Pasireotide in an insulin-requiring diabetic acromegalic patient without worsening of hyperglycemia.

Long-acting pasireotide is an effective treatment option for acromegaly, but it is associated with hyperglycemia, which could impact its use in patients with diabetes. We present a case of a 53-year-old man with acromegaly and type 2 diabetes mellitus (glycated hemoglobin (HbA1c): 7.5%), who refused surgery to remove a pituitary macroadenoma and enrolled in a Phase 3 clinical trial comparing long-acting pasireotide and long-acting octreotide in acromegalic patients. The patient initially received octreotide, but insulin-like growth factor 1 (IGF-1) levels remained elevated after 12 months (383.9 ng/mL; 193.0 ng/mL; reference range: 86.5–223.8 ng/mL), indicating uncontrolled acromegaly. He switched to pasireotide 40 mg and subsequently increased to 60 mg. Within 6 months, IGF-1 levels normalized (193.0 ng/mL), and they were mostly normal for the next 62 months of treatment with pasireotide (median IGF-1: 190.7 ng/mL). Additionally, HbA1c levels remained similar to or lower than baseline levels (range, 6.7% to 7.8%) during treatment with pasireotide despite major changes to the patient’s antidiabetic regimen, which included insulin and metformin. Uncontrolled acromegaly can result in hyperglycemia due to an increase in insulin resistance. Despite having insulin-requiring type 2 diabetes, the patient presented here did not experience a long-term increase in HbA1c levels upon initiating pasireotide, likely because long-term control of acromegaly resulted in increased insulin sensitivity. This case highlights the utility of long-acting pasireotide to treat acromegaly in patients whose levels were uncontrolled after long-acting octreotide and who manage diabetes with insulin. Learning points Long-acting pasireotide provided adequate, long-term biochemical control of acromegaly in a patient with insulin-requiring type 2 diabetes mellitus who was unresponsive to long-acting octreotide. Glycemic levels initially increased after starting treatment with pasireotide but quickly stabilized as acromegaly became controlled. Long-acting pasireotide, along with an appropriate antidiabetic regimen, may be a suitable therapy for patients with acromegaly who also have insulin-requiring type 2 diabetes mellitus. Background Acromegaly is a rare disease in which a benign somatotropic adenoma causes excessive secretion of growth hormone (GH), resulting in the overproduction of insulin-like growth factor 1 (IGF-1) (1). When GH or IGF-1 levels are not controlled, various symptoms and comorbidities can develop, including pronounced facial features, increased perspiration, headaches, paresthesia, sexual dysfunction, skeletal growth and soft-tissue swelling. Goals of treatment include reducing clinical symptoms and achieving biochemical control of hormone levels. First-line treatment for acromegaly is removal of the pituitary adenoma by transsphenoidal surgery (1). Medical treatment options are available for patients with recurrent disease after surgery, who are poor candidates for surgery, or who refuse surgery, including somatostatin analogs (SSAs) that exert pharmacological activity via binding to somatostatin receptors (2, 3). There are 5 subclasses of somatostatin receptors (sst1–5) that, when activated, inhibit the release of a variety of hormones, including GH and insulin (4). Long-acting pasireotide is an SSA injection approved by the US Food and Drug Administration (FDA) for the treatment of patients with acromegaly who have had an inadequate response to surgery or for whom surgery is not an option (2). In a 12-month Phase 3 superiority study (C2305, ClinicalTrials.gov identifier, Nbib600886), pasireotide was more effective than long-acting octreotide in providing biochemical control (normalization of IGF-1 level and GH level <2.5 ng/mL) for medically naive patients with acromegaly (5). In the 12-month crossover extension phase of the C2305 trial, 17.3% of the patients whose acromegaly was inadequately controlled with octreotide achieved biochemical control with pasireotide (6). Pasireotide, however, was associated with more hyperglycemia-related adverse events compared to octreotide (5). After beginning pasireotide treatment, mean fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) levels initially increased and then quickly stabilized for up to 26 months (7). Pasireotide has a higher affinity for sst5 (4), a key regulator of insulin secretion in the pancreas (3), than other SSAs. A randomized, open-label study in healthy volunteers demonstrated that pasireotide-associated hyperglycemia was caused by a decrease in insulin secretion, not by a decrease in insulin sensitivity (8). It is recommended that patients be monitored for pasireotide-associated hyperglycemia during treatment and prescribed an antidiabetic regimen upon initial signs of hyperglycemia (2). Currently, it is unclear whether pasireotide is a viable treatment option for insulin-requiring type 2 patients with diabetes and acromegaly. While pasireotide can cause hyperglycemia, the chronic elevation of GH in patients with acromegaly is associated with decreased insulin sensitivity and elevated glycemic levels (1). It has been reported that patients who initiate treatment with pasireotide have an initial increase in glycemic levels that peaks within several months but stabilizes once acromegaly is controlled (7, 9). Herein, we present a case study of a patient with acromegaly with insulin-requiring type 2 diabetes mellitus who refused surgery to remove a pituitary macroadenoma and participated in the C2305 trial. During the initial 12-month core phase, the patient did not achieve biochemical control while being treated with octreotide. The patient was enrolled in the extension phase and crossed over to pasireotide for an additional 68 months. Biochemical control was achieved within 6 months after initiation of treatment with pasireotide and generally remained controlled throughout the course of treatment. Moreover, while on long-term pasireotide, HbA1c levels remained stable, indicating that pasireotide may be an effective treatment option for patients with acromegaly with insulin-requiring type 2 diabetes.