The Role of Somatostatin Analogues in Treatment of Acromegaly

Abstract

Somatostatin receptor ligand (SSRL) therapy is the mainstay of medical management of patients with acromegaly, either as adjuvant or primary therapy. Octreotide long-acting release (LAR) and lanreotide autogel (ATG) account for almost all clinical use of these analogues in acromegaly. SSRL acts via stimulation of one or more somatostatin receptor subtypes (SSTR1–5). Inhibition of GH secretion occurs primarily through SSTR2; however, SSTR1 and -5 also play a role. Anti-proliferative effects encompass cell cycle arrest and apoptosis for which SSTR3 is the predominant receptor subtype implicated. Octreotide LAR and lanreotide ATG improve symptoms in almost all patients, control GH and IGF-I secretion in around 60 and 50%, respectively, and inhibit tumoural growth in at least 98% of patients. Significant tumour shrinkage is observed in 40–70%. A greater incidence and magnitude of tumour shrinkage is seen in primary therapy compared with adjuvant therapy. Tolerability is generally good, though gastrointestinal side effects are frequent, but rapid tachyphlaxis occurs. Inhibition of insulin secretion leads to problems with carbohydrate handling and chronic use leads to formation of gallstones in up to 30% of patients. Recent advances support the use of both octreotide LAR and lanreotide ATG 6 weekly for some patients, and lanreotide ATG can be self-injected to improve convenience for the patient. Recent data suggest prolonged remission can occur following SSRL withdrawal in patients who achieve long-term control on treatment. Whether use of SSRL pre-operatively to induce tumour shrinkage improves the outcome of surgery remains controversial; however, there are undoubtedly benefits to reducing anaesthetic risk. Future improvements in SSRL take advantage of the synergy between SSTR subtypes, or the SSTR and dopaminergic systems. Two molecules are currently in clinical trials, pasireotide (SOM230) which has high affinity for SSTR1, 2, 3, and 5; and BIM23A760 which is a “dopastatin” and binds DR2 and SSTR2 and 5. In addition, the prospect of prolonged acting formulations of octreotide to improve patient convenience is also in development.