Insulin sensitivity (IS) is normal but intra-abdominal fat increases during therapy of acromegaly with pegvisomant (PT)

Objectives: A substantial number of acromegalic pts. do not meet criteria for remission despite multiple therapies. The recently introduced GH-receptor antagonist pegvisomant normalizes IGF-1 in 95% of the pts. However, PT may result in functional GH-deficiency (GHD), since a normal IGF-1 may mask GHD. The 95th percentile of the IGF-1 in pts. above middle age with GHD may be equal or above the median of the age-adjusted normal range. Thus, additional indicators of GHD may be valuable in monitoring PT. The aim of this study was to assess IS and intra-abdominal fat as an indicator of functional GHD.

Methods: 6 pts. (4 f) with insufficient response to octreotide therapy (OCT) were studied. Baseline (BL): all pts. were off OCT for at least 3 months. IS and glucose tolerance (GT) were diagnosed by homeostatic model assessment (HOMA) and hyperinsulinemic-euglycemic clamp, as well as an oral and intravenous glucose tolerance test, resp. Visceral (VF) and subcutaneous (SF) abdominal fat were assessed by CT. Follow-up: after 6 mo on PT and normalization of IGF-1.

Results: IGF-1 increased after discontinuation of OCT [(mean±SD, ng/ml) 394±142 and 574±140, p=0.04, during and after OCT, resp.], and was normalized by PT (187±52 ng/ml, p=0.02 vs. BL and p=0.04 vs. OCT). Fasting glucose was normal in 5 pats at all timepoints. One patient had diabetes mellitus. Impaired GT was diagnosed in 3/5 non-diabetic pts. during OCT, while GT was normal thereafter in 5/5 pts. Indices of IS were comparable at BL and during PT (HOMA: 2.94±1.29 to 2.68±1.49, p=0.9., M-value: 3.2±2.9 to 3.6±3.1, p=0.49). VF, SF (cm2) and the VF/SF ratio increased (VF/SF: 0.79±0.46 to 1.07±0.64, p=0.04).

Conclusion: PT reduced IGF-1 and improved GT and IS compared to OCT. GT and IS were unchanged by PT compared to BL. However, VF/SF increased significantly with PT and this might indicate functional GHD. Reduced lipolysis, mediated by GHD and independent of IGF-1, may be responsible for these changes. The long-term effect of this finding on cardiovascular risk needs further evaluation.