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Advances in therapy for type 2 diabetes: GLP–1 receptor agonists and DPP–4 inhibitors

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ABSTRACT

Type 2 diabetes mellitus (T2DM) is intrinsically connected to overweight and obesity. It is a complex metabolic disorder that predisposes patients to, and is associated with, cardiovascular disease. In addition to the triumvirate of core defects associated with T2DM (involvement of the pancreatic beta cell, the muscle, and the liver), other mechanisms including hyperglucagonemia, accelerated gastric emptying, and incretin deficiency/resistance are also involved. This has led to the development of incretin-based therapies, such as glucagon-like peptide–1 (GLP-1) receptor agonists and dipeptidyl peptidase–4 (DPP-4) inhibitors. These newer therapies have beneficial effects on glycosylated hemoglobin A1c (HbA1c) levels, weight, and pancreatic beta-cell function.

KEY POINTS

  • Hormonal deficiencies in T2DM are related to abnormalities in the secretion of amylin, glucagon, and incretin hormones.
  • In clinical trials, GLP-1 receptor agonists reduced HbA1c levels, had beneficial effects on weight, and caused less hypoglycemia than insulin analogues.
  • Both GLP-1 receptor agonists and DPP-4 inhibitors improve pancreatic beta-cell function.
  • Incretin-based therapies have been incorporated into recently updated clinical guidelines for treatment of T2DM.


 

References

The prevalence of type 2 diabetes mellitus (T2DM) is increasing exponentially worldwide. According to the Centers for Disease Control and Prevention, more than 23 million Americans had diabetes in 2007. 1 Globally, the prevalence of diabetes, of which T2DM accounts for 90% to 95% of cases, 1 is expected to increase from 171 million in 2000 to 366 million in 2030. 2 The National Health and Nutrition Examination Survey (NHANES) showed that about 66% of Americans were overweight or obese between 2003–2004. 3 Data from a Swedish National Diabetes Register study showed both overweight and obesity as independent risk factors for cardiovascular disease (CVD) in patients with T2DM. 4

This article presents an overview of the evolving concepts of the pathophysiology of T2DM, with a focus on two new therapeutic classes: the glucagon-like peptide–1 (GLP-1) receptor agonists and the dipeptidyl peptidase–4 (DPP-4) inhibitors.

THE PATHOPHYSIOLOGY OF T2DM

The American Association of Clinical Endocrinologists (AACE) describes T2DM as “a progressive, complex metabolic disorder characterized by coexisting defects of multiple organ sites including insulin resistance in muscle and adipose tissue, a progressive decline in pancreatic insulin secretion, unrestrained hepatic glucose production, and other hormonal deficiencies.” 5 Other defects include accelerated gastric emptying in patients with T2DM, especially those who are obese or who have the disease for a long duration. 6,7

Hormonal deficiencies in T2DM are related to abnormalities in the secretion of the beta-cell hormone amylin, the alpha-cell hormone glucagon, and the incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). 8,9 In addition to the triumvirate of core defects associated with T2DM (involvement of the pancreatic beta cell, muscle, and liver), other mechanisms of disease onset have been advanced, including accelerated lipolysis, hyperglucagonemia, and incretin deficiency/resistance. 9 Also, the rate of basal hepatic glucose production is markedly increased in patients with T2DM, which is closely correlated with elevations in fasting plasma glucagon concentration. 9

The incretin effect—the intestinal augmentation of secretion of insulin—attributed to GLP-1 and GIP is reduced in patients with T2DM. 10 The secretion of GIP may be normal or elevated in patients with T2DM while the secretion of GLP-1 is deficient; however, cellular responsiveness to GLP-1 is preserved while responsiveness to GIP is diminished. 11

Both endogenous and exogenous GLP-1 and GIP are degraded in vivo and in vitro by the enzyme DPP-4, 12
a ubiquitous, membrane-spanning, cell-surface aminopeptidase that preferentially cleaves peptides with a proline or alanine residue in the second amino-terminal position. DPP-4 is widely expressed (eg, in the liver, lungs, kidney, lymphocytes, epithelial cells, endothelial cells). The role of DPP-4 in the immune system stems from its exopeptidase activity and its interactions with various molecules, including cyto­kines and chemokines. 13

INCRETIN-BASED THERAPIES: GLP-1 RECEPTOR AGONISTS AND DPP-4 INHIBITORS

Exenatide is a GLP-1 receptor agonist that is resistant to DPP-4 degradation. Based on preclinical studies, exenatide, which shares a 53% amino acid sequence identity with human GLP-1, is approximately 5,500 times more potent than endogenous GLP-1 in glucose lowering. 14,15 Among the acute actions of exenatide is glucose-dependent insulinotropism, the end result of which may be a reduced risk of hypoglycemia. 16 This contrasts with insulin secretagogues (eg, sulfonylureas), which increase insulin secretion regardless of glucose concentrations.

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