induced by pasireotide in patients with Cushing’s disease or acromegaly

PURPOSE: Cushing’s disease (CD) and acromegaly are characterized by excessive hormone secretion resulting in comorbidities such as impaired glucose metabolism, diabetes and hypertension. Pasireotide is a new-generation, multireceptor-targeted somatostatin receptor ligand approved for CD (subcutaneous [SC] injection formulation) and acromegaly (long-acting release [LAR] formulation). In clinical studies of pasireotide, hyperglycemia-related adverse events (AEs) were frequently observed. This review highlights differences in reported rates of hyperglycemia in pasireotide trials and discusses risk factors for and management of pasireotide-associated hyperglycemia. METHODS: Clinical trials evaluating pasireotide in patients with CD or acromegaly were reviewed. RESULTS: The frequency of hyperglycemia-related AEs was lower in patients with acromegaly treated with pasireotide LAR (57.3–67.0 %) than in patients with CD treated with pasireotide SC (68.4–73.0 %). Fewer patients with acromegaly treated with pasireotide LAR discontinued therapy because of hyperglycemia-related AEs (Colao et al. in J Clin Endocrinol Metab 99(3):791–799, 2014, 3.4 %; Gadelha et al. in Lancet Diabetes Endocrinol 2(11):875–884, 2014, 4.0 %) than did patients with CD treated with pasireotide SC (Boscaro et al. in Pituitary 17(4):320–326, 2014, 5.3 %; Colao et al. in N Engl J Med 366(10):914–924, 2012, 6.0 %). Hyperglycemia-related AEs occurred in 40.0 % of patients with acromegaly treated with pasireotide SC, and 10.0 % discontinued treatment because of hyperglycemia. Ongoing studies evaluating pasireotide LAR in patients with CD and management of pasireotide-induced hyperglycemia in patients with CD or acromegaly (ClinicalTrials.gov identifiers NCT01374906 and NCT02060383, respectively) will address these key safety issues. CONCLUSIONS: Disease pathophysiology, drug formulation, and physician experience potentially influence the differences in reported rates of pasireotide-induced hyperglycemia in CD and acromegaly. Hyperglycemic effects associated with pasireotide have a predictable pattern, can be managed with antidiabetic agents, and are reversible upon discontinuation

Acromegaly: pathogenesis & treatment

Acromegaly is a multi-system disorder whose etiology is most often traced back to a growth hormone-secreting pituitary adenoma (PA). Growth hormone (GH) secretion promotes insulin-like growth factor 1 (IGF-1) release from peripheral tissues, leading to the clinical manifestations of acromegaly. Current treatment methods for acromegaly include surgery, medical therapy, and radiation therapy. The goals of acromegaly treatment are to reduce GH levels and IGF-1 levels to age/sex-normalized levels, relieve comorbidities, normalize mortality rate, and to remove the pituitary mass causing high hormone levels. This study aims to provide a comprehensive review of current treatment methods and an analysis of novel therapies for treatment of acromegaly. The primary treatment method of acromegaly is surgery due to limited complications, relatively low cost, and remission in the majority of cases. However, surgery is not an effective treatment method for invasive macroadenomas with extension into the intracranial space. Medical therapies such as dopamine agonists (DAs) and somatostatin receptor ligands (SRLs) are effective at reducing GH and IGF-1 levels and may have anti-tumor effects. However, DAs are only effective at treating minor elevations in GH and IGF-1 levels and SRLs may cause hyperglycemia after prolonged treatment. In contrast to DAs and SRLs, Pegvisomant does not have anti-tumor effects, but it is more effective at reducing GH and IGF-1 levels. The disadvantages of Pegvisomant are the possibility of irreversible liver damage and the overwhelming cost of treatment. Stereotactic radiosurgery (SRS) is another mode of treatment for acromegaly, however, there are many disadvantages to SRS including prolonged latency period, hypopituitarism, radio-necrosis of normal brain tissue, and secondary tumor formation. Novel therapies for acromegaly include antisense drugs and modified botulin neurotoxins. Despite the success of antisense drugs and modified botulin neurotoxins in animal models, greater research is required prior to application in human clinical trials. Gene therapy is an emerging treatment method for acromegaly and proper manipulation of viral immunogenic effects could prove as a successful treatment for large macroadenomas, invasive PAs, and recurrent PAs. Despite the success of surgery in treating microadenomas and noninvasive macroadenomas, therapeutic alternatives must be explored to treat invasive PAs, macroadenomas, and recurrent PAs. Future research in immunotherapies and gene therapies may provide greater insight into the development of more effective and less invasive treatment methods for acromegaly

Feline hypersomatotropism and acromegaly tumorigenesis: a potential role for the AIP gene

Acromegaly in humans is usually sporadic, however up to 20% of familial isolated pituitary adenomas are caused by germline sequence variants of the aryl-hydrocarbon-receptor interacting protein (AIP) gene. Feline acromegaly has similarities to human acromegalic families with AIP mutations. The aim of this study was to sequence the feline AIP gene, identify sequence variants and compare the AIP gene sequence between feline acromegalic and control cats, and in acromegalic siblings. The feline AIP gene was amplified through PCR using whole blood genomic DNA from 10 acromegalic and 10 control cats, and 3 sibling pairs affected by acromegaly. PCR products were sequenced and compared with the published predicted feline AIP gene. A single nonsynonymous SNP was identified in exon 1 (AIP:c.9T > G) of two acromegalic cats and none of the control cats, as well as both members of one sibling pair. The region of this SNP is considered essential for the interaction of the AIP protein with its receptor. This sequence variant has not previously been reported in humans. Two additional synonymous sequence variants were identified (AIP:c.481C > T and AIP:c.826C > T). This is the first molecular study to investigate a potential genetic cause of feline acromegaly and identified a nonsynonymous AIP single nucleotide polymorphism in 20% of the acromegalic cat population evaluated, as well as in one of the sibling pairs evaluated

Clinical effectiveness and cost-effectiveness of pegvisomant for the treatment of acromegaly: a systematic review and economic evaluation

Background: Acromegaly, an orphan disease usually caused by a benign pituitary tumour, is characterised by hyper-secretion of growth hormone (GH) and insulin-like growth factor I (IGF-1). It is associated with reduced life expectancy, cardiovascular problems, a variety of insidiously progressing detrimental symptoms and metabolic malfunction. Treatments include surgery, radiotherapy and pharmacotherapy. Pegvisomant (PEG) is a genetically engineered GH analogue licensed as a third or fourth line option when other treatments have failed to normalise IGF-1 levels. Methods: Evidence about effectiveness and cost-effectiveness of PEG was systematically reviewed. Data were extracted from published studies and used for a narrative synthesis of evidence. A decision analytical economic model was identified and modified to assess the cost-effectiveness of PEG. Results: One RCT and 17 non-randomised studies were reviewed for effectiveness. PEG substantially reduced and rapidly normalised IGF-1 levels in the majority of patients, approximately doubled GH levels, and improved some of the signs and symptoms of the disease. Tumour size was unaffected at least in the short term. PEG had a generally safe adverse event profile but a few patients were withdrawn from treatment because of raised liver enzymes. An economic model was identified and adapted to estimate the lower limit for the cost-effectiveness of PEG treatment versus standard care. Over a 20 year time horizon the incremental cost-effectiveness ratio was pound81,000/QALY and pound212,000/LYG. To reduce this to pound30K/QALY would require a reduction in drug cost by about one third. Conclusion: PEG is highly effective for improving patients' IGF-1 level. Signs and symptoms of disease improve but evidence is lacking about long term effects on improved signs and symptoms of disease, quality of life, patient compliance and safety. Economic evaluation indicated that if current standards (UK) for determining cost-effectiveness of therapies were to be applied to PEG it would be considered not to represent good value for money

Adiponectin and Cardiac Hypertrophy in Acromegaly

Background. Adiponectin is an adipocytes-derived hormone which has been shown to possess insulin-sensitizing, antiatherogenic, and anti-inflammatory properties. In acromegaly, the data on adiponectin is contradictory. The relationship between adiponectin levels and cardiac parameters has not been studied.Objectives. The aim of this study was to find out how adiponectin levels were affected in acromegalic patients and the relationship between adiponectin levels and cardiac parameters.Material and Methods. We included 30 subjects (15 male, 15 female), diagnosed with acromegaly and 30 healthy (10 male, 20 female) subjects. Serum glucose, insulin, GH, IGF-1 and adiponectin levels were obtained and the insulin resistance of the subjects was calculated. Echocardiographic studies of the subjects were performed.Results. We determined that adiponectin levels were significantly higher in the acromegalic group than the control group. In the acromegalic group, there was no statistically significant relation between serum adiponectin and growth hormone (GH), or insulin-like growth factor-1 (IGF-1) levels (p = 0.3, p = 0.1). We demonstrated that cardiac function and structure are affected by acromegaly. IVST, PWT, LVMI, E/A ratio, DT, ET, IVRT, VPR, and LVESV values were increased and the results were statistically significant. In the acromegalic group, adiponectin levels were positively related with left ventricle mass index (LVMI) but this correlation was found to be statistically weak (p = 0.03). In our study, there was a positive correlation between VAI and LVM. We also could not find any correlation between VAI and adiponectin levels.Conclusions. Although insulin resistance and high insulin levels occur in active acromegaly patients, adiponectin levels were higher in our study as a consequence of GH lowering therapies. Our study showed that adiponectin levels may be an indicator of the cardiac involvement acromegaly. However, the usage of serum adiponectin levels in acromegalic patients as an indicator of cardiac involvement should be supported with other, wide, multi-centered studies

The role of stereotactic radiosurgery in the multimodal management of growth hormone–secreting pituitary adenomas

Growth hormone (GH)–secreting pituitary adenomas represent a common source of GH excess in patients with acromegaly. Whereas surgical extirpation of the culprit lesion is considered first-line treatment, as many as 19% of patients develop recurrent symptoms due to regrowth of previously resected adenomatous tissue or to continued growth of the surgically inaccessible tumor. Although medical therapies that suppress GH production can be effective in the management of primary and recurrent acromegaly, these therapies are not curative, and lifelong treatment is required for hormonal control. Stereotactic radiosurgery has emerged as an effective adjunctive treatment modality, and is an appealing alternative to conventional fractionated radiation therapy. The authors reviewed the growing body of literature concerning the role of radiosurgical procedures in the treatment armamentarium of acromegaly, and identified more than 1350 patients across 45 case series. In this review, the authors report that radiosurgery offers true hormonal normalization in 17% to 82% of patients and tumor growth control in 37% to 100% of cases across all series, while minimizing adverse complications. As a result, stereotactic radiosurgery represents a safe and effective treatment option in the multimodal management of primary or recurrent acromegaly secondary to GH-secreting pituitary adenomas

Time spent with cats is never wasted: Lessons learned from feline acromegalic cardiomyopathy, a naturally occurring animal model of the human disease

<div><p>Background</p><p>In humans, acromegaly due to a pituitary somatotrophic adenoma is a recognized cause of increased left ventricular (LV) mass. Acromegalic cardiomyopathy is incompletely understood, and represents a major cause of morbidity and mortality. We describe the clinical, echocardiographic and histopathologic features of naturally occurring feline acromegalic cardiomyopathy, an emerging disease among domestic cats.</p><p>Methods</p><p>Cats with confirmed hypersomatotropism (IGF-1>1000ng/ml and pituitary mass; n = 67) were prospectively recruited, as were two control groups: diabetics (IGF-1<800ng/ml; n = 24) and healthy cats without known endocrinopathy or cardiovascular disease (n = 16). Echocardiography was performed in all cases, including after hypersomatotropism treatment where applicable. Additionally, tissue samples from deceased cats with hypersomatotropism, hypertrophic cardiomyopathy and age-matched controls (n = 21 each) were collected and systematically histopathologically reviewed and compared.</p><p>Results</p><p>By echocardiography, cats with hypersomatotropism had a greater maximum LV wall thickness (6.5mm, 4.1–10.1mm) than diabetic (5.9mm, 4.2–9.1mm; Mann Whitney, p<0.001) or control cats (5.2mm, 4.1–6.5mm; Mann Whitney, p<0.001). Left atrial diameter was also greater in cats with hypersomatotropism (16.6mm, 13.0–29.5mm) than in diabetic (15.4mm, 11.2–20.3mm; Mann Whitney, p<0.001) and control cats (14.0mm, 12.6–17.4mm; Mann Whitney, p<0.001). After hypophysectomy and normalization of IGF-1 concentration (n = 20), echocardiographic changes proved mostly reversible. As in humans, histopathology of the feline acromegalic heart was dominated by myocyte hypertrophy with interstitial fibrosis and minimal myofiber disarray.</p><p>Conclusions</p><p>These results demonstrate cats could be considered a naturally occurring model of acromegalic cardiomyopathy, and as such help elucidate mechanisms driving cardiovascular remodeling in this disease.</p></div

AIP and MEN1 mutations and AIP immunohistochemistry in pituitary adenomas in a tertiary referral center.

Background: Pituitary adenomas have a high disease burden due to tumor growth/ invasion and disordered hormonal secretion. Germline mutations in genes such as MEN1 and AIP are associated with early onset of aggressive pituitary adenomas that can be resistant to medical therapy. Aims: We performed a retrospective screening study using published risk criteria to assess the frequency of AIP and MEN1 mutations in pituitary adenoma patients in a tertiary referral center. Methods: Pituitary adenoma patients with pediatric/adolescent onset, macroadenomas occurring ≤30 years of age, familial isolated pituitary adenoma (FIPA) kindreds and acromegaly or prolactinoma cases that were uncontrolled by medical therapy were studied genetically. We also assessed whether immunohistochemical staining for AIP (AIP-IHC) in somatotropinomas was associated with somatostatin analogs (SSA) response. Results: Fifty-five patients met the study criteria and underwent genetic screening for AIP/MEN1 mutations. No mutations were identified and large deletions/duplications were ruled out using MLPA. In a cohort of sporadic somatotropinomas, low AIP-IHC tumors were significantly larger (P = 0.002) and were more frequently sparsely granulated (P = 0.046) than high AIP-IHC tumors. No significant relationship between AIP-IHC and SSA responses was seen. Conclusions: Germline mutations in AIP/MEN1 in pituitary adenoma patients are rare and the use of general risk criteria did not identify cases in a large tertiary-referral setting. In acromegaly, low AIP-IHC was related to larger tumor size and more frequent sparsely granulated subtype but no relationship with SSA responsiveness was seen. The genetics of pituitary adenomas remains largely unexplained and AIP screening criteria could be significantly refined to focus on large, aggressive tumors in young patients

Pasireotide Long-Acting Release Treatment for Diabetic Cats with Underlying Hypersomatotropism

BACKGROUND: Long‐term medical management of hypersomatotropism (HS) in cats has proved unrewarding. Pasireotide, a novel somatostatin analogue, decreases serum insulin‐like growth factor 1 (IGF‐1) and improves insulin sensitivity in cats with HS when administered as a short‐acting preparation. OBJECTIVES: Assess once‐monthly administration of long‐acting pasireotide (pasireotide LAR) for treatment of cats with HS. ANIMALS: Fourteen cats with HS, diagnosed based on diabetes mellitus, pituitary enlargement, and serum IGF‐1 > 1000 ng/mL. METHODS: Uncontrolled, prospective cohort study. Cats received pasireotide LAR (6–8 mg/kg SC) once monthly for 6 months. Fructosamine and IGF‐1 concentrations, and 12‐hour blood glucose curves (BGCs) were assessed at baseline and then monthly. Product of fructosamine concentration and insulin dose was calculated as an indicator of insulin resistance (Insulin Resistance Index). Linear mixed‐effects modeling assessed for significant change in fructosamine, IGF‐1, mean blood glucose (MBG) of BGCs, insulin dose (U/kg) and Insulin Resistance Index. RESULTS: Eight cats completed the trial. Three cats entered diabetic remission. Median IGF‐1 (baseline: 1962 ng/mL [range 1051–2000 ng/mL]; month 6: 1253 ng/mL [524–1987 ng/mL]; P < .001) and median Insulin Resistance Index (baseline: 812 μmolU/L kg [173–3565 μmolU/L kg]; month 6: 135 μmolU/L kg [0–443 μmolU/L kg]; P = .001) decreased significantly. No significant change was found in mean fructosamine (baseline: 494 ± 127 μmol/L; month 6: 319 ± 113.3 μmol/L; P = .07) or MBG (baseline: 347.7 ± 111.0 mg/dL; month 6: 319.5 ± 113.3 mg/dL; P = .11), despite a significant decrease in median insulin dose (baseline: 1.5 [0.4–5.2] U/kg; 6 months: 0.3 [0.0–1.4] U/kg; P < .001). Adverse events included diarrhea (n = 11), hypoglycemia (n = 5), and worsening polyphagia (n = 2). CONCLUSIONS AND CLINICAL IMPORTANCE: Pasireotide LAR is the first drug to show potential as a long‐term management option for cats with HS

Acromegaly, Mr Punch and caricature.

The origin of Mr Punch from the Italian Pulcinella of the Commedia dell'arte is well known but his feature, large hooked nose, protruding chin, kyphosis and sternal protrusion all in an exaggerated form also suggest the caricature of an acromegalic. This paper looks at the physical characteristics of acromegaly, the origin of Mr Punch and the development of caricature linking them together in the acromegalic caricature that now has a life of its own