Efficacy of 12-month treatment with the GH receptor antagonist pegvisomant in patients with acromegaly resistant to long-term, high-dose somatostatin analog treatment: effect on IGF-I levels, tumor mass, hypertension and glucose tolerance

Abstract

Objective: We aimed to investigate the efficacy of pegvisomant in patients with acromegaly resistant to long-term (^24-month), high-dose treatment with octreotide-LAR (40 mg/month) or lanreotide (120 mg/month). Design:This was an open, prospective study. Subjects and Methods: We studied 16 patients with acromegaly (nine women; aged 28 -61 years). The main outcome measures were IGF-I levels, blood pressure, glucose tolerance and safety (liver function and tumor size). Pegvisomant was given at doses of 10-40 mg s.c. daily. Dose titration was performed every month by IGF-I assay. Results: Three patients spontaneously stopped pegvisomant treatment after 6-9 months because of poor compliance; from the measurement of serum pegvisomant, another patient was found not to inject herself properly. After 6 months, IGF-I levels decreased by 63^19% (767.8^152.9 vs 299.8^162.9 mg/l, P , 0.0001, t-test); serum IGF-I levels normalized in 57%. After 12 months, IGF-I levels normalized in nine (75%) patients and were reduced by over 50% in another three (25%). The mean tumor volume remained stable during the study (1198^1234 vs 1196^1351 mm 3 , P ¼ 0.37): it did not change (^25% vs basal) in nine patients, increased by 39.4% and 40.8% in two and decreased by 30.8 -46.5% in four. The total/high-density lipoprotein (HDL):cholesterol ratio (from 4.4^1.0 to 3.7^0.6, P¼0.0012), glucose levels (from 5.6^1.2 to 4.4^1.4 mmol/l, P ¼ 0.026), insulin levels (from 12.4^6.7 to 8.1^3.0 mUl/l, P ¼ 0.0023) and homeostasis model assessment (HOMA) index (from 3.4^2.1 to 1.9^1.0, P ¼ 0.0017) decreased. Conclusions: Treatment for 12 months with pegvisomant normalized IGF-I levels, and improved cardiovascular risk parameters and insulin sensitivity in patients with acromegaly resistant to long-term, high-dose treatment with somatostatin analogs. The tolerance of treatment was good.

Experience with pegvisomant treatment in acromegaly in a single Brazilian tertiary reference center: efficacy, safety and predictors of response

“…Pegvisomant is highly effective in normalizing IGF-I levels, even in patients resistant to other treatments (30), and this was confirmed in our series with a high percentage (85%) of disease control. Our results are closer to the data reported in the initial clinical trials with pegvisomant monotherapy and those from series of other tertiary centers than to the data reported in the last update of the Acrostudy (20)(21)(22)31,32).…”

“…Acromegaly is associated with enhanced mortality and a high morbidity when normalization of GH and IGF-I levels is not achieved (2). Although surgery and tumor-directed drugs (SA and DA) permit disease control in the majority of patients, there are some cases that require additional treatments (4,30). In our series, the majority of patients (78%) were submitted to surgery, and all but one patient was treated with first-generation SA, with association with cabergoline tried in 78%.…”

The German ACROSTUDY: past and present

“…All progressions were relatively minor size increases that could not be recognized clinically. Other reports of tumor size increase (5,13,15,(18)(19)(20) did not pay tribute to potential tumor size increase before pegvisomant therapy and also did not evaluate for potential somatostatin induced tumor shrinkage and subsequent rebound, although in an individual patient such a course is described (13). In this cohort and in the medical literature, except for one patient, whose tumor progression occurred during combination therapy with pegvisomant and somatostatin analogs (19), all hitherto reported tumor size increases were observed during monotherapy with pegvisomant (20).…”

“…The pivotal studies had demonstrated its safety and efficacy (4,5). However, while in the clinical studies up to 97% of patients treated with this drug achieved normal IGF1 levels (4,5,13), the GPOS found much lower normalization rates (7,8) reaching a maximum of 71.3% at 24 months. It reflects the reality of patient care in difficultto-treat acromegaly.…”

60 YEARS OF NEUROENDOCRINOLOGY: Acromegaly

“…In contrast to SSA, PEG decreases fasting plasma glucose (Urbani et al 2013) and improves glucose tolerance (Colao et al 2006) and insulin sensitivity (Schreiber et al 2007). Switching from SSA to PEG significantly improves diabetes control in diabetic ACM cases .…”