Developments in Pharmacotherapy for Acromegaly: Current and Emerging Approaches.

ContextTreatment of acromegaly is multimodal for many patients, and medical treatments include somatostatin receptor ligands (SRLs), dopamine agonists (DAs), and growth hormone receptor antagonists (GHRAs). However, recent real-world evidence on treatment patterns for patients with acromegaly is limited.ObjectiveThis study evaluated medication usage, treatment changes, adherence, persistence, comorbidities, and health care resource utilization using deidentified data from MarketScan, a US claims database.MethodsEligible patients (n = 882) were those receiving monotherapy or combination therapy for ≥90 days without treatment gaps.ResultsMean age at diagnosis was 48.6 years; 50.1% of patients were female. Over half (59.4%) had 1 line of treatment (LOT); 23.1% had 2 LOTs; 17.5% had at least 3 LOTs. Most patients (94.6%) initiated treatment with monotherapies. The most common first-line monotherapy treatments were cabergoline (DA, 36.8%), octreotide long-acting release (first-generation SRL, 29.5%), and lanreotide depot (first-generation SRL, 22.5%). Adherence for first-line treatments (proportion of days covered) was higher for first-generation SRLs (lanreotide depot: 0.8) compared with DAs (0.7). Treatment persistence (time between the first treatment record and a change in LOT/censoring) in LOT 1 was higher for GHRAs (24.8 months) and first-generation SRLs (20.0 months) compared with DAs (14.4 months). Female patients and those diagnosed at a younger age were more likely to have shorter treatment persistence. The most prevalent comorbidities were hyperlipidemia, essential hypertension, and sleep apnea.ConclusionPatients with more comorbidities had more health care visits during the first year after diagnosis, suggesting increased disease burden. Real-world evidence on treatment patterns provides insights into recommendations for individualized therapy.

Morbidity and mortality rates in patients with active acromegaly are higher than the general population. Adequate biochemical control restores mortality to normal rates. Now, medical therapy has an increasingly important role in the treatment of patients with acromegaly. Somatostatin receptor ligands (SRLs) are considered the standard medical therapy, either after surgery or as a first-line therapy when surgery is deemed ineffective or is contraindicated. Overall, octreotide and lanreotide are first-generation SRLs and are effective in ~20%–70% of patients. Pegvisomant, a growth hormone receptor antagonist, controls insulin-like growth factor 1 in 65%–90% of cases. Consequently, a subset of patients (nonresponders) requires other treatment options. Drug combination therapy offers the potential for more efficacious disease control. However, the development of new medical therapies remains essential. Here, emphasis is placed on new medical therapies to control acromegaly. There is a focus on pasireotide long-acting release (LAR) (Signifor LAR®), which was approved in 2014 by the US Food and Drug Administration and the European Medicine Agency for the treatment of acromegaly. Pasireotide LAR is a long-acting somatostatin multireceptor ligand. In a Phase III clinical trial in patients with acromegaly (naïve to medical therapy or uncontrolled on a maximum dose of first-generation SRLs), 40 and 60 mg of intramuscular pasireotide LAR achieved better biochemical disease control than octreotide LAR, and tumor shrinkage was noted in both pasireotide groups. Pasireotide LAR tolerability was similar to other SRLs, except for a greater frequency and degree of hyperglycemia and diabetes mellitus. Baseline glucose may predict hyperglycemia occurrence after treatment, and careful monitoring of glycemic status and appropriate treatment is required. A precise definition of patients with acromegaly who will derive the greatest therapeutic benefit from pasireotide LAR remains to be established. Lastly, novel therapies and new potential delivery modalities (oral octreotide) are summarized.

ContextThere are limited head-to-head trials comparing pharmacological treatments for acromegaly.ObjectiveSystematically review the efficacy and safety of pharmacological treatments for acromegaly and conduct a network meta-analysis (NMA) enabling indirect comparisons.MethodsMEDLINE and Embase were searched to identify randomized controlled trials (RCTs) of acromegaly therapies. Screening and data extraction followed PRISMA guidelines. Feasibility assessment evaluated homogeneity and consistency assumptions required for NMA. Bayesian NMAs estimated relative treatment effects and ranking probabilities.ResultsTwenty-two records covering 18 RCTs were included. Biochemical control rates were comparable among long-acting injectable somatostatin receptor ligands (SRLs), including lanreotide autogel (LAN-ATG), octreotide long-acting release (OCT-LAR), pasireotide, the GH receptor antagonist pegvisomant, oral octreotide (O-OCT), octreotide subcutaneous depot (SC-OCT-D), and the once-daily oral SRL paltusotine. Paltusotine demonstrated significantly higher biochemical control vs O-OCT and SC-OCT-D (odds ratios [ORs], 95% credible intervals [CrIs]: 7.34 [1.48-36.07] and 7.85 [1.72, 36.25]). Pasireotide showed significantly higher biochemical control vs OCT-LAR (OR: 2.03 [1.29-3.23]). Paltusotine had significantly lower discontinuations due to adverse events (AEs) vs O-OCT and SC-OCT-D, (ORs: 0.022 [0.001-0.424] and 0.022 [0.001-0.343]), with similar rates to other treatments. Treatment-emergent AEs (TEAEs) and serious TEAEs were comparable across treatments. Rankings suggested paltusotine as the treatment with the highest probability of ranking as the most effective (or tolerable) treatment across all endpoints studied.ConclusionThis systematic review and NMA consolidate recent high-quality RCT evidence for acromegaly treatments. Paltusotine emerges as a promising alternative to injectable SRLs, with favorable efficacy, safety, and AE-related discontinuation patterns. These findings may inform clinical decision-making and guideline development, if confirmed by clinical experience.

American Association of Clinical Endocrinologists and American College of Endocrinology Disease State Clinical Review: Management of Acromegaly Patients: What is the Role of Pre-Operative Medical Therapy?

Disclosure: M. Fleseriu: Advisory Board Member; Self; Amryt, Ipsen, Recordati Rare Diseases, Pfizer, Inc. Grant Recipient; Self; Amryt, Crinetics, Ionis Pharmaceuticals Inc. A.L. Barkan: None. T.C. Brue: Advisory Board Member; Self; Advanz Pharma, Debio Pharm, Recordati Rare Diseases. Consulting Fee; Self; Ipsen, Recordati Rare Diseases, Novartis Pharmaceuticals, Pfizer, Inc. Grant Recipient; Self; Pfizer, Inc. Other; Self; Ipsen, Recordati Rare Diseases, Novartis Pharmaceuticals, Pfizer, Inc. E. Duquesne: Employee; Self; Ipsen. A. Houchard: Employee; Self; Ipsen. Stock Owner; Self; Ipsen. M. del Pilar Schneider: Employee; Self; Ipsen. A. Ribeiro-Oliveira Jr.: Employee; Self; Ipsen. Stock Owner; Self; Ipsen. S. Melmed: Advisory Board Member; Self; Ionis Pharmaceuticals Inc., Ipsen, Novo Nordisk, Recordati Rare Diseases. Grant Recipient; Self; Pfizer, Inc. Background: Medical treatment for acromegaly (characterized by excess growth hormone [GH] production) includes somatostatin receptor ligands (SRLs), dopamine agonists (DAs), and GH receptor antagonists (GHRAs). However, there are few real-world treatment evaluations in the US. We present treatment patterns for patients receiving medications for acromegaly (1/1/2010-7/31/2022). Methods: De-identified data were extracted from MarketScan®, a US health insurance claims database. Eligible patients: those receiving monotherapy or combination therapy (≥2 treatments overlapping for >3 months [m]) for ≥90 days without treatment gaps; ≥2 claims associated with acromegaly; data ≥3 m before and ≥6 m after diagnosis/first treatment claim (earlier date); and ≥18 years (y) old at diagnosis. Outcomes were: demographic characteristics; treatment frequency by line of treatment (LOT) and changes between LOTs (Sankey plot); treatment persistence for first LOT (LOT 1) monotherapies (Kaplan-Meier estimator); and treatment up-/downtitration (≥30% dose change, evaluated for octreotide long-acting release [OCT] and lanreotide depot [LAN]). Biochemical control values were unavailable in the database. Results: Of 882 patients, 50.1% were female; mean age at diagnosis was 48.6 y (standard deviation 13.6 y). In the cohort, 59.4% had exactly 1 LOT, 23.1% had exactly 2 LOTs, and 17.5% had exactly 3 LOTs. The most common LOT 1 medication class was first-generation SRLs: OCT (27.7%) and LAN (21.1%). Other LOT 1 classes were Das (cabergoline; 34.5%) and GHRAs (pegvisomant; 10.5%). Only 7 patients received second-generation SRL pasireotide and no patients received oral octreotide in LOT 1. Most patients initiated treatment with monotherapies (94.6%). In monotherapy LOT 1, GHRAs had the longest median persistence (pegvisomant; 24.8 m; 95% confidence interval [CI]: 16.59-32.49 m; n=93), followed by OCT and LAN (20.0 m; 95% CI: 16.98-23.87 m; n=430). Das had the shortest persistence (cabergoline; 14.4 m; 95% CI: 12.23-16.82 m; n=304). Among patients receiving OCT or LAN, 67.6% had ≥1 dose increase and 45.0% had ≥1 dose reduction. Conclusions: Despite guidelines recommending DA monotherapy for few select patients with acromegaly,1 our real-world analysis found that approximately one-third of patients initiated treatment with this class with the shortest treatment persistence. OCT and LAN monotherapies were also commonly used as LOT 1 and had longer persistence. GHRAs, the class with the longest persistence, were not common monotherapy in LOT 1, possibly because they do not target pituitary adenomas directly. Interestingly, only 5% of patients initiated treatment with combination therapies. Recommendations for individualized therapy2 should consider medication persistence and real-world treatment patterns. 1Giustina et al. Rev Endocr Metab Disord. 2020 2Fleseriu et al. Lancet Diabetes Endocrinol. 2022 Presentation: Thursday, June 15, 2023

TPS4178 Background: Somatostatin receptor ligands (SRLs) are first-line standard of care therapies for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), showing efficacy in tumor/symptom control with an established safety profile. Yet, disease progression may occur despite standard-dose SRL treatment, requiring more aggressive and toxic therapies. Retrospective/non-randomized data suggest higher-dose SRLs may benefit patients with GEP-NETs who do not respond to standard-dose treatment and provide improved disease control. Octreotide depot (CAM2029) is a novel high-exposure, subcutaneous (SC) formulation. Clinical trials showed ̃500% higher CAM2029 bioavailability versus octreotide long-acting release (LAR) (Tiberg et al. 2015), and maintenance/reduction of NET symptoms (Pavel et al. 2019). Prospective, randomized data are needed to confirm the efficacy/safety of novel SRLs with higher bioavailability such as CAM2029, vs standard-dose SRLs including octreotide LAR and lanreotide Autogel (ATG). Methods: SORENTO is a randomized, multi-center, open-label, active-controlled Phase 3 trial, aiming to enroll 302 adults with GEP-NETs. Key eligibility criteria: advanced, well-differentiated NET of GEP/presumed GEP origin; ≥1 measurable SR positive (by nuclear imaging) lesion according to RECIST 1.1; no or < 6 months consecutive treatment with long-acting SRLs. Notably, patients with Grade 3 GEP-NETs (excluded by CLARINET/PROMID trials) are eligible. Patients will be randomized 1:1 to CAM2029 20 mg Q2W, or active comparator (octreotide LAR 30 mg intramuscular or lanreotide ATG 120 mg SC, Q4W). CAM2029 self/carer administration is allowed after ≥3 successful supervised administrations. Randomization stratified by: histological grade, tumor origin, intended comparator. Primary outcome: progression free survival (PFS; time from randomization to date of first documented disease progression [RECIST 1.1] or death), assessed by a Blinded Independent Review Committee. The study is powered to detect a hazard ratio of 0.65. Key secondary outcomes: overall survival; response rate; rescue medication use; patient satisfaction; adverse events. After primary PFS analysis, patient overall survival will be followed for up to 2 years. If CAM2029 displays superiority in the primary analysis, the comparator group may switch to CAM2029 20 mg Q2W. Patients in any treatment group experiencing progressive disease in the randomized part of the study may proceed to an open-label extension with intensified CAM2029 treatment, to investigate effects of higher frequency dosing. First patient randomized in Nov-2021, with readout (following 194 events) expected by 2024 end. This novel head-to-head superiority trial is anticipated to demonstrate the potential benefits of CAM2029 as a first line-therapy in patients with well-differentiated GEP-NETs. Clinical trial information: NCT05050942.

Disclosure: A. Halstrom: None. G.A. Dobri: None. Acromegaly is a rare disorder characterized by tumoral hypersecretion of growth hormone (GH) leading to overproduction of insulin-like growth factor 1 (IGF-1). Patients present with physical changes, and systemic complications. Treatment involves surgery and medical therapy with the goal of normalizing IGF-1. First line medical therapy consists of first-generation injectable somatostatin receptor ligands (SRL) (octreotide LAR, lanreotide autogel). Dopamine agonists (cabergoline) can be used in patients with mild IGF-1 elevation. If IGF-1 levels do not normalize, pasireotide or pegvisomant can be tried. Until recently, SRLs were administered only as a deep tissue injection. Patients have reported injection site reactions, frustration, and breakthrough acromegaly symptoms between doses. Two trials were conducted which showed that oral octreotide is an effective alternative for patients after achieving biochemical control with the injectable formulation. Two cases are presented below in which patients with acromegaly were treated with de novo oral octreotide either or as combination therapy with cabergoline, after a significant time lapse since injection SRL. Our first case is a 24 year old female with a 19mm mammosomatotroph adenoma, resected 8 years prior, with questionable remnant on postoperative MRI and biochemically active acromegaly. She was started on octreotide LAR 20mg which was titrated up to 30mg. However, she had not achieved biochemical control, with lowest IGF-1 543ng/mL (83-456ng/mL), Z-score 2.4, and GH 5.8ng/mL (<= 7.1ng/mL). She wanted a break from medical therapy and discontinued octreotide LAR. She was later started on pegvisomant 15mg but stopped after 10 days due to an allergic reaction and was switched to cabergoline. Cabergoline was up titrated to 3.5mg weekly, still without biochemical control, IGF-1 417ng/mL (103-326ng/mL), Z-score 2.5, GH 7.69ng/mL (0.05-8ng/mL), at which time oral octreotide 20mg twice daily was started and cabergoline decreased to 2.5mg weekly. Oral octreotide was increased to 60mg daily and IGF-1 levels normalized to 294ng/mL (83-456ng/mL), Z-score 1. The second case is a 70 year old female with type 2 diabetes, arthritis, left ventricular hypertrophy, obstructive sleep apnea and colon polyps found to have a 10mm pituitary adenoma with IGF-1 481ng/mL (32-238ng/mL), Z-score 3.1, GH 1.28ng/mL (0.05-8ng/mL). She declined surgical resection and opted for medical management. Oral octreotide 20mg twice daily was started and further increased to 60mg daily IGF-1 went as low as 327ng/mL (28-231ng/mL), Z-score 2.5 and GH 0.4ng/mL (0.05-8ng/mL). The dose was increased to 80 mg daily are lab results are pending. These are the first two published cases describing a novel approach to treating acromegaly in which patients were found to have a biochemical response to de novo oral octreotide either alone or combined with cabergoline. Presentation: Thursday, June 15, 2023

During the past two decades, the discovery of new drugs in the treatment of acromegaly contributed to the remission of this disease in about 95% of patients. In addition to the availability of new medications, recent years have also seen advances in surgical techniques in pituitary surgery. Newer drugs have contributed to a decrease in the use of radiotherapy for tumors that secrete growth hormone and a lower frequency of somatotropinoma reoperations. Raising awareness about this disease, early diagnosis, and accompanying comorbidities, enabled timely treatment. All of this led to a reduction in the mortality rate of patients, to the level in the general population. In treating of acromegaly, a multidisciplinary approach is essential, in addition to endocrinologists and neurosurgeons, radiologists, pathologists, and geneticists play an active role. The most common complications of acromegaly are: cardiovascular diseases, metabolic abnormalities such as diabetes and dyslipidemia, respiratory dysfunction, joint deformities, vertebral fractures, and the appearance of tumors. The diagnosis of acromegaly is based on the characteristic clinical picture of enlarged hands and feet, nose and ears, increased levels of IGF-I for age, insuppressibility of growth hormone (GH) in the glucose load test (OGTT), as well as imaging of the pituitary gland by magnetic resonance (MRI). Acromegaly therapy involves a combination of several modalities: surgery for growth hormone-secreting pituitary adenoma, medical therapy, and radiotherapy. Medical therapy includes three groups of drugs: 1) somatostatin receptor ligands (SRLs) of the first generation (octreotide LAR and lanreotide Autogel) and second generation (pasireotide LAR), 2) Dopamine-DA agonists (bromocriptine and cabergoline) and 3) growth hormone receptor antagonists (pegvisomant). The goal of writing this review paper is to point out the importance of timely diagnosis of acromegaly and adequate treatment of patients to reduce comorbidities, prolong life, and improve their quality of life.

PurposeThis systematic literature review investigated whether extended dosing intervals (EDIs) of pharmacological acromegaly treatments reduce patient burden and costs compared with standard dosing, while maintaining effectiveness.MethodsMEDLINE/Embase/the Cochrane Library (2001–June 2021) and key congresses (2018–2021) were searched and identified systematic literature review bibliographies reviewed. Included publications reported on efficacy/effectiveness, safety and tolerability, health-related quality of life (HRQoL), and patient-reported and economic outcomes in longitudinal/cross-sectional studies in adults with acromegaly. Interventions included EDIs of pegvisomant, cabergoline, and somatostatin receptor ligands (SRLs): lanreotide autogel/depot (LAN), octreotide long-acting release (OCT), pasireotide long-acting release (PAS), and oral octreotide; no comparator was required.ResultsIn total, 35 publications reported on 27 studies: 3 pegvisomant monotherapy, 11 pegvisomant combination therapy with SRLs, 9 LAN, and 4 OCT; no studies reported on cabergoline, PAS, or oral octreotide at EDIs. Maintenance of normal insulin-like growth factor I (IGF-I) was observed in ≥ 70% of patients with LAN (1 study), OCT (1 study), and pegvisomant monotherapy (1 study). Achievement of normal IGF-I was observed in ≥ 70% of patients with LAN (3 studies) and pegvisomant in combination with SRLs (4 studies). Safety profiles were similar across EDI and standard regimens. Patients preferred and were satisfied with EDIs. HRQoL was maintained and cost savings were provided with EDIs versus standard regimens.ConclusionsClinical efficacy/effectiveness, safety, and HRQoL outcomes in adults with acromegaly were similar and costs lower with EDIs versus standard regimens. Physicians may consider acromegaly treatment at EDIs, especially for patients with good disease control.

Disclosure: G. Ravel: None. C. Berardet: Employee; Self; Amolyt Pharma. C. Chalmey: Employee; Self; Amolyt Pharma. H. Kurasaki: Employee; Self; Peptidream Inc. T. Tomiyama: Employee; Self; Peptidream Inc. P. Reid: Employee; Self; Peptidream Inc. D. Duracher: Employee; Self; Amolyt Pharma. R. Datta: Consulting Fee; Self; Amolyt Pharma. M. Aouadi: Employee; Self; Amolyt Pharma. M.D. Culler: Employee; Self; Amolyt Pharma. There is a strong rationale for combining a growth hormone (GH) receptor antagonist (GHRA) with somatostatin analog (SSA) therapy for acromegalic patients. While SSAs are the primary medical therapy for treatment of acromegaly, insulin-like growth factor 1 (IGF1) levels fail to normalize with SSA monotherapy in most patients. Even in patients with controlled IGF1, GH levels can remain elevated and induce symptoms by interacting with GH receptors throughout the body. In addition, while GHRAs have no significant effect on the causative pituitary tumor, SSAs can often induce tumor stabilization or shrinkage. AZP-3813 is a 16-amino acid, bicyclic peptide GHRA which has been demonstrated to potently decrease IGF1 in both rats and dogs. In order to examine the effect of combining AZP-3813 with a SSA in decreasing IGF1, 8-week old, male, Sprague Dawley rats were implanted subcutaneously with Alzet model 2002 minipumps containing either vehicle or the SSA, octreotide (OCT), at concentrations required to deliver either 20 or 40μg OCT/kg/day. Blood samples for IGF1 measurement were collected before, and 48 and 72 hours after pump implantation. Immediately following the 72-hour blood collection, rats from each infusion group were injected subcutaneously with either vehicle or AZP-3813 at 0.3, 1, 3, 10 or 30mg/kg (n=7/group). A subsequent blood sample was collected 24 hours after the injection of vehicle or AZP-3813, which also corresponded to 96 hours after pump implantation. Plasma levels of IGF1 were assessed by radioimmunoassay. In rats infused with vehicle, the 0.3mg/kg dose of AZP-3813 had no effect on IGF1 as compared with baseline; however, with higher doses a clear, dose-related decrease in IGF1 was observed ranging from -7 ± 3.0% with 1mg/kg AZP-3813 to -29 ± 2.0% with 30mg/kg. OCT infusion alone at 20μg/kg/day produced a -10 ± 3.6% decrease in IGF1, while injection of AZP-3813 into rats infused with 20μg/kg/day OCT, produced an enhanced, dose-related decrease, ranging from -7 ± 3.8% with 0.3mg/kg AZP-3813 to -38 ± 3.4% with 30mg/kg. A clear additive relationship was observed by focusing on the 3mg/kg dose of AZP-3813, which, alone, decreased IGF1 by -13 ± 2.8% in vehicle-infused rats. When injected into rats infused with OCT, which alone decreased IGF1 by -10 ± 3.6%, a combined decrease of -23 ± 3.3% was observed. The magnitude of the combined decrease was not statistically different from the decrease obtained with 30mg/kg AZP-3813 alone in vehicle-infused rats; thus, demonstrating a 10-fold increase in the effectiveness of AZP-3813 when combined with OCT. Similar results were observed with 40μg/kg/day OCT infusion. These results demonstrate the enhanced efficacy of AZP-3813 in decreasing IGF1 when combined with the SSA, OCT, and support the development of AZP-3813 as an add-on therapy in patients inadequately controlled with SSA treatment. Presentation: 6/3/2024

Since the initial use of medical treatment for acromegaly, several advances have been made in the understanding of the pathophysiology of growth hormone producing tumors, resulting in the development of multiple medical options and novel treatments. Currently there are three major classes of medication available for the treatment of acromegaly: somatostatin receptor ligands, growth hormone receptor antagonists, and dopamine agonists. Somatostatin receptor ligands are the treatment of choice for acromegaly due to their effectiveness in controlling growth hormone excess in approximately 60% of patients and their beneficial effects on tumor volume. Clinical trials have demonstrated efficacy of pegvisomant in up to 97% of patients, but long term data and safety have yet to be established. Dopamine agonists are inexpensive, but their use is hampered by their lack of efficacy compared to other medications. Medical therapy has an established role as adjuvant therapy after non-curative surgery, as well as primary therapy for selected patients unsuitable for surgical resection. Medical treatment to control growth hormone hypersecretion is often needed after radiation therapy until the effects are evident. Preliminary data suggest a potential role for medical treatment prior to surgical resection, surgical debulking to improve medical efficacy, and combination therapy with multiple medications from the three classes. More studies are required, however, to validate the utility of these approaches in treating acromegaly. With the available therapies, disease control can be achieved in nearly all patients with acromegaly.

We have generated two independent dwarf mouse lines with decreased GH action; however, only one has extended longevity. Why? Decreased signaling through the GH/IGF-1 axis in vertebrates, or comparable pathways in invertebrates, has repeatedly been shown to extend lifespan. A prominent example is mice with a disruption in the GH receptor gene (GHR−/−) generated in our laboratory two decades ago [1]. GHR−/− mice are completely resistance to GH action, which causes a reproducible extension of lifespan regardless of the genetic strain of mice [1, 2] and is officially recognized as the longest-lived laboratory mouse (http://methuselahfoundation.org/). In 1991, our laboratory first described another dwarf mouse line that expresses a growth hormone receptor antagonist (GHA) transgene [3]. The expressed transgene is a mutated bovine GH gene in which the codon for the smaller glycine amino acid at position 119 is replaced with a larger amino acid, which causes steric hindrance when it interacts with the GHR resulting in a classical receptor antagonist [4]. This work ultimately led to the discovery of a pharmaceutical agent, pegvisomant, for the treatment of acromegaly. However, besides providing the basic information for development of this therapeutic, these GHA transgenic mice also provide a novel mouse strain to assess the outcome of a reduction in GH action on health and aging. Noteworthy is the fact that GHA mice do not experience significantly longer lifespans as do other mouse lines with a reduction in the GH/IGF-1 axis, such as the aforementioned GHR−/− mice [2]. As a result, GHA mice have not been as extensively studied. Regardless, comparing the phenotype of GHA mice with other long-lived lines, such as GHR−/− mice, should reveal the most important traits caused by reduced GH action that are responsible for lifespan extension. A summary comparing the phenotypes of GHR−/− and GHA mice is provided in Figure ​Figure1.1. An important distinction between GHA mice and GHR−/− mice is that the GHA does not completely inhibit GH signaling, while inhibition of GH signaling in GHR−/− mice is complete. Thus, we have generated two dwarf mice each with either low or no GH induced intra-cellular signaling (and each with low levels of IGF-1) yet only one has extended longevity. Figure 1 Phenotypic comparison between GHA mice and long-lived GHR−/− mice as compared to control mice (WT). Again, what molecular mechanisms account for this difference in lifespan between these two dwarf lines? GHA mice generally have a phenotype intermediate between that of control and GHR−/− mice, especially as it relates to size, readouts of the GH/IGF-1 axis and measures of glucose homeostasis. For example, GHA mice are dwarf, but not as dramatic as seen in GHR−/− mice [2]. As compared to controls, circulating IGF-1 are reduced in both lines but by only ~25-40% in GHA mice as opposed to >80% in GHR−/− mice [2]. While GHR−/− mice are extraordinarily insulin sensitive, glucose homeostasis is moderately improved in young GHA mice with low to normal plasma levels of glucose and insulin [2, 5]. However, insulin levels deteriorate with advancing age in male GHA mice [2, 6]. Perhaps the more marginal decreases in IGF-1 or the lack of dramatic alterations in glucose metabolism are sufficient in GHA mice to curb significant gains in longevity. Interestingly, while dwarf throughout life, the body weight of male GHA mice gradually catches up to that of control mice with advancing age [2, 6]. The increase in body weight in later adult life is not due to increases in body length or lean tissue; thus, it is not due to catch up growth. Rather, the increase in body weight is due to marked increases in adipose tissue [6]. Where do GHA mice deposit their adipose tissue and could that be relevant to longevity? Like GHR−/− mice, GHA mice display dramatic increases in the subcutaneous fat depot [5, 7]. However, unlike GHR−/− mice, intra-abdominal fat pads (including visceral depots) become enlarged with advancing age in GHA mice, which may contribute to their deterioration in glucose homeostasis over time [6]. Despite many similarities in the adipokine profiles of GHR−/− and GHA mice (elevated leptin, adiponectin and resistin), only GHA mice experience a very dramatic increase in leptin levels with age that coincides with their progressive obesity [5-8]. With their severe obesity at older ages, it is curious that GHA mice do not live any shorter than littermate controls. Thus, repression of GH signaling via expression of the antagonist appears to confer some protection from complications that are commonly associated with obesity. How do GHA mice compare to GHR−/− in tumor incidence, cardiovascular function, lipid metabolism, cognition, and other measures of health? More studies are needed. Nevertheless, GHA mice are valuable tools as they defy the common pathologies that accompany excess fat mass, and they offer an exception to the dogma that a decrease in GH action increases lifespan. But more importantly, GHA mice are likely a more clinically relevant mouse line to study than GHR−/− mice; after all, repression of GH action is achievable through pharmacological intervention with the use of a GHA (pegvisomant) whereas total repression of GH action, as in GHR−/− mice, is not nor would it be clinically desirable. Therefore, a better evaluation of the GHA phenotype, disease status, and metabolic state in both sexes and across lifespan is warranted.

Comparative Efficacy of Medical Treatment for Acromegaly: A Systematic Review and Network Meta-Analysis of Integrated Randomized Trials and Observational Studies

Surgery is considered the treatment of choice in acromegaly, but patients with persistent disease after surgery or in whom surgery cannot be considered require medical therapy. Somatostatin receptor ligands (SRLs) octreotide (OCT), lanreotide, and the more recently approved pasireotide, characterized by a broader receptor ligand binding profile, are considered the mainstay in the medical management of acromegaly. However, in the attempt to offer a more efficacious and better tolerated medical approach, recent research has been aimed to override some limitations related to the use of currently approved drugs and novel SRLs therapies, with potential attractive features, have been proposed. These include both new formulation of older molecules and new molecules. Novel OCT formulations are aimed in particular to improve patients’ compliance and to reduce injection discomfort. They include an investigational ready-to-use subcutaneous depot OCT formulation (CAM2029), delivered via prefilled syringes and oral OCT that uses a “transient permeability enhancer” technology, which allows for OCT oral absorption. Another new delivery system is a long-lasting OCT implant (VP-003), which provide stable doses of OCT throughout a period of several months. Finally, a new SRL DG3173 (somatoprim) seems to be more selective for GH secretion, suggesting possible advantages in the presence of hyperglycemia or diabetes. How much these innovations will actually be beneficial to acromegaly patients in real clinical practice remains to be seen.

Current guidelines recommend the use of long-acting somatostatin receptor ligands (SRLs) first when surgery fails to correct GH/IGF-I hypersecretion in patients with acromegaly. In this issue of the journal, a pro- and contra debate will outline which arguments are in favour and which are against positioning pegvisomant (PEGV), a GH receptor antagonist, as the first-line treatment modality of acromegaly. The task of the pros was to promote a paradigm shift towards repositioning PEGV as first-line treatment as PEGV is safe and more effective than the first- and second-generation of SRLs. SRLs, when prescribed together with PEGV can still reduce tumour size when necessary, while they decrease the necessary dose of PEGV by around 50% in the average patient. They conclude that PEGV must move up towards the first-line treatment. For the cons, SRLs remain the first-line medical treatment. Indeed, even if, in recent studies, the remission rate is lower than initially claimed, SRLs are still effective not only for normalizing GH/IGF-I levels in half of the patients but also for inducing tumour shrinkage, improving comorbidities and headaches and reversing excess mortality. They are more convenient for use with their monthly administration and have a remarkable safety profile as demonstrated by the very prolonged experience acquired by more than 30 years of use. Finally, the cost-effectiveness of first-generation SRLs is better than that of PEGV. For all these reasons, cons consider that SRLs remain the best first medical treatment in patients requiring medical therapy.