Available online 24 January 2024, 101875

Author links open overlay panel, Abstract

“First-generation” somatostatin receptor agonists (SSTRAs) octreotide and lanreotide are the most commonly used first-line pharmacological therapy for patients with acromegaly. A subset of patients respond only partially or not at all to the first-generation SSTRA, necessitating the use of additional pharmacological agents or other modes of therapy. Pasireotide is a “second-generation” SSTRA that has multi-receptor activity. Prospective studies have shown promise in the use of pasireotide in patients with poor response to first-generation SSTRA. Here we elucidate the molecular pathways of resistance to first-generation SSTRA, the mechanism of action, pre-clinical and clinical evidence of the use of pasireotide in patients having incomplete / lack of response to first-generation SSTRA. We also discuss the clinical, pathological, and radiological markers predicting response to pasireotide, and the difference in side-effect profiles of pasireotide, compared to first-generation SSTRA.

Section snippetsINTRODUCTION

The management of acromegaly has significantly changed over the decades. In the early 20th century, surgical and radiation therapy were the only available treatment avenues. Dopamine agonists were the earliest pharmacological therapies available for acromegaly and offered modest benefits. [1]

In the 1970s, Yen et al. demonstrated the efficacy of intravenous somatostatin (SST) in the reduction of growth hormone (GH) secretion in patients with acromegaly. [2] SST acts on somatostatin receptors

PASIREOTIDE: PRE-CLINICAL / CLINICAL EVIDENCE

Cell culture studies have produced varying outcomes regarding the effectiveness of pasireotide. Bruns et al. compared the use of pasireotide and octreotide in a rat anterior pituitary cell model, revealing a fourfold greater GH suppression with pasireotide. [38] In-vivo comparison in rat models in the same study showed greater 6-hour GH suppression and greater IGF-1 lowering after 126 days of treatment with pasireotide compared to octreotide. Conversely, Murray et al. found no difference in GH

COMPARATIVE EFFICACY OF PASIREOTIDE

Given the encouraging results in pre-clinical models, human studies were pursued to assess the role of pasireotide in acromegaly.

In a cohort of 12 patients, a single dose of pasireotide had similar efficacy compared to a single dose of octreotide in acutely lowering GH and IGF-1 levels in 8 patients, with 3 patients having a significantly better response with pasireotide compared to octreotide and 1 patient having a better response to octreotide. [43]

Petersenn et al. performed a phase 2

SIDE EFFECTS OF PASIREOTIDE

Many of the side effects of pasireotide are similar to first-generation SSTRAs; the most frequent include diarrhea, nausea, abdominal discomfort, and cholelithiasis. However, the rates of worsening hyperglycemia and incidence of new-onset diabetes are much higher in pasireotide-treated patients compared to octreotide and lanreotide. All of the phase 2 and phase 3 trials have demonstrated this finding. More importantly, the phase 3 trials excluded patients with uncontrolled hyperglycemia (A1C >

TREATMENT OF PASIREOTIDE-INDUCED HYPERGLYCEMIA

Baseline glycemic testing, close self-monitoring using point-of-care glucose monitoring, and regular outpatient monitoring for the first 3-6 months after initiation of pasireotide are essential to help in early diagnosis, potential dose adjustment of pasireotide, and treatment of hyperglycemia.

Various strategies have been tried for the treatment of pasireotide-induced hyperglycemia, with a primary focus on agents that increase endogenous insulin release. Breitschaft et al. studied different

ROLE OF PASIREOTIDE IN ACROMEGALY MANAGEMENT

As per current guidelines, surgical therapy is the gold standard for the management of somatotropinomas when a cure is possible. Pharmacological therapy is indicated in cases of residual disease post-initial surgery without an indication of repeat surgery and in cases where surgery is unlikely to cure the disease, is contraindicated because of comorbidities, or is declined. Preoperative SSTRA therapy is sometimes used in cases of upper airway soft-tissue overgrowth causing potential intubation

CONCLUSIONS

In conclusion, pasireotide is an important tool in the management of acromegaly in patients who have shown poor / no response to first-generation SSTRA. Multiple clinical and histological parameters can be used to support the clinical decision of using pasireotide over first-generation SSTRA. Pasireotide can significantly worsen hyperglycemia to a higher degree than first-generation SSTRA and should be avoided in patients with uncontrolled hyperglycemia.

SUMMARY

Pasireotide is a potent multi-receptor SSTRA, noted to have a higher degree of response in patients resistant or partially responsive to first-generation SSTRA. T-2 MRI hyperintensity, sparsely-granulated histopathology of adenoma sample, lower SSTR-2: SSTR-5 receptor expression profile, and positive AIP mutational status are clinical markers that predict a superior response to pasireotide compared to first-generation SSTRA. Pasireotide causes a significantly higher degree of

PRACTICE POINTS•

Pasireotide is a 2nd generation multi-receptor SSTRA, with prominent SSTRA-5 activity, compared to first-generation SSTRA, which has a predominant SSTR-2 affinity and low SSTR-5 affinity

•

Pasireotide has shown increased efficacy in the subset of patients with partial response or resistance to first-generation SSTRA

•

Pasireotide causes higher rates of hyperglycemia-related adverse events compared to first-generation SSTRA and use has not been studied in patients with uncontrolled diabetes mellitus.

•RESEARCH AGENDA•

Better, more accurate predictors of response to first generation SSTRA and pasireotide are needed

•

Specific guidelines on management of pasireotide-induced hyperglycemia need to be established

•

More accurate data on the effect of pasireotide on tumor volume are needed

•

Data on the long-term side effects of pasireotide are needed

CONFLICT OF INTEREST /FUNDING SOURCE

Dr. Salvatori sat on the Advisory board for Novo Nordisk, Camurus, and Amryt

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