How to Position Pasireotide LAR Treatment in Acromegaly

Eva C. Coopmans; Ammar Muhammad; Aart J. van der Lely; Joseph A. M. J. L. Janssen; Sebastian J. C. M. M. Neggers

Disclosures

J Clin Endocrinol Metab. 2019;104(6):1978-1988. 

In This Article

Safety and Tolerability

Pasireotide LAR is well tolerated and has a safety profile comparable to that of first-generation SRLs, except for a greater frequency and degree of hyperglycemia-related adverse events.[20,21] Phase II and III studies in acromegaly have demonstrated that pasireotide LAR therapy is associated with more hyperglycemia-related adverse events than therapy with first-generation SRLs.[19–22,24,32] Mechanistic studies of healthy volunteers have shown that pasireotide inhibits both insulin secretion and incretin hormone responses and modestly suppresses glucagon secretion. However, the available data do not show that pasireotide affects hepatic or peripheral insulin sensitivity.[33,34] The effects of pasireotide on insulin, glucagon, and incretin secretion can be explained from its SSTR binding profile. SSTR5 is known to be expressed on pancreatic β-cells, which mediate insulin secretion, but also on enteroendocrine L-cells, which produce glucagon-like peptide 1 (GLP-1).[35–37] In contrast, SSTR2 is expressed mainly on pancreatic α-cells, which mediate glucagon secretion,[38,39] and this may explain the observed modest effect of pasireotide on glucagon secretion.

Hyperglycemia occurs early after the start of pasireotide treatment, with fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) levels increasing in the first 3 months and remaining stable thereafter with additional antidiabetic medication.[23] In a recently published study by Fleseriu et al.[32] designed to assess the safety of pasireotide LAR therapy in patients with acromegaly, hyperglycemia-related adverse events were reported in 46% of all patients, and 9% discontinued pasireotide LAR because of hyperglycemia.[32] In the C2404, patients with higher baseline glucose levels (FPG >5.55 mmol/L) and those receiving antidiabetic medication developed higher levels of FPG and HbA1c after pasireotide LAR than patients with normoglycemia at baseline.[40]

In the PAPE study, the incidence of diabetes mellitus doubled from 33% at baseline to 69% after 24 weeks of treatment and increased further to 77% after 48 weeks of treatment.[11,12] We observed a higher frequency of hyperglycemia-related adverse events (98%, of which 77% were grade 1 or 2) than in previous studies.[11,12,19–22,24,32] This difference could be due to inclusion of older and more diabetic patients and the use of a more liberal HbA1c cutoff <9% at inclusion. In addition, the reduction of PEGV dosage at the start of the study may have exacerbated insulin resistance through an increase in GH-mediated diabetogenic action.

In the PAPE study the degree of pasireotide-induced hyperglycemia was directly related to the degree of glycemic control at baseline. We found an inverse correlation between the β-cell function determined with the oral glucose tolerance test at baseline and the change in HbA1c between baseline and after 24 weeks' follow-up.[12] Patients who showed reduced insulin secretion during the oral glucose tolerance test had a greater risk of an increase in HbA1c levels during pasireotide treatment. These data suggest that β-cell function at baseline is probably an important determinant for the risk of hyperglycemia during pasireotide LAR treatment. Patients using pasireotide LAR and PEGV combination treatment did not show lower HbA1c levels than patients using pasireotide LAR monotherapy.[12] This observation suggests that PEGV cannot overcome pasireotide-induced hyperglycemia. Patients who needed insulin treatment were those who developed rapid hyperglycemia after the first injection of pasireotide LAR. The noninsulin group showed a slower onset of hyperglycemia after the start of pasireotide treatment, and the diabetes they developed was less severe. In general, diabetes in the latter group could be managed and controlled with oral antidiabetic medication after the third injection.

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