Unattainable glycemic control is often a result of ongoing deterioration of beta-cell function.
Currently, 20.8 million Americans have diabetes; type 2 diabetes accounts for 90% to 95% of cases and another 90 million with prediabetes. This true epidemic is believed to result from both genetic and lifestyle factors causing a state of high insulin resistance.
Current treatments focus on reducing hyperglycemia and improving insulin sensitivity. These modalities are attractive in theory, as they appear to target the primary defects associated with type 2 diabetes. Even though we have a wide array of treatment options available, glycemic control declines over time.
According to the American Diabetes Association (ADA) guidelines state that metformin, along with lifestyle changes, should be considered first-line therapy in patients with type 2 diabetes. If diabetes remains uncontrolled with first-line therapy or if contraindications to metformin therapy exist, step 2 therapies, including insulin, sulfonylureas, or thiazolidinediones (TZDs), may be employed. The use of these traditional agents may be limited, however, because of several factors. Because of this, new avenues of treatment are required. One approach is to target the incretin mimetic hormones, a key area of previously unexplored pathophysiology. Incretin hormones are secreted by intestinal cells in response to a meal, provoking glucose-induced pancreatic insulin secretion.
Glucagon-like peptide-1 (GLP-1), an incretin hormone, has been the subject of intense research. When blood glucose levels are elevated, GLP-1 stimulates insulin secretion, decreases glucagon secretion, improves beta-cell function, and slows gastric emptying. GLP-1 production is reduced in patients with type 2 diabetes. Furthermore, once GLP-1 is produced, it is rapidly degraded by the dipeptidyl peptidase IV (DPP-4) enzyme, produced in the intestines. In an attempt to harness the beneficial effects of GLP-1, research has focused on inhibiting DPP-4.
DPP-4 is found throughout the body, however, the highest concentrations are found in the kidneys, intestines, and bone marrow. So by preventing the breakdown of the GLP-1 inhibitor, its action can be extended. In summary, DPP-4 inhibits the degradation of incretins such as GLP-1 by inhibiting the enzyme dipeptidyl peptidase IV (DPP-4). The incretin effect is prolonged, enhancing glycemic control through various mechanisms, primarily by stimulating insulin synthesis and secretion in a glucose-dependant manner and by reducing glucagon secretion.
DPP-4 Inhibitors offer some advantages over existing oral options for the management of type 2 diabetes such as a negligible risk of hypoglycemia compared with sulfonylureas and, in general, a weight-neutral profile. All of these agents, including alogliptin, have been evaluated as monotherapy and in combination with other antidiabetic agents.
Although all the DPP-4s share a common mechanism of action, there are some key differences within the class. Selectivity for DPP-4 differs among the agents, as it is greater than 10,000-fold for linagliptin and alogliptin, greater than 2,500-fold for sitaglitpin, and less than 100-fold for saxagliptin. The clinical significance of these differences is currently unclear.
There are pharmacokinetic differences among the DPP-4s as well. For example, linagliptin has a long terminal half-life (up to 184 h), whereas the terminal half-life of sitagliptin is between 10 hours and 12 hours. In addition, linagliptin is cleared primarily through nonrenal pathways, whereas 79% of an oral dose of sitagliptin is excreted unchanged in the urine. Metabolism of saxagliptin by cytochrome P450 3A4/5 yields an active metabolite, whereas none of the other DPP-4s metabolize to active components.
The efficacy and safety of alogliptin as monotherapy were evaluated in more than 14 trials involving some 8,500 patients. Across these trials, use of alogliptin was associated with a 0.4% to 0.6% reduction in glycosylated hemoglobin (A1C) levels after 6 months compared with placebo. The safety and efficacy of the alogliptin–metformin combination were demonstrated in four clinical trials involving more than 2,500 patients. Compared with alogliptin alone, the alogliptin–metformin combination reduced A1C levels by 1.1% after 6 months.