How do somatostatin analogs work?

From Lewis S. Blevins, Jr. MD  –  Somatostatin analogs are a class of drugs that are chemically modified forms of native somatostatin.   They are meant to act like somatostatin.   Somatostatin is produced in our bodies, including in the hypothalamus, and exerts a negative impact on certain cellular processes.  Somatostatin is a ubiquitous hormone present in most areas where there are neuroendocrine tissues.  For example, in the gut, it inhibits the production of some hormones involved in digestion.     Chemical modifications of the somatostatin analogs have prolonged the half-life of the drugs relative to that of native somatostatin and have enhanced the ability of the drug to bind to the normal somatostatin receptor.

Almost all pituitary cells possess somatostatin receptors and respond to somatostatin in some way.  Somatostatin binds to its receptor located on the surfaces of the cells. Somatostatin bound to its receptor initiates a cascade of events in the cells that change cellular processes.   For example, somatostatin produced by the hypothalamus has an inhibitory effect on growth hormone secretion by the growth hormone producing cells of the pituitary gland.  Growth hormone releasing hormone has a positive impact on growth hormone secretion. Somatostatin probably exists to modulate the overall tone of growth hormone production and is the dominant hormone from the hypothalamus affecting growth hormone release.  Though ACTH-producing cells possess somatostatin receptors we are not clear on the specific role that somatostatin has on the regulation of ACTH secretion.

There are 5 types of somatostatin receptors.  They are labeled SSTR1 sequentially to SSTR-5.   Some pituitary tumors express one or more of these in greater amounts than the others.  For example, the SSTR-2 receptors seem to be most prominent in patients with acromegaly. The SSTR-2 and SSTR-5 receptors are expressed in the ACTH-producing pituitary adenomas of patients with Cushing’s disease.  Unfortunately, however, the expression of these receptors by pituitary tumors is not universal.  In other words, only a fraction of tumors express these receptors and are thus potentially treatable with somatostatin analogs.

There are at least 3 commercially available somatostatin analogs. These are: Octreotide (Sandostatin), Lanreotide (Somatuline), and Pasireotide (Signafor).   The first iteration of octreotide had to be administered every 6-8 hours. Octreotide LAR (long acting release) is administered every 28 days by injection.  The first iteration of lanreotide was administered every 2 weeks. Lanreotide Autogel is administered every 4-8 weeks.   The first iteration of Pasireotide was administered twice daily. Pasireotide LAR is administered every 4 weeks.

Somatostatin analogs inhibit the secretion of other hormones. Thus, that may cause impaired release of cholecystokinin affecting gallbladder contractility leading to gallstones. Digestive enzymes are inhibited and affected patients may have abnormalities in digestion and absorption of nutrients leading to abdominal pain, flatulence, cramps, and even diarrhea or constipation.  The drugs may inhibit insulin secretion leading to diabetes.  This seems to be far more common with Pasireotide.  There may inhibition of glucagon secretion leading to low blood glucose levels.  Rare patients develop a slow heart rate as a consequence of heart block.

Octreotide, Lanreotide, and Pasireotide are effective in patients with acromegaly.  This class of drugs acts on the SSTR-2 receptor expressed in some patients with growth hormone producing pituitary adenomas. These drugs control the IGF-I and growth hormone levels in roughly 40% of all patients with acromegaly.  A proportion of patients will have shrinkage of their tumors or else prevention of additional tumor growth.  A head-to-head study showed that Pasireotide LAR was more effective than Octreotide LAR.  The selection of one agent over another in patients with acromegaly depends largely on insurance coverage, patient convenience, choice of injection materials, etc.

Pasireotide is the only somatostatin analog effective in patients with Cushing’s disease.  This drug acts on theSSTR-2 and SSTR-5 receptors expressed on the cells of some of the ACTH-producing pituitary tumors.   The 24-hour urine free cortisol excretion rates are normalized in just over one-quarter of patients while cortisol excretion rates are decreased by 50% in just over 40% of patients.

The “story” behind all of this drug therapy for acromegaly and Cushing’s disease is a very interesting one.   It speaks to the importance of biomedical research in physiology and medicine at the molecular cell biology level.   This is largely funded by government entities.  Such led to the detection of somatostatin, its receptors, and the knowledge about expression in different tissue types.   More importantly, however, is the investment in research and drug development by pharmaceutical companies to bring novel designer drugs to patients with rare disorders.

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