Managing pasireotide-associated hyperglycemia: a randomized, open-label, Phase IV study

Abstract

Purpose Pasireotide is an effective treatment for acromegaly and Cushing’s disease, although treatment-emergent hyperglycemia can occur. The objective of this study was to assess incretin-based therapy versus insulin for managing pasireotide-associated hyperglycemia uncontrolled by metformin/other permitted oral antidiabetic drugs. Methods Multicenter, randomized, open-label, Phase IV study comprising a core phase (≤ 16-week pre-randomization period followed by 16-week randomized treatment period) and optional extension (ClinicalTrials.gov ID: NCT02060383). Adults with acromegaly (n = 190) or Cushing’s disease (n = 59) received long-acting (starting 40 mg IM/28 days) or subcutaneous pasireotide (starting 600 µg bid), respectively. Patients with increased fasting plasma glucose (≥ 126 mg/dL on three consecutive days) during the 16-week pre-randomization period despite metformin/other oral antidiabetic drugs were randomized 1:1 to open-label incretin-based therapy (sitagliptin followed by liraglutide) or insulin for another 16 weeks. The primary objective was to evaluate the difference in mean change in HbA1c from randomization to end of core phase between incretin-based therapy and insulin treatment arms. Results Eighty-one (32.5%) patients were randomized to incretin-based therapy (n = 38 received sitagliptin, n = 28 subsequently switched to liraglutide; n = 12 received insulin as rescue therapy) or insulin (n = 43). Adjusted mean change in HbA1c between treatment arms was – 0.28% (95% CI – 0.63, 0.08) in favor of incretin-based therapy. The most common AE other than hyperglycemia was diarrhea (incretin-based therapy, 28.9%; insulin, 30.2%). Forty-six (18.5%) patients were managed on metformin (n = 43)/other OAD (n = 3), 103 (41.4%) patients did not require any oral antidiabetic drugs and 19 patients (7.6%) were receiving insulin at baseline and were not randomized. Conclusion Many patients receiving pasireotide do not develop hyperglycemia requiring oral antidiabetic drugs. Metformin is an effective initial treatment, followed by incretin-based therapy if needed. ClinicalTrials.gov ID: NCT02060383.

Pasireotide—a novel somatostatin receptor ligand after 20 years of use

“…Moreover, the study was the first one to unequivocally and directly demonstrate the efficacy of incretin drugs in treating PAS-induced carbohydrate metabolism disturbances. Interestingly, the study showed no differences in terms of impaired carbohydrate metabolism between the patients with acromegaly treated with PAS-LAR and those with Cushing's disease treated with PAS-LAR or subcutaneous PAS [28]. This finding is not consistent with those of other studies, where the rates and severity of hyperglycemia in patients with acromegaly treated with PAS-LAR seem to be lower than those in patients with Cushing's disease treated with subcutaneous PAS [55,58].…”

“…PASinduced hyperglycemia was the most common adverse event observed in this study; however, it caused treatment discontinuation in only 5% of patients [27]. Demonstrating that incretin effect inhibition is one of the fundamental mechanisms behind PAS-induced hyperglycemia was the primary purpose for the use of GLP-1 receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors in PAS-induced hyperglycemia treatment [59] [28]. The study by Samson et al also showed that the patients randomized to receive incretin drugs had lower HbA1c levels and fewer hypoglycemic episodes in comparison with those reported in insulin-treated patients.…”

“…2 Comparison of different somatostatin receptor ligands binding affinities to subtypes of somatostatin receptors (materials from Recordati, modified) [5,8,9] adrenocorticotropic hormone (ACTH) secretion, respectively [26,27]. Another point of this binding profile is the increased blood glucose in some patients [28]. This results from the inhibition of both insulin secretion and the incretin effect and only a modest suppression of glucagon, all of which are reversible upon discontinuation of PAS [29,30].…”

“…By its high-affinity binding to SSTR5, PAS potently suppresses insulin secretion, whereas the drug's inhibitory effect on glucagon secretion is only modest, PAS does not influence insulin resistance [29,31,32]. Before starting PAS therapy, patients should undergo an assessment of glucose metabolism and, in diabetic patients, anti-diabetic treatment should be initiated or optimized [14,28].…”

“…Impaired carbohydrate metabolism is also more commonly observed in Cushing's disease than in acromegaly [79,80]. A recent study on the optimal management of PAS-induced hyperglycemia showed the baseline levels of both fasting plasma glucose and HbA1c to be considerably higher in patients with Cushing's disease than in those with acromegaly [28]. The mechanism in which impaired carbohydrate metabolism develops in Cushing's disease is complex.…”