Acromegaly is a rare chronic disorder characterized by increased growth hormone (GH) secretion and elevated insulin-like growth factor-I (IGF-I) levels.1,2 In Spain, there is a prevalence of approximately 60 cases per million, but estimates vary between 15.7 and 75.8 in different regions.3–5

Three drug classes are available for medical therapy: somatostatin analogues (SSA), dopamine agonists, and GH receptor antagonists, namely pegvisomant.1,2 SSAs, such as lanreotide or octreotide are administered as first-line therapy or as second-line therapy in patients undergoing unsuccessful surgery and are currently considered a cornerstone in the treatment of acromegaly.6

Historically, dopamine agonists have been used in the treatment of acromegaly but their efficacy as monotherapy is low.2,7 Current guidelines recommend that dopamine agonists be considered particularly in patients with mild biochemical activity, such as in the setting of modestly elevated serum IGF-I levels, with or without concomitant treatment with SSAs.1,8 Efficacy of the addition of dopamine agonist cabergoline in patients partially responding to SSA,9–14 has been reported to be 52% in terms of normalization of IGF-I as noted in the meta-analysis by Sandret et al.15 Pegvisomant is often used as a long-term medical therapy in patients with inadequate response or complete resistance to SSAs.1,16–19 In patients with an inadequate response to SSAs, the addition of weekly pegvisomant to full-dose SSA therapy may be effective for further lowering of IGF-I levels.1,20–23 and offers the benefit of reduced pegvisomant injection frequency. In a study of long-term weekly pegvisomant in combination with long-acting SSAs in 141 patients with acromegaly with persistently elevated IGF-I levels (>1.2× upper limit of normal [ULN]) or poor quality of life after 6 months of SSAs monotherapy, 97% of patients derived efficacy (defined as the lowest measured IGF-I level during treatment).24

Evidence from real-life scenarios is a research priority, especially in acromegaly, where multiple large clinical trials are not possible. Specifically, it is important to show that evidence from randomized clinical trials such as treatment schedules, clinical and economic outcomes, could be translated to real-life setting and to show that treatment patterns and clinical outcomes are similar in real-world patients. A systematic review of evidence from real-life scenarios on treatment of acromegaly concluded that although definitions of disease control varied across studies in different real-world settings, approximately half of acromegaly patients have uncontrolled disease.25 The aims of this retrospective study were to evaluate the real-world efficacy (biochemical control and tumour size) and safety of the SSA lanreotide treatment combinations for acromegaly in routine clinical practice.

ACROCOMB, a retrospective observational multicentre study of the Spanish Society of Endocrinology and Nutrition (SEEN), evaluated the clinical use of lanreotide combined with cabergoline or pegvisomant in patients with active acromegaly. This study included data from the clinical histories of 108 patients treated between 2006 and 2011 in 44 Spanish centres with lanreotide/cabergoline (N=61, cabergoline cohort) or lanreotide/pegvisomant (N=47, pegvisomant cohort).

Criteria for including a patient into the study were: (1) having received medical treatment for acromegaly with a single agent without achieving adequate control or (2) having a mixed GH and prolactin pituitary adenoma in which combined treatment with lanreotide was indicated as a first pharmacologic option. Additionally, patients should have been treated with lanreotide (Somatuline Autogel injections, IPSEN) and cabergoline or pegvisomant (Somavert injections, Pfizer) following the prescribing information and the specific practices at each centre. Furthermore, patients were required to have a reported GH and IGF-I value before initiating combination treatment and at least one value for GH and IGF-I during combined treatment. IGF-I and GH were measured locally at each centre following local laboratory protocols. The ULN for IGF-I was determined for the immunoassay used at each participating centre. Inmulite (Siemens) was used in approximately 70% of the patients, while in the other 30% the Liason (DiaSorin) and the iSYS assay (IDS) were used. The IGF-I values are reported as %ULN and are age-adjusted. Patients with normalized age-adjusted IGF-I values are those with IGF-I values ≤100% ULN.

Efficacy was assessed by age-adjusted IGF-I levels, age-adjusted prolactin levels, and GH levels at baseline, after 6 months of treatment and at the end of the study (EOS). EOS was considered as the last registered visit in which a patient was receiving the combined treatment. Information on the radiologic evaluations performed at baseline or at EOS was also recorded if available. A clinically significant reduction in tumour size was defined as a decrease >2mm in microadenoma or a decrease >20% in macroadenoma and an increase was defined as growth of >2mm in microadenoma or growth of >20% in macroadenoma. Safety was assessed by the detection of the reported adverse events and their potential related causality with lanreotide, cabergoline, or pegvisomant as identified by the treating physician. Specific safety assessments focused on hepatic, cardiac and glycaemic adverse events were also collected. Hepatic function tests included the measurement of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) levels at baseline and at EOS. Patients in which pegvisomant was incorporated to their treatment regimen with lanreotide had liver test functions every 4–6 weeks for the first six months of therapy. Hyperglycaemia was assessed by measuring basal glycaemia and Hb1Ac at baseline and at EOS. When indicated, echocardiograms were used to detect cardiac abnormalities.

Descriptive summary statistics are presented for all variables. The following variables were evaluated in a univariate and multivariate analysis: baseline values of GH, baseline values of IGF-I, radiotherapy, age, final lanreotide dose, final cabergoline dose, and duration of combined treatment. An analysis of variance (ANOVA) of repeated measures (time factor) was used to study the possible evolution of quantitative variables (such as GH). A two-way ANOVA test was used when the effect of another factor was being assessed. In the case of categorical variables, a chi-squares test was used. A multivariate logistic regression was used to analyze the variables’ dependency on the normalization of final IGF-I values (normal up to 100% of ULN). Statistical significance was considered for a p value <0.05. All analyses were performed with the statistical software package SPSS (v20.0).

The ACROCOMB study was conducted in accordance with Good Clinical Practice/regulatory guidelines and relevant local legislation by the Spanish Agency for Medicines and Health Products (AEMPS). The study was authorized by the Ethics Committee of the participating hospitals. The ACROCOMB study was sponsored by Spanish Society of Endocrinology and Nutrition (SEEN) and funded by Ipsen Pharma, Spain.

In this large retrospective series of patients with acromegaly reflecting the use of lanreotide combination therapy in routine clinical practice, both the combination with cabergoline and the combination with pegvisomant appear to be clinically useful in many patients with active acromegaly not fully controlled on monotherapy. Normalization of IGF-I values was reported in approximately half of the patients that received lanreotide/cabergoline and in 70% of patients receiving lanreotide/pegvisomant. However, even with the best clinical handling with currently available drugs, 50% of patients in the cabergoline cohort and 30% in the pegvisomant cohort remained uncontrolled at EOS. Overall, these data highlight the heterogeneous nature of the disease, a fact well known by treating clinicians. These clinicians must decide on the best treatment for each patient, but are not yet able to rely on biomarkers for predicting a positive therapeutic result in the clinical practice.

The result in the cabergoline cohort is similar to what was reported in a meta-analysis of 5 studies of cabergoline and SSA treatment in 77 patients, where 52% of patients achieved normal IGF-I levels15 and to what has been reported in other studies on this combination.9–14 In a long-term retrospective study of 66 acromegalic patients partially responding to octreotide, the addition of cabergoline led to a 73% of the patients achieving a GH <2.5ng/mL, 34% of the patients an IGF-1 <1.2× ULN and 30.2% reaching both biochemical goals.26 The rates of IGF-I normalization in the pegvisomant cohort are lower than those reported in controlled clinical studies with this combination therapy, which typically report biochemical response in ≥95% of patients,20,21,24,27 but are similar to what has been reported in the study by van der Lely et al.,23 which specifically selected patients resistant to SSAs, and a recent Italian retrospective study of clinical practice,28 both of which had a patient population comparable to the ACROCOMB study population.

Approximately one third to one half of patients receiving treatment with SSAs have partial but insufficient long-term disease control; among these patients, approximately 10-25% can be considered highly medically resistant,6 meaning a very poor response to maximal doses of SSAs. A challenge as well as a clear clinical need in acromegaly is to define biomarkers that could reasonably identify responders and non-responders to SSA therapy in order to save time and expenses when treating our patients with SSAs, the accepted first option for medical treatment of acromegaly. Moreover, considering that acromegaly is usually diagnosed late in the disease evolution, adding delays in controlling GH hypersecretion leads to a further comorbility development. While SSAs treatment is the cornerstone of acromegaly medical management, it is important to be able to provide effective treatment regimens to patients in which hormonal control is not achieved with SSAs monotherapy.6 Hormonal control in patients partially responding to SSAs was the main reason for receiving combination therapy with an additional drug. However, a significant proportion of patients was not receiving the full dose of lanreotide or was receiving lanreotide on an extended treatment regimen (>q4w). These situations reflect the reality of clinical practice, in which therapeutic agents are administered at lower doses than those theoretically possible, potentially due to inadequate dosing by the prescribing physicians, inadequate patient compliance, or due to side effects not allowing up titration.17,18,29,30 Using lower doses of lanreotide and cabergoline/pegvisomant might explain, at least in part, the lack of IGF-I normalization in a subset of patients in the ACROCOMB study. Potentially, the use of higher doses of SSAs or increasing the administration frequency could help to achieve a higher response to treatment, as reported in the Italian randomized controlled study that evaluated the biochemical efficacy of increasing SSAs frequency or dose in patients with persistently uncontrolled acromegaly despite conventional titration SSAs therapy.31

More than half of the patients in the cabergoline cohort that did not achieve IGF-I normalization were receiving cabergoline doses below <2mg/week, lower than what has been reported to be effective for combination treatment with SSAs. This implies a certain degree of therapeutic inertia in clinical practice if we take into account that cabergoline was started after lanreotide in most of the patients. Moreover, one third of the patients in the pegvisomant cohort were receiving pegvisomant monotherapy and failed to achieve therapeutic goals before the lanreotide combination was started; it is remarkable that so many patients were receiving pegvisomant monotherapy, considering that SSA monotherapy is the usual recommended first-line treatment. It is notable that many of the patients with poor biochemical control had not been titrated to maximal doses of lanreotide or pegvisomant during monotherapy; thus it is possible to speculate that higher efficacy might have been attained in the present study if more patients would have been titrated to a higher dose. In a survey of European physicians treating patients with acromegaly that evaluated their perceived definition of biochemical control and real-world treatment decision making, half of the physicians responding considered it acceptable for a patient to have IGF-I 1× >ULN, and one fifth considered IGF-I ≥1.5× ULN acceptable.32 This suggests a therapeutic inertia situation although the specific reasons why lanreotide or cabergoline/pegvisomant doses were not up titrated are not known.

In our study, the combined treatment with lanreotide was well tolerated without significant liver enzyme elevations, cardiac abnormalities, or glucose alterations. An increased risk of cardiac valve disease has been reported in patients with Parkinson's disease33 treated with very high doses of cabergoline. However, a study that specifically evaluated the incidence of cardiac abnormalities in a series of 42 patients with acromegaly treated with cabergoline did not find a higher incidence of valve abnormalities.34,35 Moreover, another large cross-sectional study from the UK did not support an association between the use of dopamine agonists for the treatment of hyperprolactinemia and cardiac valvulopathy.36 Hypertransaminasemia is one of the most frequently described adverse events of pegvisomant, ranging from 1.2% to 38%, with higher rates of occurrence when patients receive a combination with an SSA,18–21,37 especially within the first year of combination treatment.24 Liver enzyme elevations appear to be reversible and normalize either with continued treatment or after discontinuation of therapy. It is noteworthy that there were no increases in transaminase levels to more than 3 times the ULN in this study and the rates of clinically relevant liver enzyme elevations were lower than in other studies with pegvisomant.21,23,27 Furthermore, although increases in blood glucose are a known effect of SSAs38,39 in our study there were no changes in glycaemia and Hb1Ac.

Limitations of our study include its retrospective and observational design. Importantly, data were collected retrospectively from several centres using different local laboratories and assays with different sensitivities to measure GH and IGF-I and it is widely recognized that there tends to be a lack of consistency between results from different labs and assays; however, taken as a whole, results reflect what occurs in the clinical practice setting. Moreover, our study has a large number of patients and provides a realistic profile of the efficacy and safety of lanreotide combination therapy in clinical practice across many Spanish centres. In this sense, the rate of IGF-I normalization is high for clinical series, even though in our study neither the patient population nor the treatment provided by the physicians were homogeneous, as evidenced by the lower doses of medication received in certain cases.

Overall, our study supports a more relevant role of drug combination in the treatment algorithm of acromegaly after insufficient SSA monotherapy response. Future studies involving the definition of response biomarkers to specific drugs are required in order to help clinicians in the process of treatment decision allowing a quicker normalization of biochemical and hormonal parameters of acromegalic patients.40

Sponsored by Spanish Society of Endocrinology and Nutrition (SEEN); Funding by a grant from Ipsen Pharma, Spain.

No conflict of interest: RV, CB, RC, CF, SM, TM, TL, MM.

Conflicts of interest include:

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  Employment and consultancies: MP-D: consultancies from Pfizer.

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  Grants, fees and honoraria: MP-D has received lecture honoraria from Novartis, Pfizer and Ipsen; FC: has received lecture honoraria from Novartis and Pfizer and unrestricted research grants from Ipsen Pharma; MP: speaker fees from Ipsen and Pfizer; AS: Clinical trials and donations for investigator-initiated research projects by Ipsen, Novartis and Pfizer; AP: advisory board Pfizer; IB: Advisory fees: Pfizer; research grants: Pfizer; lectures fees: Pfizer, Novartis.

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  Board membership: MP-D: Pfizer.