Purpose The Phase 3 CHIASMA OPTIMAL trial (NCT03252353) evaluated efficacy and safety of oral octreotide capsules (OOC) in patients with acromegaly who previously demonstrated biochemical control while receiving injectable somatostatin receptor ligands (SRLs). Methods In this double-blind study, patients (N=56) stratified by prior SRL dose were randomized 1:1 to OOC or placebo for 36 weeks. Primary endpoint was maintenance of biochemical control at end of treatment (mean IGF-I ≤1.0 x ULN; weeks 34 and 36). Time to loss of IGF-I response and proportion requiring reversion to injectable SRLs were assessed as broader control measures. Results Mean IGF-I were 0.80 and 0.97 x ULN for OOC and 0.84 and 1.69 x ULN for placebo, at baseline and end of treatment, respectively. Mean GH changed from 0.66 to 0.60 ng/mL for OOC and 0.90 to 2.57 ng/mL for placebo. Normalization of IGF-I levels (≤1.0 x ULN) was maintained in 58.2% for OOC versus 19.4% for placebo (P=0.0079); GH levels were maintained (1.0 or ≥1.3 x ULN definitions) for patients receiving placebo was 16 weeks; for patients receiving OOC, it was not reached for both definitions during the 36-week trial (P<0.0001). Of the patients in the OOC group, 75% completed the trial on oral therapy. The OOC safety profile was consistent with previous SRL experience. Conclusions OOC may be an effective therapy for patients with acromegaly who previously were treated with injectable SRLs.

Background: Cushing's Syndrome (CS) which is caused by isolated Corticotropin-releasing hormone (CRH) production, rather than adrenocorticotropin (ACTH) production, is extremely rare. Methods: We describe the clinical presentation, course, laboratory values and pathologic findings of a patient with isolated ectopic CRH causing CS. We review the literature of the types of tumors associated with this unusual syndrome and the behavior of these tumors by endocrine testing. Results: A 56 year old woman presented with clinical and laboratory features consistent with ACTH-dependent CS. Pituitary imaging was normal and cortisol did not suppress with a high dose dexamethasone test, consistent with a diagnosis of ectopic ACTH. CT imaging did not reveal any discrete lung lesions but there were mediastinal and abdominal lymphadenopathy and multiple liver lesions suspicious for metastatic disease. Laboratory testing was positive for elevated serum carcinoembryonic antigen and the neuroendocrine marker chromogranin A. Serum markers of carcinoid, medullary thyroid carcinoma, and pheochromocytoma were in the normal range. Because the primary tumor could not be identified by imaging, biopsy of the presumed metastatic liver lesions was performed. Immunohistochemistry was consistent with a neuroendocrine tumor, specifically small cell carcinoma. Immunostaining for ACTH was negative but was strongly positive for CRH and laboratory testing revealed a plasma CRH of 10 pg/ml (normal 0 to 10 pg/ml) which should have been suppressed in the presence of high cortisol. Conclusions: This case illustrates the importance of considering the ectopic production of CRH in the differential diagnosis for presentations of ACTH-dependent Cushing's Syndrome.

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 HbA_1c 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 HbA_1c 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.

Glucagon-like peptide 1 receptor (GLP-1R) agonists provide good glycemic control combined with low hypoglycemia risk and weight loss. Here, we summarize the recently published data for this therapy class, focusing on sustainability of action, use in combination with basal insulin, and the efficacy of longer acting agents currently in development. The safety profile of GLP-1R agonists is also examined. GLP-1R agonists provide sustained efficacy and their combination with basal insulin is well tolerated, providing additional glycemic control and weight benefits compared with basal insulin alone. Data suggest that the convenience of longer acting agents may be at the expense of efficacy. Despite the initial concerns, most evidence indicates that GLP-1R agonists do not increase the risk of pancreatitis or thyroid cancer. However, the extremely low incidence of these events means further investigations are required before a causal link can be eliminated. Large-scale clinical trials investigating the long-term cardiovascular safety of this therapy class are ongoing and may also provide important insights into pancreatic and thyroid safety. GLP-1R agonists offer sustained glycemic efficacy, weight loss benefits, and a low risk of hypoglycemia. The results of ongoing trials should help to clarify the safety of this therapy class.