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DPP-4 Inhibitors

by Mark T. Marino, MD

DPP-4 is a protein that is found both circulating in the blood and attached to cell membranes. It breaks down several hormones, not just GLP-1, and helps transmit signals from outside cells to the inside. DPP-4 was originally identified as a protein on lymphocytes, a type of white blood cell in the immune system. It was later found on many different types of tissue, including the kidneys, lungs, liver, intestines, pancreas, blood vessels, and brain. The breakdown of GLP-1 occurs within several minutes of DPP-4 being released into the blood.
Several studies have shown that people with Type 2 diabetes tend to have impaired GLP-1 secretion as well as elevated DPP-4 activity. This combination results in substantially reduced insulin production. Researchers have found that after gastrointestinal surgery to treat obesity (such as gastric banding or gastric bypass), GLP-1 levels increase and glucose control improves, suggesting that enhanced GLP-1 activity may be one way that these surgeries help reverse Type 2 diabetes in many patients.

Since DPP-4 inhibitors only enhance the body’s own ability to release insulin and regulate blood glucose, these drugs can only treat Type 2 diabetes. Their effect is dependent on some function of the insulin-releasing beta cells in the pancreas, and people with Type 1 diabetes generally do not have a significant number of functioning pancreatic beta cells.

Results of clinical trials
Many compounds believed to inhibit the activity of DPP-4 have been tested in humans. The ones that have been developed the furthest for medical use are sitagliptin (Januvia), approved by the Food and Drug Administration (FDA) in 2006, saxagliptin (Onglyza), approved by the FDA in 2009, and vildagliptin (Galvus), whose approval has been delayed by the FDA pending further data on people with kidney disease. (Vildagliptin was approved in Europe in 2007.) Another drug in the same family, alogliptin, was recently tested in large, Phase III trials (the results of Phase III trials provide much of the information that the FDA requires to grant marketing approval).

Numerous studies have been carried out to evaluate the effects of DPP-4 inhibitors in people with diabetes. These studies have generally shown an increase in both GLP-1 and insulin, as well as a decrease in blood glucose and glucagon levels after meals with use of the drugs. Long-term DPP-4 inhibition has been shown to reduce HbA1c levels, as well (HbA1c is a measure of blood glucose control over the previous 2–3 months). Since only sitagliptin is currently available in the United States, studies of it are probably the most widely relevant.

Sitagliptin was tested as a stand-alone treatment in five large studies whose size ranged from 151 to 743 participants. In the largest study, subjects had an average starting HbA1c level of 7.9%. The participants were divided into six groups, with one group receiving a placebo (inactive pill), four groups receiving different doses of sitagliptin, and one group receiving glipizide, a diabetes drug that stimulates the pancreas to release more insulin. All groups were treated for 12 weeks. When compared with the placebo group, all of the drug-treated groups had a reduction in average HbA1c level. The group that took 50 mg of sitagliptin experienced an average drop of 0.77%, and the glipizide group saw a drop of 1.0%. (A 1% drop in HbA1c level has been found to reduce microvascular complications, like diabetic eye and kidney disease, by 35% and is believed to reduce the risk of heart disease and overall death, as well.) While the glipizide group had a greater average reduction in HbA1c level, that group also had a much higher rate of low blood glucose, or hypoglycemia, (17%) than groups that took sitagliptin (4%) and experienced greater average weight gain (2.4 pounds versus no change in weight).

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