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.
Exenatide received US Food and Drug Administration (FDA) approval in 2005 and is indicated for the treatment of patients with T2DM.13,17 Exenatide is administered BID as a subcutaneous (SC) injection in doses of 5 or 10 μg within 1 hour before the two major meals of the day, which should be eaten about 6 hours apart.18
Approved in 2006, sitagliptin was the first DPP-4 inhibitor indicated for adjunctive therapy to lifestyle modifications for the treatment of patients with T2DM.17 The recommended dosage of oral sitagliptin is 100 mg QD. A single-tablet formulation of the combination of sitagliptin and metformin was approved by the FDA in 2007.19 Another DPP-4 inhibitor, saxagliptin, was approved in July 2009 for treatment of patients with T2DM either as monotherapy or in combination with metformin, sulfonylurea, or a thiazolidinedione (TZD).20 The DPP-4 inhibitor vildagliptin is approved in the European Union and Latin America but not in the United States. Vildagliptin is available as a 50- or 100-mg daily dosage; it has been recommended for use at 50 mg QD in combination with a sulfonylurea or at 50 mg BID with either metformin or a TZD.18
GLP-1 RECEPTOR AGONISTS AND DPP-4 INHIBITORS IN DEVELOPMENT
Exenatide is currently being evaluated as a once-weekly formulation.21,22 Compared with the BID formulation, exenatide once weekly has been shown to produce significantly greater improvements in glycemic control, with similar reductions in body weight and no increased risk of hypoglycemia.21
Also undergoing regulatory review is the partly DPP-4–resistant acylated GLP-1 receptor agonist liraglutide.13 Liraglutide, a human analogue GLP-1 receptor agonist, has 97% linear amino acid sequence homology to human GLP-1.23,24 Based on its prolonged degradation time and resulting 10- to 14-hour half-life, liraglutide is anticipated to be dosed once daily.13,25,26
Other GLP-1 receptor agonists and DPP-4 inhibitors are in varying stages of development.27 Albiglutide is a long-acting GLP-1 receptor agonist that is generated by the genetic fusion of a DPP-4–resistant GLP-1 to human albumin. Based on pharmacokinetic studies, albiglutide has a half-life of 6 to 8 days. AVE0010, an exendin-4-based GLP-1 receptor agonist, was shown in a 28-day T2DM clinical trial to have an affinity four times greater than native GLP-1 for the human GLP-1 receptor.27 Taspoglutide (R1583), a human analogue GLP-1 receptor agonist, was evaluated in three randomized, placebo-controlled studies as a GLP-1 receptor agonist. Alogliptin, a DPP-4 inhibitor currently in development, has been shown to be safe and effective in studies as monotherapy and in combination with other antidiabetes agents.28–30