Body Composition Changes With Long-Term Pegvisomant Therapy of Acromegaly

Adriana P. Kuker; Wei Shen; Zhezhen Jin; Simran Singh; Jun Chen; Jeffrey N. Bruce; Pamela U. Freda

Disclosures

J Endo Soc. 2021;5(3) 

In This Article

Abstract and Introduction

Abstract

Context: In active acromegaly, the lipolytic and insulin antagonistic effects of growth hormone (GH) excess alter adipose tissue (AT) deposition, reduce body fat, and increase insulin resistance. This pattern reverses with surgical therapy. Pegvisomant treats acromegaly by blocking GH receptor (GHR) signal transduction and lowering insulin-like growth factor 1 (IGF-1) levels. The long-term effects of GHR antagonist treatment of acromegaly on body composition have not been studied.

Methods: We prospectively studied 21 patients with active acromegaly who were starting pegvisomant. Body composition was examined by whole body magnetic resonance imaging, proton magnetic resonance spectroscopy of liver and muscle and dual-energy x-ray absorptiometry, and endocrine and metabolic markers were measured before and serially during 1.0 to 13.4 years of pegvisomant therapy. The data of patients with acromegaly were compared with predicted and to matched controls.

Results: Mass of visceral AT (VAT) increased to a peak of 187% (1.56–229%) (P < .001) and subcutaneous AT (SAT) to 109% (–17% to 57%) (P = .04) of baseline. These remained persistently and stably increased, but did not differ from predicted during long-term pegvisomant therapy. Intrahepatic lipid rose from 1.75% to 3.04 % (P = .04). Although lean tissue mass decreased significantly, skeletal muscle (SM) did not change. IGF-1 levels normalized, and homeostasis model assessment insulin resistance and HbA1C were lowered.

Conclusion: Long-term pegvisomant therapy is accompanied by increases in VAT and SAT mass that do not differ from predicted, stable SM mass and improvements in glucose metabolism. Long-term pegvisomant therapy does not produce a GH deficiency-like pattern of body composition change.

Introduction

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) are important regulators of body composition and metabolism,[1,2] but in acromegaly both are abnormal due to GH and IGF-1 excess. In particular, the lipolytic, anabolic, and sodium and water retaining effects of GH excess underlie key features of the acromegaly phenotype.[3,4] We and others have shown that fat mass, especially that of visceral adipose tissue (VAT) and intrahepatic lipid (IHL) are reduced in active acromegaly and rise with surgical therapy.[5–10] Interestingly, active acromegaly presents a unique constellation, an acromegaly-specific lipodystrophy, characterized by lower adiposity with insulin resistance (IR) and, after surgical treatment, of increased adiposity yet a lowering of IR.

Pegvisomant, a GH receptor (GHR) antagonist, treats acromegaly by blocking GH action in peripheral tissues and the liver,[11,12] thus lowering IGF-1 levels. Normalization of circulating IGF-1 levels with pegvisomant therapy is associated with improvements in the clinical and metabolic abnormalities of acromegaly.[13–15] However, since pegvisomant is a potent antagonist at all GH receptors, it could be questioned whether, if in sufficient doses, some degree of functional GH deficiency could be manifest in tissues with its long-term use that is not reflected in serum IGF-1 levels. Since GH deficiency is associated with increased central adiposity, IR, and reduced muscle mass,[16,17] an investigation of the long-term effects of pegvisomant on body composition was warranted to determine if this normalizes. Prior small, short-term studies showed a rise in abdominal fat with pegvisomant therapy[18] and a rise in hepatic lipid with this added to a somatostatin analog,[19] but the long-term effects of GHR antagonism on adipose tissue (AT) mass, skeletal muscle (SM) mass, or the effects of pegvisomant alone on hepatic or muscle lipid have not been reported. Therefore, we investigated, for the first time, the long-term effects of pegvisomant treatment of acromegaly on AT mass and distribution as assessed by both total body magnetic resonance imaging (MRI) and dual-energy x-ray absorptiometry (DXA), and ectopic lipid deposition in liver and muscle by proton magnetic resonance spectroscopy (1HMRS). We also aimed to determine how changes in metabolic abnormalities and GH and IGF-1 levels relate to body composition changes with long-term pegvisomant therapy.

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