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Ammar Muhammad, Eva C Coopmans, Patric J D Delhanty, Alof H G Dallenga, Iain K Haitsma, Joseph A M J L Janssen, Aart J van der Lely and Sebastian J C M M Neggers

Objective

To assess the efficacy and safety after 48 weeks of treatment with pasireotide long-acting-release (PAS-LAR) alone or in combination with pegvisomant in patients with acromegaly. In addition, we assessed the relation between insulin secretion and pasireotide-induced hyperglycemia.

Design

The PAPE extension study is a prospective follow-up study until 48 weeks after the core study of 24 weeks.

Methods

Fifty-nine out of 61 patients entered the extension study. Efficacy was defined as the percentage of patients achieving IGF-I normalization (≤1.2× the upper limit of normal (ULN)) at 48 weeks through protocol-based adjustment of pegvisomant and PAS-LAR doses. At baseline, insulin secretion was assessed by an oral glucose tolerance test (OGTT).

Results

At the end of the study, median IGF-I was 0.98× ULN, and 77% of patients achieved normal IGF-I levels with a mean pegvisomant dose of 64 mg/week, and an overall cumulative pegvisomant dose reduction of 52%. Frequency of diabetes mellitus increased from 68% at 24 weeks to 77% at 48 weeks, and nine patients discontinued PAS-LAR treatment, mainly because of severe hyperglycemia. Pasireotide-induced hyperglycemia was inversely correlated with baseline insulin secretion (r = −0.37, P < 0.005).

Conclusions

PAS-LAR normalizes IGF-I levels in most acromegaly patients, with a 50% pegvisomant-sparing effect. However, PAS-LAR treatment coincided with a high incidence of diabetes mellitus. The risk for developing diabetes during PAS-LAR treatment seems inversely related to insulin secretion at baseline.

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Laila Füchtbauer, Daniel S Olsson, Eva C Coopmans, Bengt-Åke Bengtsson, Lise-Lott Norrman, Sebastian J C M M Neggers, Ann Hellström and Gudmundur Johannsson

Objective

Excess of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), as in acromegaly, is associated with increased risk of diabetes, but whether retinal vessels are altered is unknown. The aim of this study was to evaluate retinal vessel morphology in patients with acromegaly at diagnosis and after treatment and to describe the prevalence of diabetic retinopathy in patients with long-standing acromegaly and diabetes.

Design

Two independent observational studies, one being prospective and the other retrospective and cross-sectional.

Methods

Retinal vessel morphology of 26 patients with acromegaly was examined at diagnosis and 1 year after treatment and compared to 13 healthy controls. Cross-sectional evaluation of 39 patients with long-standing acromegaly and diabetes was performed. Fundus photographs were digitally analyzed for vessel morphology.

Results

Patients with acromegaly had a median (interquartile range) of 34.3 (30.0–39.0) vessel branching points compared to 27.0 (24.0–29.0) for healthy controls (P < 0.001). Tortuosity of arterioles and venules remained unchanged. Vessel morphology did not change significantly after treatment. Patients with acromegaly and diabetes for a median of 14 years also had a high number of branching points (34.2 (32.5–35.6)), but the prevalence of diabetic retinopathy was not higher than expected in diabetic patients without acromegaly.

Conclusions

Patients with acromegaly have an increased number of vascular branching points in the retina without an alteration of macroscopic vessel morphology. This is consistent with an angiogenic effect of GH/IGF-1 in humans. The prevalence of diabetic retinopathy was not increased in patients with acromegaly and diabetes.

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Eva C Coopmans, Sebastiaan W F van Meyel, Kay J Pieterman, Jolique A van Ipenburg, Leo J Hofland, Esther Donga, Adrian F Daly, Albert Beckers, Aart-Jan van der Lely and Sebastian J C M M Neggers

Prolactinomas are the most commonly encountered pituitary adenomas in the clinical setting. While most can be controlled by dopamine agonists, a subset of prolactinomas are dopamine-resistant and very aggressive. In such tumors, the treatment of choice is neurosurgery and radiotherapy, with or without temozolomide. Here, we report a patient with an highly aggressive, dopamine-resistant prolactinoma, who only achieved biochemical and tumor control during pasireotide long-acting release (PAS-LAR) therapy, a second-generation somatostatin receptor ligand (SRL). Interestingly, cystic degeneration, tumor cell necrosis or both was observed after PAS-LAR administration suggesting an antitumor effect. This case shows that PAS-LAR therapy holds clinical potential in selective aggressive, dopamine-resistant prolactinomas that express somatostatin (SST) receptor subtype 5 and appears to be a potential new treatment option before starting temozolomide. In addition, PAS-LAR therapy may induce cystic degeneration, tumor cell necrosis or both in prolactinomas.