Author(s): Travis E Sonnett [[dagger]â ] 1 , Jennifer D Robinson 1 , Kurt A Bowen 1
diabetes mellitus; DPP-4; exenatide; GLP-1; incretin; liraglutide; saxagliptin; sitagliptin; vildagliptin
It is estimated that 285 million people live with diabetes worldwide, a number that is projected to grow to 438 million by 2030  . Type 2 diabetes mellitus (T2DM) accounts for 90% of global diabetes prevalence  . Although once thought to be an adult disease, T2DM has been diagnosed in morbidly obese children and adolescents in recent years  . The economic impact of diabetes is profound; it is estimated that the world will spend US$376 billion on diabetes care in 2010  . Both prevention and the development of improved therapeutic interventions will be necessary to mitigate the effects of this quickly growing epidemic.
Obesity has been indicated as the most significant risk factor for T2DM, with up to 87% of diabetics being overweight or obese [2,3] . While T2DM reaches epidemic levels, obesity is also on the rise, with estimates indicating that 33.8% of the US population is obese (BMI ≥â¥ 30.0 kg/m2 )  . The correlation between obesity and T2DM indicates the strong need for weight loss-inducing interventions in the treatment of T2DM, as even modest weight loss can lead to improved glycemic control [5,6] . While lifestyle changes, such as a healthy diet and exercise, intuitively lead to weight loss, such interventions often fail due to a lack of patient compliance  .
Traditional antidiabetic agents do not address the role obesity plays in T2DM by inducing weight loss; in fact, sulfonylureas, thiazolidinediones (TZDs) and insulin are associated with weight gain  . Incretin therapies offer new hope in the treatment of T2DM. Such agents work by slowing enzymatic degradation of the gastrointestinal hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, or by mimicking endogenous GLP-1  . Furthermore, incretin therapy works in a glucose-dependent manner, which significantly reduces the occurrence of hypoglycemia [10,11] . The GLP-1 agonists exenatide and liraglutide are efficacious at lowering hemoglobin A1c (HbA1c ) and are associated with clinically significant weight loss [11,12] . The dipeptidyl peptidase-4 (DPP-4) inhibitors saxagliptin, sitagliptin and vildagliptin, also efficacious at lowering A1c , have not been associated with weight gain and, therefore, may serve as an alternative to oral antidiabetic agents that cause iatrogenic weight gain.
In addition to weight gain, sulfonylureas and insulin can cause hypoglycemic episodes, which not only carry significant morbidities but, if not immediately treated, can be fatal  . Although the risk of hypoglycemia is serious, due to the progressive nature of T2DM, sulfonylureas or insulin are often required to maintain glycemic control  . Incretin-based therapies have an improved safety profile when compared with these older antidiabetic agents in that they have not been associated with hypoglycemia  .
Current treatment guidelines
Owing to apparent benefits and an increased safety profile, incretin-based therapies have been included in current treatment algorithms. The American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) consensus algorithm, published in October 2009, encourages early use of a GLP-1 agonist or DPP-4 inhibitor and prioritizes their...