Medical Therapy
Three drug classes are available to treat acromegaly (Fig. 1), each with unique advantages and disadvantages. In patients with uncontrolled hormonal levels after surgery, SSAs are the treatment option of first choice. Dopamine agonists and GHRAs are generally indicated after SSA failure.
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Figure 1.
Illustration showing medical therapy targets in the GH/IGF-I pathway. The SSAs directly inhibit GH secretion and control both GH and IGF-I levels; DAs reduce GH hypersecretion; and GHRAs (GHRas) directly block peripheral GH-dependent release of IGF-I and GH effects, have no direct effects on the pituitary tumor, and cause no decrease in GH levels. GHRH = growth hormone releasing hormone.
Somatostatin Analogs
Somatostatin acts as an endocrine inhibitor to a number of endocrine cells including GH-secreting pituitary cells, pancreatic beta cells releasing insulin, and a number of gastrointestinal tract hormones. Somatostatin ligands or "analogs" bind with varying affinity to the 5 SSTRs described above and mimic the GH suppressive effects of native somatostatin. A potential added benefit of SSAs is their antiproliferative effect.
Somatostatin analogs represent the mainstay of medical treatment for acromegaly, and most pituitary centers now have 25 years of experience with their use. Three SSAs are approved for use in the US: short-acting octreotide, octreotide LAR (Sandostatin LAR), and Somatuline Depot (lanreotide Autogel; Table 2). Octreotide was first approved for use in the US in 1995, followed by octreotide LAR in 1998 and lanreotide in 2007.
Short-acting Octreotide
Octreotide is approximately 20 times more potent than native somatostatin and has a half-life of 1.5 hours. It is administered as a subcutaneous injection 3 times a day with an immediate biochemical response, suppressing both basal and stimulated GH secretion for up to 5 hours.
With the development of long-acting SSAs, short-acting octreotide is rarely used, except in the acute octreotide test. We consider acute suppression tests valuable tools for evaluating a patient's tolerance of therapy, but their prognostic value in predicting long-term response, despite initial reports, is limited.
Octreotide LAR
Octreotide LAR is a formulation consisting of octreotide incorporated into microspheres of a slowly dissolving polymer that provides smooth and reliable steady-state kinetics when administered intramuscularly once a month. The injection of 20–30 mg results in peak drug levels at 28 days with integrated GH suppression for up to 49 days. The pharmacodynamics suggest that although GH suppression will be observed after the first dose, maximal suppression is not observed until after the administration of 3 doses. This timeframe should be kept in mind by clinicians when assessing the response to a given dose. Accurate drug administration is imperative, and a dedicated physician-nurse care provider team is essential for long-term care.
The 2 largest studies of octreotide LAR compiled 261 patients, with more than one-half pretreated with short-acting octreotide and the remainder naïve to medical treatment; GH suppression to < 2.5 μg/L and normal IGF-I was achieved in 63%–75% of patients.
Lanreotide Autogel
A recent development has been the introduction of a supersaturated aqueous formulation, lanreotide Autogel, in a prefilled syringe that requires deep subcutaneous administration every 28 days. Lanreotide has a linear pharmacokinetic profile over a dose range of 60–120 mg after both single and repeat injections. This new formulation has the potential to increase dosing intervals, and the user-friendly characteristic for the patient to self-administer (or a partner to administer) could result in improved compliance.
A randomized placebo-controlled study in an unselected population (99 patients) published in 2010 showed that lanreotide Autogel was effective in controlling both GH and IGF-I hypersecretion: 54% of patients had normalized IGF-I and 38% had both normalized IGF-I and a GH level ≤ 2.5 ng/ml. This drug was well tolerated by all patients in the long term.
Similar to other SSAs studied, patients who were not naïve to medical treatment at the beginning of the study were more likely to respond. This study also confirmed an improved response in patients with prior pituitary surgery and less severe acromegaly at baseline.
It is difficult to appreciate the true efficacy of SSAs in achieving biochemical control due to varied study entry criteria and desirable cutoff goals. A 2005 meta-analysis by Freda et al. showed that overall GH and IGF-I were normalized in 49%–56% and 48%–66% of patients, respectively, with the efficacy of octreotide LAR higher than that of a slow-release lanreotide (not used in the US). Note, however, that Freda and colleagues' study was flawed by the inclusion of more than 50% of patients who were preselected with previous octreotide responsiveness. The currently available SSAs octreotide and lanreotide seem equally effective, with the majority of patients achieving symptom control and biochemical control being achieved in approximately one-half of unselected patients. Further meta-analysis of prospective randomized trials on the efficacy of each SSA with respect to GH control and tumor shrinkage is warranted.
Somatostatin analogs are generally safe and well tolerated. The most frequent adverse events of SSA treatment are abdominal symptoms (usually improving over time), glucose intolerance, and gallbladder sludge or stones.
Other potential drawbacks of SSA use are its high cost and patient compliance. In an Italian study, however, the cost of caring for patients who did not respond to SSA was much higher than for those who did respond. Recent evidence has suggested that these agents can be used at lower doses or at less frequent intervals with obvious cost and compliance implications. Both octreotide LAR and lanreotide have been successfully used at 6- to 8-week intervals.