Pituitary-independent effect of octreotide on IGF1 generation

112

Objective: In acromegaly, 25-50% of patients respond inadequately to conventional long-acting somatostatin analogue (SSA) therapy. Response may be improved by increasing SSA frequency or dose. This study evaluated the biochemical efficacy and safety of high-dose octreotide in patients with acromegaly. Design: A 24-week prospective, multicentre, randomised, open-label trial conducted from 12 December 2005 to 23 October 2007 in patients with persistently uncontrolled acromegaly despite R6 month conventional SSA therapy. Methods: Patients with R50% reduction in GH levels during previous SSA treatment were randomised to high-dose (60 mg/28 days) or high-frequency (30 mg/21 days) octreotide i.m. injection. Primary end-points were week 12 and 24 reduction in serum IGF1 and GH from baseline. Secondary end points included IGF1 normalisation and tumour shrinkage rates, and safety/tolerability evaluations. Results: Significantly, more patients (10 out of 11) achieved week 24 IGF1 reduction in the high-dose than the high-frequency group (8 out of 15; P!0.05). In the high-dose group only, week-24 IGF1 values were significantly reduced (PZ0.02) versus baseline. Normalisation of IGF1 occurred only with the high-dose regimen (4/11; PZ0.02). Out of 14 patients experiencing adverse events, 5 reported drug-related gastrointestinal effects. No dose-response relationship was seen. Safety parameters were similar between treatment groups, apart from a slight decrease in HbA1c in the high-dose group only. Conclusion: High-dose octreotide treatment is safe and effective (normalisation of IGF1 levels) in a subset of patients with active acromegaly inadequately controlled with long-term SSA. Individualised octreotide doses up to 60 mg/28 days may improve outcomes of SSA therapy.

Section: Discussionsupporting

confidence: 75%

High-dose intramuscular octreotide in patients with acromegaly inadequately controlled on conventional somatostatin analogue therapy: a randomised controlled trial

Giustina¹,

Bonadonna²,

Bugari³

et al. 2009

112

“…It is known that co-administration of octreotide reduces serum IGF1 levels in GH-substituted adult hypopituitary patients (28,29), which supports a pituitary-independent effect of somatostatin that is not restricted to patients with acromegaly. Moreover, the suppressive effect of somatostatin on insulin secretion (13) may result in reduced hepatic IGF1 production, and hence lower serum IGF1 levels, in as much as insulin stimulates hepatic GHR synthesis and activity (30).…”

Section: Discussionmentioning

confidence: 78%

Conventional and novel biomarkers of treatment outcome in patients with acromegaly: discordant results after somatostatin analog treatment compared with surgery

Rubeck

Madsen²,

Andreasen³

et al. 2010

Self Cite

Context: Control of disease activity in acromegaly is critical, but the biochemical definitions remain controversial. Objective: To compare traditional and novel biomarkers and health status in patients with acromegaly treated with either surgery alone or somatostatin analog (SA). Design and methods: Sixty-three patients in long-term remission based on normalized total IGF1 levels after surgery alone (nZ36) or SA (nZ27) were studied in a cross-sectional manner. The groups were comparable at diagnosis regarding demographic and biochemical variables. Each subject underwent 3 h of serum sampling including a 2-h oral glucose tolerance test (OGTT). Health status was measured by two questionnaires: EuroQoL and Acrostudy (Patient-assessed-Acromegaly symptom questionnaire (PASQ)). Results: Total and bioactive IGF1 (mg/l) levels were similar (total: 185G10 (SA) versus 171G8 (surgery) (PZ0.28); bioactive: 1.9G0.2 vs 1.9G0.1 (PZ0.70)). Suppression of total and free GH (mg/l) during OGTT was blunted in the SA group (total GH nadir : 0.59G0.08 (SA) versus 0.34G0.06 (surgery) (PZ0.01); free GH nadir : 0.43G0.06 vs 0.19G0.04 (P!0.01)). The insulin response to OGTT was delayed, and the 2-h glucose level was elevated during SA treatment (PZ0.02). Disease-specific health status was better in patients after surgery (PZ0.02). Conclusions: i) Despite similar and normalized IGF1 levels, SA treatment compared with surgery alone was associated with less suppressed GH levels and less symptom relief; ii) this discordance may be due to specific suppression of hepatic IGF1 production by SA; iii) we suggest that biochemical assessment during SA treatment should include both GH and IGF1.

“…A GH-independent suppressive effect of SMSA on serum IGF1 levels has been documented in two studies in humans (41,42). Both studies involved administration of octreotide for 7 days during continued GH treatment in adult GH deficiency (GHD) patients.…”

Section: How Somatostatin Analogs Workmentioning

confidence: 99%

“…Both studies involved administration of octreotide for 7 days during continued GH treatment in adult GH deficiency (GHD) patients. This resulted in a significant 16-18% reduction in serum IGF1 levels with a concomitant reduction in insulin levels and elevated levels of IGFBP1 (41,42).…”

Section: How Somatostatin Analogs Workmentioning

confidence: 99%

Hypothesis: Extra-hepatic acromegaly: a new paradigm?

Neggers

Kopchick

Jørgensen

et al. 2011

Medical treatment of acromegaly with long-acting somatostatin analogs (LA-SMSA) and the GH receptor antagonist, pegvisomant (PEGV), has made it possible to achieve normal serum IGF1 concentrations in a majority of patients with acromegaly. These two compounds, however, impact the GH-IGF1 axis differently, which challenges the traditional biochemical assessment of the therapeutic response. We postulate that LA-SMSA in certain patients normalizes serum IGF1 levels in the presence of elevated GH actions in extra-hepatic tissues. This may result in persistent disease activity for which we propose the term extra-hepatic acromegaly. PEGV, on the other hand, blocks systemic GH actions, which are not necessarily reliably reflected by serum IGF1 levels, and this treatment causes a further elevation of serum GH levels. Medical treatment is therefore difficult to monitor with the traditional biomarkers. Moreover, the different modes of actions of LA-SMSA and PEGV make it attractive to use the two drugs in combination. We believe that it is time to challenge the existing concepts of treatment and monitoring of patients with acromegaly.