DPP-4 Inhibitors (Sitagliptin, Alogliptin, Saxagliptin, Vildagliptin) in Type 2 Diabetes Mellitus
Background on Diabetes
More than 23 million children and adults have diabetes mellitus in the United States, a number that equals nearly 8% of the population. Listed as the 7th leading cause of mortality in the United States, diabetes mellitus increases the risk of other life-threatening conditions such as heart disease or stroke by two-three times.
In general, Type 2 diabetes involves disturbances in the normal physiological processes leading to increased resistance to the hormone Insulin which is responsible for maintaining blood sugar levels. Increased resistance to the action of Insulin within cells, leads to hyperglycemia (meaning increased levels of sugar in the blood) and elevated sugar levels eventually lead to micro- and macrovascular complications if not aggressively managed.
Existing Type 2 Diabetes Medications
Even though several medications such as oral hypoglycemic drugs (example, Metformin) and artificial insulin (administered as injections) have been used to treat Diabetes, more than 50% of Americans have less than desirable control of their blood sugar. And as Type 2 Diabetes is a progressively worsening disease (the resistance to insulin deteriorates and so does the capacity of the beta-cells within the pancreas to synthesize insulin diminishes), achieving better glucose control becomes more challenging.
The Incretin Effect of GLP-1 and GIP.
More recently, the role of the incretin hormone response and its deficiency in patients with type 2 diabetes have been explored and targeted for new therapies with novel mechanisms of action. It has been known since the 1960s that the gastrointestinal system has a role in stimulating the secretion of insulin, a phenomenon known as the Incretin Effect. In fact it is estimated that upto 60% if the insulin secreted in response to eating a meal maybe due to the Incretin effect (which is mediated by the action of the K-cells in the duodenum – a loop in the small intestines and the entero-endocrine cells in the distul part of the intestines).
The Incretin effect is mediated by the action of two peptide molecules – glucose-dependent insulinotropic peptide (GIP), and glucagon-like peptide-1 (GLP-1). These two peptides act in several ways to signal greater Insulin secretion and also signal the appetite satiety centers in the brain to reduce glucose intake. However, both the GIP and the GLP-1 neurpeptides have a very short life because they are rapidly broken down by an enzyme called Dipeptidyl Peptidase (DPP) (peptidase are a class of enzymes that break down peptide molecules).
New Treatments. The Role of Dipeptidyl Peptidase-4 Inhibitors.
Because DPP breaks down the insulin secretion stimulating peptides, GLP-1 and GIP, delaying the breakdown by blocking the action of DPP, could theoretically improve glucose control. This is exactly the reasoning behind the DPP-4 inhibitor class of drugs. By blocking the enzymatic inactivation of the incretins, DPP-4 inhibitors make it possible for higher levels of active incretins to circulate and carry out their physiologic glucoregulatory functions.
The oral DPP-4 inhibitors Sitagliptin and Saxagliptin gained U.S. FDA approval in 2006 and 2009, respectively. Vildagliptin is approved for use in the European Union and countries in southeast Asia. New DPP-4 inhibitors, such as alogliptin, are being investigated across the united states. More details about the DPP-4 Inhibitors can be found in this excellent review.
Clinical Trials of DPP-4 Inhibitors
Several clinical trials are underway to either test the effectiveness of the existing DPP-4 inhibitors, comparing them to other treatments or in dose combinations. Clinical Trials are also in place to test the effectiveness of new DPP-4 inhibitors like Alogliptin. Here is a list of clinical trials
- Diabetes clinical Trial of Alogliptin in Columbus, Ohio
- Diabetes Clinical Trial of New Treatment to Control Blood Sugar and Reduce CVD Risk in Houston