Endocrine Abstracts

Background: In the core phase of the PAPE study until 24 weeks we have shown that switching to pasireotide LAR (PAS-LAR) in well-controlled acromegaly patients receiving combination therapy of somatostatin analogues and pegvisomant (PEGV), normalizes IGF1 levels in the majority of patients. PAS-LAR induced a significant PEGV sparing effect, but this was at the expense of a higher incidence of diabetes. This extension study until 48-weeks assesses the efficacy, safety and quality of life (QoL) of PAS-LAR monotherapy or in combination with PEGV by optimization of PAS-LAR and PEGV dose.

Methods: 59 out of 61 patients entered the extension phase. Well-controlled patients receiving PAS-LAR monotherapy continued with the same dose, while uncontrolled patients had to restart PEGV therapy. In patients on PAS-LAR and PEGV combination therapy, the PEGV dose was titrated based on a protocol with the goal to achieve normalized IGF1 levels. At baseline, an oral glucose tolerance test (OGTT) was performed, and at each study visit QoL was assessed using the AcroQoL and PAQ3 questionnaires.

Results: At the start of the present study, median IGF1 was 0.94×the Upper Limit of Normal (ULN) with a mean PEGV dose of 134 mg/week, and 32.8% of patients had pre-existing diabetes. At 48 weeks, median IGF1 was 0.98×ULN, and 77% of patients achieved normal IGF1 levels with a mean PEGV dose of 64 mg/week. Cumulative PEGV dose reduction between baseline and 48 weeks was 52%. After 48 weeks IGF1 levels were normal in 93% of patients receiving PAS-LAR monotherapy, and 71% of patients receiving combination therapy. The incidence of diabetes increased to 77%. Nine patients discontinued PAS-LAR therapy, mainly due to hyperglycemia-related adverse events. Pasireotide-induced hyperglycemia was inversely related to insulin secretion during OGTT at baseline (Stumvoll, r=−0.37, P=0.005). Global AcroQoL score significantly improved (5.5%, P<0.0001) during treatment with PAS-LAR. The greatest improvement was observed in the physical dimension.

Conclusions: Switching to PAS-LAR monotherapy or in combination with PEGV controlled IGF1 levels in the majority of acromegaly patients after about fifty percent reduction in cumulative PEGV dose, however this coincides with a higher incidence of diabetes. The main driver of pasireotide-induced hyperglycemia seems residual β-cell function at baseline. Long-term treatment of acromegaly with PAS-LAR is a trade-off between the benefits of biochemical control and an improvement in QoL versus the burden of long-term sequelae of the pasireotide-induced diabetes.