Endocrine Abstracts

Background: The PAOLA study assessed the efficacy/safety of pasireotide LAR vs continued treatment with octreotide LAR/lanreotide Autogel in patients with inadequately controlled acromegaly. An exploratory objective was to measure changes in various associated biomarkers, including IGF1 and IGFBP2 (released from white fat cells and known to prevent insulin resistance), glucose and HbA1c.

Methods: Adult patients (GH >2.5 μg/l and IGF1 >1.3×ULN) had received octreotide LAR 30 mg/lanreotide Autogel 120 mg monotherapy for≥6 months and were randomized to: pasireotide LAR 40 mg (n=65) or 60 mg (n=65); or continued treatment with octreotide LAR/lanreotide Autogel (n=68; active control). Blood samples for biomarker assessment were taken before each drug administration.

Results: Pasireotide LAR 40 and 60 mg dose dependently decreased average GH, IGF1 and IGFBP3, without tachyphylaxis of response. Patients who received antidiabetic medication during pasireotide treatment (54% of population) had significantly (P<0.05) higher baseline glucose (114 mg/dl (95% CI: 110,119)) and HbA1c (6.2% (6.1,6.4)) levels than patients who received no antidiabetic medication (95.8 mg/dl (92.8,98.9); 5.6% (5.5,5.7), respectively). Peak glucose (115 mg/dl (110,120)) and HbA1c (5.9% (5.8,6.0)) levels in patients who did not receive antidiabetic medication were small compared with those receiving antidiabetic medication (155 mg/dl (143,168); 7.5% (7.1,8.0), respectively). IGFBP2 levels increased from baseline to week 24: 42.4 ng/ml (37.0,48.6) to 62.2 ng/ml (51.9,74.5) and 45.3 ng/ml (39.0,52.5) to 60.1 ng/ml (49.8,72.4) in patients who received and did not receive antidiabetic medication respectively.

Discussion: As elevated GH causes insulin resistance, patients with inadequately controlled acromegaly might be particularly sensitive to developing pasireotide-induced hyperglycaemia. Increased IGFBP2 levels were an unexpected observation given the increased glucose levels.

Conclusions: The effects of pasireotide LAR on glucose homeostasis may be attenuated by increased insulin sensitivity due to the compensatory increase in IGFBP2. Patients not receiving antidiabetic medication (~50% of the population) had significantly lower baseline glucose levels than those who did, and pasireotide-induced hyperglycaemia was mild and decreased over time.