Overview and Introduction
Alogliptin (NESINA), a dipeptidyl peptidase IV (DPP-4) inhibitor, was approved by the FDA on January 25, 2013 to improve blood sugar control in adults with type 2 diabetes. This drug had been submitted for FDA approval in 2007, but the agency requested further data, including cardiovascular outcomes. This agent is marketed alone (NESINA), or combined with metformin (KAZANO), or with pioglitazone (OSENI). Alogliptin has been studied as monotherapy in 8,500 individuals with diabetes in a total of fourteen phase III clinical trials, with metformin in 2,500 patients in four trials, and with piogliltazone in 1,500 subjects in four trials. This new agent, like the other DPP-4 inhibitors, has a mechanism of action that affects both pancreatic ß-cell survival as well as ß-cell secretory function. These medications do not incite hypoglycemia and are weight-neutral. While questions on safety, durability of glycemic control, and impact on immune function await longer-term trials, to date, this agent appears to have comparable efficacy and safety to that of other DPP-4 inhibitors.
Endocrine cells in the gastrointestinal tract release incretin hormones in response to stimulation by intraluminal glucose. An oral glucose load produces a greater insulin response than that of an isoglycemic infusion of intravenous glucose, due to the two main incretins: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). This effect, known as the incretin effect, is attenuated in those with type 2 diabetes. In individuals with type 2 diabetes the effect of GLP-1 is largely retained, while that of GIP is markedly decreased. Thus, GLP-1 has garnered interest as a potential therapeutic target. GLP-1 enhances postprandial insulin release from the pancreas in a glucose-dependent fashion, slows gastric emptying, suppresses glucagon production, reduces appetite, and may promote ß-cell preservation in individuals with type 2 diabetes. As the t1/2 of GLP-1 is <2 minutes, it is not useful clinically. This hormone, however, is rapidly degraded by dipeptidyl peptidase IV (DPP-4). Thus, DPP-4 inhibitors, such as alogliptin, act to increase the concentration of GLP-1 by preventing its inactivation. Aloglipitin was the first DPP-4 inhibitor submitted for FDA approval in December 2007. However, its approval was delayed because in 2008, the FDA issued new, more stringent guidelines regarding cardiovascular safety concerns for diabetes drugs. Thus, alogliptin's NDA was held up, and three other DPP-4 inhibitors (sitagliptin (JANUVIA), saxagliptin (ONGLYZA), and linagliptin (TRADJENTA)) were approved sooner.
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