Acromegaly

PurposeThe 14th Acromegaly Consensus Conference was convened to consider biochemical criteria for acromegaly diagnosis and evaluation of therapeutic efficacy.MethodsFifty-six acromegaly experts from 16 countries reviewed and discussed current evidence focused on biochemical assays; criteria for diagnosis and the role of imaging, pathology, and clinical assessments; consequences of diagnostic delay; criteria for remission and recommendations for follow up; and the value of assessment and monitoring in defining disease progression, selecting appropriate treatments, and maximizing patient outcomes.ResultsIn a patient with typical acromegaly features, insulin-like growth factor (IGF)-I > 1.3 times the upper limit of normal for age confirms the diagnosis. Random growth hormone (GH) measured after overnight fasting may be useful for informing prognosis, but is not required for diagnosis. For patients with equivocal results, IGF-I measurements using the same validated assay can be repeated, and oral glucose tolerance testing might also be useful. Although biochemical remission is the primary assessment of treatment outcome, biochemical findings should be interpreted within the clinical context of acromegaly. Follow up assessments should consider biochemical evaluation of treatment effectiveness, imaging studies evaluating residual/recurrent adenoma mass, and clinical signs and symptoms of acromegaly, its complications, and comorbidities. Referral to a multidisciplinary pituitary center should be considered for patients with equivocal biochemical, pathology, or imaging findings at diagnosis, and for patients insufficiently responsive to standard treatment approaches.ConclusionConsensus recommendations highlight new understandings of disordered GH and IGF-I in patients with acromegaly and the importance of expert management for this rare disease.

ObjectiveTo report the final long-term safety and efficacy analyses of patients with acromegaly treated with pegvisomant from the ACROSTUDY.DesignGlobal (15 countries), multicentre, non-interventional study (2004-2017).MethodsThe complete ACROSTUDY cohort comprised patients with acromegaly, who were being treated with pegvisomant (PEGV) prior to the study or at enrolment. The main endpoints were long-term safety (comorbidities, adverse events (AEs), pituitary tumour volumes, liver tests) and efficacy (IGF1 changes).ResultsPatients (n = 2221) were treated with PEGV for a median of 9.3 years (range, 0-20.8 years) and followed up for a median of 7.4 years (range, 0-13.9 years). Before PEGV, 96.3% had received other acromegaly treatments (surgery/radiotherapy/medications). Before PEGV treatment, 87.2% of patients reported comorbidities. During ACROSTUDY, 5567 AEs were reported in 56.5% of patients and of these 613 were considered treatment-related (in 16.5% of patients) and led to drug withdrawal in 1.3%. Pituitary imaging showed a tumour size increase in 7.1% of patients; the majority (71.1%) reported no changes. Abnormal AST or ALT liver tests occurred in 3.2% of patients. IGF1 normalization rate improved over time, increasing from 11.4% at PEGV start to 53.7% at year 1, and reaching 75.4% at year 10 with the use of ≥30 mg PEGV/day in an increasing proportion of patients.ConclusionThis comprehensive review of the complete cohort in ACROSTUDY confirmed the overall favourable benefit-to-risk profile and high efficacy of PEGV as mono- and combination therapy in patients with an aggressive course/uncontrolled/active acromegaly requiring long-term medical therapy for control.

Growth hormone (GH) and its mediator insulin-like growth factor-1 (IGF-1) have manifold effects on the kidneys. GH and IGF receptors are abundantly expressed in the kidney, including the glomerular and tubular cells. GH can act either directly on the kidneys or via circulating or paracrine-synthesized IGF-1. The GH/IGF-1 system regulates glomerular hemodynamics, renal gluconeogenesis, tubular sodium and water, phosphate, and calcium handling, as well as renal synthesis of 1,25 (OH)2 vitamin D3 and the antiaging hormone Klotho. The latter also acts as a coreceptor of the phosphaturic hormone fibroblast-growth factor 23 in the proximal tubule. Recombinant human GH (rhGH) is widely used in the treatment of short stature in children, including those with chronic kidney disease (CKD). Animal studies and observations in acromegalic patients demonstrate that GH-excess can have deleterious effects on kidney health, including glomerular hyperfiltration, renal hypertrophy, and glomerulosclerosis. In addition, elevated GH in patients with poorly controlled type 1 diabetes mellitus was thought to induce podocyte injury and thereby contribute to the development of diabetic nephropathy. This manuscript gives an overview of the physiological actions of GH/IGF-1 on the kidneys and the multiple alterations of the GH/IGF-1 system and its consequences in patients with acromegaly, CKD, nephrotic syndrome, and type 1 diabetes mellitus. Finally, the impact of short- and long-term treatment with rhGH/rhIGF-1 on kidney function in patients with kidney diseases will be discussed.

ContextPaltusotine is a nonpeptide, selective somatostatin receptor 2 agonist in development as once-daily oral treatment for acromegaly.ObjectiveTo evaluate efficacy and safety of paltusotine in patients with biochemically uncontrolled acromegaly not currently receiving medical therapy.MethodsIn this phase 3, randomized, double-blind, placebo-controlled trial, adults with medically untreated acromegaly at randomization (stratum 1: medication-naïve or off acromegaly medications ≥4 months [IGF-I ≥ 1.3 × upper limit of normal {ULN}]; stratum 2: controlled on a somatostatin receptor ligand and underwent washout [IGF-I increase ≥30% to ≥1.1 × ULN]) received paltusotine or placebo for 24 weeks.ResultsA total of 111 patients (stratum 1, n = 82; stratum 2, n = 29) enrolled (paltusotine, n = 54; placebo, n = 57). The primary endpoint of IGF-I normalization at 24 weeks was met in 55.6% of paltusotine-treated patients vs 5.3% for placebo (odds ratio [OR]: 42.81; 95% CI, 8.44-455.82; P ConclusionIGF-I normalized in significantly more patients with uncontrolled acromegaly treated with paltusotine vs placebo. Paltusotine was associated with rapid, sustained IGF-I reduction, significant symptom improvement and stable or reduced pituitary tumor size and was well tolerated.