Drug treatment strategies for secondary diabetes in patients with acromegaly

ABSTRACT

Introduction

Acromegaly is a rare disease due to oversecretion of growth hormone (GH). Even though the disease is often portrayed by its most apparent clinical features, given the abundance of GH receptors throughout the body, it truly is a systemic disease leading to numerous complications and comorbidities. A distinct medical issue in the context of acromegaly is diabetes: It can be a complication as a consequence of GH excess and its mediators, but it can also result from treatment of acromegaly.

Areas covered

This review provides an overview of the effects of acromegaly pathophysiology on glucose homeostasis. Furthermore, it devotes an extensive section on the influence that acromegaly treatment has on glucose metabolism, including approved as well as currently investigated drugs. It also summarizes observations from the use of anti-diabetic medication in patients with acromegaly.

Expert opinion

Glucose imbalance is an important aspect of acromegaly comorbidity and deserves more attention. Even though numerous studies have investigated glucose homeostasis in acromegaly, there is still a clear need for more basic, translational, and also clinical research to advance the understanding of the underlying mechanisms and how to best address them.

KEYWORDS:

• Diabetes mellitus
• insulin resistance
• insulin secretion
• pancreatic islet cells
• somatostatin analogues
• pasireotide
• pegvisomant
• acromegaly
• pituitary

Article highlights

• Diabetes mellitus is a common comorbidity in acromegaly patients and its prevalence ranges from 15.8% to 37.6% in larger series. Acromegaly-related diabetes mellitus is distinct from ‘typical’ type 2 diabetes mellitus where GH levels are actually reduced due to increased somatostatin secretion.

• Growth hormone has a bimodal effect on carbohydrate metabolism: it stimulate beta-cell proliferation as well as insulin synthesis and secretion, but its predominant effect antagonizes insulin action and increases lipolysis. It therefore leads to increases in glucose as well as insulin resistance. IGF-I increases insulin sensitivity and glucose uptake. GH excess is the main driver of abnormal glucose homeostasis in acromegaly.

• Surgery leads to improvements of glycemia. However, this is mostly seen in patients with preserved beta-cell function. Somatostatin analogues have an unfavorable effect on insulin secretion, but indirectly may improve glucose tolerance by counteracting the deleterious effects of GH excess on glucose homeostasis. The net effect is therefore primarily determined by the improvements of biochemical activity of acromegaly. Therefore, regular glucose monitoring is recommended during SSA treatment, especially at the beginning. Hyperglycemia is a common finding in patients treated with second-generation somatostatin analogues.

• Cabergoline exerts a positive, but nominally mild effect on glucose tolerance. Pegvisomant is advantageous for glucose homeostasis in acromegaly.

• Further basic and translational as well as clinical research is needed to elucidate the exact mechanisms of hyperglycemia in acromegaly and how to best address this therapeutically.

Declaration of interest

S Stormann has received personal fees and grants from Novartis, Ipsen, and Pfizer Inc. J Schopohl has meanwhile received personal fees and grants from Novartis, Ipsen and Pfizer as well as grants from Chiasma and OPKO. He furthermore is a consultant for Ipsen and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.