PASIREOTIDE-INDUCED HYPERGLYCEMIA INACROMEGALY PATIENTS: EVALUATION OF PATHOPHISIOLOGICAL MECHANISMS AND EFFICACY OF ANTIDIABETIC TREATMENT

Pasireotide LAR (PAS) has a safety profile similar to first-generation somatostatin in analogues (SSA), except for a higher frequency of hyperglycaemia-related adverse events. However, consensus on the best management of PAS-induced hyperglycaemia in acromegalic patients has still to be defined. The current study aim at investigating the effects of long-term PAS treatment on glucose metabolism, besides GH and IGF-I control, by evaluating the clinical management of hyperglycemia adverse events in acromegalic patients followed in two Italian referral Centers, participating to the PAOLA study, a randomized, Phase III study assessing the efficacy and safety of PAS compared with patients with inadequately controlled acromegaly during first-generation SSA. Moreover, the role of metabolic parameters (weight, BMI, fasting glucose and HbA1c levels) and markers of disease activity (GH, IGF-I, duration of PAS treatment) were investigated as potential predictors of hyperglycemia development. A total of 31 patients (16 F/15 M, mean age 47.6 years) entered the present study, including 18 randomized to PAS (group 1), and 13 to continued treatment with octreotide LAR 30 mg or lanreotide Autogel 120 mg (group 2) for six months (core study). All patients in group 2 who remained uncontrolled at 6 months had the opportunity to switch to PAS in the extension phase. In all patients, fasting glucose and HbA1c were evaluated every 6 months, according to the study protocols. At baseline, pre-existing diabetes mellitus (DM) was found in five patients (27.7%) in group 1 and one (7.7%) in group 2 (p=0.34), whereas pre-existing prediabetes, defined as impaired glucose tolerance (IGT) or impaired fasting glucose (IFG), was seen in one patients (5.5%, IGT) in group 1 and in three patients (23.1%, 2 IGT, 1 IFG) in group 2 (p=0.34). Patients were treated with PAS for a mean time of 34 months (6-67 months). Hyperglycemia-related adverse events were reported in 15 patients (83.3%) in group 1, occurring after a mean time of 5 months (1-16 months). One patient required treatment discontinuation because of diabetes adverse event. Four out five patients with DM at baseline (80%) reported worsening of hyperglycemia during PAS treatment. One patient with IGT at baseline (100%) developed overt DM. Six (50%) and four (33.3%) patients with normal glucose tolerance (NGT) at baseline developed IFG and DM, respectively, during PAS treatment. In group 2, three (23%) patients reported hyperglycemia-related adverse events during the core phase (during first-generation SSA therapy), after a mean time of two months. Particularly, overt DM occurred in two patients (15.3%) with baseline NGT and in one patient (7.7%) with IGT at baseline. All cases were of mild severity, defined as grade 1. During the extension phase, nine patients (69.2%) reported hyperglycemia-related adverse events after a mean time of seven months (2-17 months) from the beginning of PAS treatment. One diabetic patient (33.3%) reported worsening hyperglycemia. Among patients with NGT at baseline, three (16.6%) developed pre-diabetes (2 IFG, 1 IGT), and two patients (15.3%) developed overt DM during PAS treatment. All cases reported in group 1 and 2 were of mild-to-moderate severity, defined as grade 2-3, and were judged to be related to PAS. The risk to develop hyperglycemia correlated neither with baseline BMI, weight, GH, IGF-I, glucose and HbA1c levels, or duration of PAS treatment (p=0.41). Similarly, glucose status did not significantly correlate with biochemical control at the last follow-up (p=0.66). At study entry, three patients (16.6%) in group 1 and one patient (7.7%) in group 2 were already treated with antidiabetic drugs. In group 1, starting of new antidiabetic treatment was required in eight patients (44.4 %) throughout the study, and metformin (MET) was the drug of choice in all these patients. Four (50%) out eight patients did not control glucose and HbA1c levels despite MET monotherapy, needing further therapies. In fact, MET was associated with DPP-4 inhibitor in one patient (25%), GLP-1 agonist in two patients (50%), and GLP-1 agonist and glargine insulin in one patient (25%) to control hyperglycemia. Two patients previously treated with antidiabetic drugs (1 patient with MET plus glargine insulin, and 1 patient with glargine insulin monotherapy) needed a dose adjustment to control hyperglycemia. In group 2, one patient (7.7%) started MET during the core phase. During the extension phase, starting of new antidiabetic treatment was required in seven patients (53.8%), and MET was the drug of choice in all these patients. Three (42.8%) out seven patients did not control glucose and HbA1c levels despite MET monotherapy, requiring further therapies. MET was associated with DPP-4 inhibitor in one patient (33.3%), GLP-1 agonist in two patients (33.3%), and GLP-1 agonist and detemir insulin in one patient (33.3%) to control hyperglycemia. The results of the present study confirm the known negative effect of PAS on glucose metabolism, however treatment intensification with DPP4 inhibitor and GLP-1 agonist resulted in good glycemic control in most patients. Further studies are needed to deeply evaluate the mechanism of PAS-induced hyperglycemia in acromegalyc patients, investigating the effect of PAS on insulin secretion and hepatic/peripheral insulin sensitivity.