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DPP-4 Inhibitors
A Novel Class of Drugs for Type 2 Diabetes

by Mark T. Marino, MD

In 2006, a new class of medicine for Type 2 diabetes was introduced to the U.S. market. Called DPP-4 inhibitors, these drugs work in a way that is different from any previous diabetes treatment. Sitagliptin (brand name Januvia) was the first drug in this class to be approved; it can be used alone or in combination with other oral diabetes drugs. Saxagliptin (Onglyza), another DPP-4 inhibitor, received approval in July 2009.

Research history
At the turn of the 20th century, several different researchers were examining the role of the intestines and the pancreas in diabetes. Research soon demonstrated, through experiments with animals and autopsies of people who had died of diabetes complications, that Type 1 diabetes was caused by a problem with the pancreas. After extracts of the pancreas were shown to treat diabetes, a research team at the University of Toronto (Frederick Banting and Charles Best) isolated insulin in 1921.

Further experiments went on to explore the relationship between the pancreas and the intestines. Some of these demonstrated that intestinal extracts could lower blood glucose by stimulating the pancreas to produce more insulin. Hormones from the intestines with this effect are called incretins. Significant research on incretins was not conducted again until the 1960’s, when researchers were faced with a puzzle: When people were given the same amount of glucose at different times by vein and by mouth, the amount of insulin produced was much greater when the glucose was given by mouth. The researchers concluded that the gastrointestinal tract was signaling the pancreas to produce insulin. The hunt was on for the exact chemicals involved in this process, and finally a hormone was isolated: gastric inhibitory polypeptide, or GIP. A second hormone called glucagon-like polypeptide 1, or GLP-1, was later isolated.

GLP-1 was found to have a profound effect on stimulating the release of insulin from the pancreas. It was also found to be active for a very short time in the blood. This is because it is broken down quickly by an enzyme called dipeptidyl peptidase 4, or DPP-4. A drug that could inhibit the action of DPP-4 would extend the insulin-releasing effect of GLP-1.

Function in the body
Drugs that inhibit the action of DPP-4 are intervening in a complex set of reactions that occur when food is eaten. In response to meals, specialized cells in the intestines called L cells secrete GLP-1. L cells are mainly found in the ileum, the last segment of the small intestine, and in the large intestine (also known as the colon). GLP-1 appears to be secreted, however, before food from a meal reaches these areas of the intestines. The L cells have receptors for a variety of hormones secreted by the digestive system, which helps them determine the type of nutrients that have been consumed and control the amount of GLP-1 they release. It is thought that hormonal signals from the upper intestine, as well as a chemical released by nerves in response to eating, stimulate the release of GLP-1.

GLP-1 has several effects in the body other than stimulating the release of insulin. It also slows stomach emptying, inhibits the release of glucagon (glucagon is a hormone that signals the liver to release glucose and is usually elevated in people with Type 2 diabetes), and enhances the survival and growth of pancreatic beta cells, which secrete insulin. It has been found in laboratory studies that animals treated with DPP-4 inhibitors seem to have an increased number of pancreatic beta cells, indicating that these drugs may stimulate beta-cell growth (most likely through the action of GLP-1). This effect has not yet been demonstrated in humans, but if confirmed, it means that DPP-4 inhibitors could play a significant role in delaying and possibly reversing the progression of Type 2 diabetes.

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).

In another 12-week study, participants with an average starting HbA1c level of 7.8% were divided into four sitagliptin groups with different dose sizes and a placebo group. The group that received 100 mg once daily had the greatest average reduction in HbA1c level, 0.56%.

The three other studies tested daily doses of either 100 mg or 200 mg of sitagliptin over a period of 12–24 weeks. These studies showed average reductions in HbA1c level of 0.60% to 1.05%. Sitagliptin used alone to treat Type 2 diabetes generally lowered HbA1c levels 0.77% more than a placebo did.

Sitagliptin was also tested in combination with other drugs in four major trials. Three of the trials used sitagliptin combined with one other drug. These include studies that compared sitagliptin plus pioglitazone (Actos) with pioglitazone alone, and ones that compared sitagliptin plus metformin with both metformin alone and glipizide plus metformin. The studies ranged in length from 24 to 52 weeks. When sitagliptin was combined with metformin and with pioglitazone, the average HbA1c level of participants decreased by 0.65% and 0.70% more, respectively, than in those who took metformin alone and pioglitazone alone. When sitagliptin plus metformin was compared with glipizide plus metformin, there was no significant difference in reduction of HbA1c levels; both groups experienced an average drop of 0.67% (from an average starting HbA1c level of 7.5%).

Sitagliptin was also tested in combination with both glimepiride and metformin. (Like glipizide, glimepiride stimulates the pancreas to release more insulin.) In this study, participants were divided into four treatment groups, receiving either glimepiride only, sitagliptin and glimepiride, metformin and glimepiride, or sitagliptin, metformin, and glimepiride. Compared with glimepiride alone, the addition of sitagliptin reduced the average HbA1c level by 0.6% more, and compared with metformin plus glimepiride, the addition of sitagliptin caused a drop of 0.9% more.

Based on all of the studies mentioned, the recommended dose of sitagliptin is 100 mg taken once daily, either alone or in combination with metformin, a sulfonylurea drug such as glipizide or glimepiride, or a thiazolidinedione such as pioglitazone. It should be noted that these recommendations were created prior to the new warnings that thiazolidinediones may lead to an increased rate of heart problems, notably congestive heart failure. Sitagliptin is also available in a combination pill with metformin (Janumet) in two dose sizes.

Pros and cons
As the studies that were just described show, sitagliptin tends to lower HbA1c levels about as much as glipizide (and in some cases, not quite as much). It is not automatically clear, then, how sitagliptin should fit into diabetes treatment. The American Diabetes Association has not said in a definitive way how DPP-4 inhibitors should be used; it simply states that they may play a role in diabetes care. This is due to the relatively few studies done on sitagliptin compared with the wealth of information available for other drugs, as well as the newness of the data on sitagliptin.

Yet sitagliptin does have potential advantages over other drugs, as well as known disadvantages and side effects. One disadvantage is that compared with placebo, sitagliptin causes a small weight gain (about 1 pound on average). used in combination with metformin, however, it is associated with a loss of 5.5 pounds on average, compared with a gain of 2 pounds from the combination of metformin and glipizide.

Since sitagliptin is metabolized, or broken down, primarily by the kidneys and only metabolized by the liver to a small extent, the potential for it to interact with other drugs is relatively low; this finding has been confirmed in studies that have directly tested drug interactions in humans. However, this also means that the dose size of sitagliptin may need to be reduced for people in the later stages of kidney disease.

Sitagliptin results in a low incidence of hypoglycemia, comparable to that of placebo, when tested as a stand-alone therapy. It is associated with a somewhat higher rate of hypoglycemia when used in combination with other drugs, especially with a sulfonylurea such as glipizide or glimepiride.

As mentioned earlier, DPP-4 was discovered through its association with the immune system, and some researchers thought that inhibiting it might impair the immune system. So far, data from clinical studies have not demonstrated a serious immunosuppresive effect. They do indicate, though, that sitagliptin increases the risk of upper respiratory infections and nasopharyngitis (inflammation of the nose and pharynx), found in 6.3% and 5.2% of study subjects, respectively, who took sitagliptin versus 3.3% and 3.4% for placebo.

The most worrying side effects are those reported since the drug came onto the market. These reactions seem to be allergic in nature and include anaphylaxis, a bodywide reaction that results in low blood pressure, and angioedema, a swelling of the tongue, face, and throat. Both of these may be life-threatening. The reactions have occurred anytime from immediately after taking the first dose until three months after starting the drug. There have also been reports of skin reactions, including a very severe type of drug reaction called Stevens–Johnson syndrome. Other diabetes drugs are not typically associated with Stevens–Johnson syndrome.

One more choice
DPP-4 inhibitors may be a useful addition to the treatment options for Type 2 diabetes. While the current DPP-4 inhibitors do not seem to have major, clearcut advantages over other therapies, they may be a reasonable alternative for people who cannot take certain other drugs. They may also be used with metformin when blood glucose control is not ideal. Whether these drugs could be used to preserve or improve pancreatic beta-cell function, as well, will be determined through further clinical trials. As options for treating Type 2 diabetes expand, new drugs, including DPP-4 inhibitors, help make it possible for more people to follow an effective, individualized plan for their diabetes.

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