Introduction: Pasireotide (PAS) is an effective treatment for Cushings disease (CD) but its use is burdened by the high incidence of diabetes mellitus (DM). We aimed to evaluate the effect of a single subcutaneous injection of PAS on glucose metabolism in CD patients, to identify factors predicting rapid deterioration of glycaemic control.
Methods: 14 patients [(f/m=12/2, mean age 43±11.3 years, follow-up 17 months (2-63)] with CD treated with PAS (600 μg b.i.d.) were studied; before treatment initiation, all patients were submitted to an acute PAS test (600 mcg s.c.) with measurements of ACTH, cortisol, glucose, insulin, c-peptide, insulin, GIP, glucagon, GLP-1, ACTH and cortisol at time 0 and then every 30 minutes for 2 hours to predict the development of DM.
Results: There was a significant reduction in urinary free cortisol (UFC, 582±456 vs 254±356 nmol/24h, P=0.001) and late night salivary cortisol (LNSC, 12.2±11.6 vs 3.8±1.7 nmol/L, P=0.003) in all cohort with concomitant improvement of weight (P=0.01) and waist circumference (P=0.02). Overall 10/14 patients reached UFC normalization whereas LNSC was within normal range only in 4 cases. A single PAS dose produced a significant decrease of all hormonal parameters assessed (P<0.0001), except for glycaemia which reached the highest value 120 after the injection (baseline 4.65±0.52 vs peak 8.91±3.63 mmol/L, P<0.0001). Overall 7/14 patients developed DM within the first 2 months of therapy. Among baseline characteristics, non-DM patients did not differ in age, weight, visceral adiposity, HOMA-index, fasting glucose and severity of CD from those who did not have glucose metabolism alterations; however, compared to non-DM patients, DM patients displayed higher baseline fasting c-peptide (respectively 694.4±109.6 vs 947.4±318.4 pmol/L, P=0.05) and HbA1c levels (30±3.0 vs 37.1±1.8 mmol/mol, P=0.001), with the latter being normal in all cases. Finally, glucose peak tent to be higher in DM-patients than in those who did not develop hyperglycaemia (7.2±2.2 vs 10.6±4.1mmol/L, P=0.06).
Conclusions: PAS confirmed to be a valuable tool for the treatment of CD. It was able to rapidly suppress insulin secretion and the incretin system with a subsequent increase in glucose levels into the diabetic range producing also a concomitant decrease in glucagon values. Patients at higher risk of DM during PAS therapy were those with higher fasting c-peptide at elevated serum glucose peak during the acute test. Interestingly baseline HbA1c, seems to predict the risk of PAS-induced DM.
18 - 21 May 2019
European Society of Endocrinology