Diabetes Drugs: DPP-4 Inhibitors

Editor’s Note: This is the ninth post in our miniseries about diabetes drugs. Tune in on October 9 for the next installment.


dpp4inhibitorsDPP-4 inhibitors, a relatively new class of drugs for Type 2 diabetes, were introduced in 2006. Sitagliptin (brand name Januvia), the first medicine in this class, was approved for the treatment of Type 2 diabetes in October 2006; in July 2009, a second DPP-4 inhibitor, saxagliptin (Onglyza), was approved. These drugs are approved for use as additional therapy in people with Type 2 diabetes alone or in combination with metformin (brand name Glucophage and others), sulfonylureas (Diabinese, DiaBeta, Glynase, Micronase, Glucotrol, Glucotrol XL, Amaryl), and thiazolidinediones (Actos, Avandia).

This very recent addition of a new class of drugs might seem like the result of the latest research, but in fact, the science behind DPP-4 inhibitors goes back to research started in the early 1900’s. As I mentioned in my post on GLP-1 agonists, the hormone glucagon-like peptide-1, or GLP-1, has a profound effect on both stimulating the release of insulin from the pancreas and delaying stomach emptying. Unfortunately, it is active only for a very short time because it is broken down by an enzyme called dipeptidyl peptidase-4, or DPP-4. Blocking DPP-4 prolongs the effect of GLP-1, and hence enhances insulin secretion and the slowed emptying of the stomach.

It is known that people with Type 2 diabetes have impaired GLP-1 secretion and elevated DPP-4 activity, so blocking DPP-4 could directly address some of the issues in people with diabetes. Since DPP-4 inhibitors enhance the body’s own ability to release insulin, they can only be used in the treatment of Type 2 diabetes. Of note, researchers have found that after certain types of gastrointestinal surgery to treat obesity, GLP-1 levels increase and glucose control improves, suggesting that enhanced GLP-1 activity may be partially responsible for helping with blood glucose management in people who have had this surgery.

As the first DPP-4 inhibitor approved, there is more data available for sitagliptin than for saxagliptin. The recommended initial dose of sitagliptin is 100 milligrams once a day, but for people with kidney disease, lower doses are recommended. Research indicates that this medicine causes a reduction in HbA1c (an indicator of blood glucose control over the previous 2–3 months) of approximately 0.7%. (By comparison, metformin reduces HbA1c by roughly 1.1%.) In combination, a dose of 50 milligrams of sitagliptin and 1,000 milligrams of metformin produces an HbA1c reduction of roughly 1.9%.

A major study evaluated sitagliptin in people who had not achieved adequate blood glucose control with metformin alone. The study showed no real differences in HbA1c reductions produced by a combination of sitagliptin and metformin compared to a combination of glipizide (Glucotrol) and metformin. However, those on the sitagliptin treatment had a significantly lower incidence of hypoglycemia (low blood glucose) compared to those on the glipizide treatment. Additionally, there was an average weight loss of roughly three pounds among people taking sitagliptin, while people taking glipizide gained approximately two pounds, on average.

The recommended dose of saxagliptin is 2.5 milligrams or 5 milligrams; for people with moderate or severe kidney impairment, 2.5 milligrams is recommended. The removal of saxagliptin from the body can be slowed by the use of certain drugs such as the antifungal ketoconazole (Nizoral and others). For people taking these drugs, the dose of saxagliptin should be limited to 2.5 milligrams.

When used by itself, saxagliptin results in HbA1c reductions between 0.4% and 0.5%. When added to metformin, the HbA1c reductions are approximately 0.7%, with similar results being produced by the combination of saxagliptin and a thiazolidinedione (pioglitazone [Actos] or rosiglitazone [Avandia]) or glipizide.

Side effects seen with the use of sitagliptin include inflammation of the nasal passages and throat, upper respiratory tract infections, and headache. By itself, sitagliptin poses a low risk for causing low blood glucose; this risk is significantly increased when a sulfonylurea is taken in combination with sitagliptin. The U.S. Food and Drug Administration recently released information indicating that there may be a connection between sitagliptin and pancreatitis (a serious inflammation of the pancreas that usually requires hospitalization), based on reports of this condition occurring in 88 people using sitagliptin in the roughly three years since its approval.

Side effects of saxagliptin include upper respiratory tract infection, urinary tract infection, and headache, but not at rates much greater than those seen with placebo (inactive treatment). Although this medicine poses a low risk of hypoglycemia when used by itself, the risk is slightly increased when saxagliptin is used along with a sulfonylurea.

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  • Linda, the Pharmacist

    Is there a role for the DPP-4 inhibitors in patients already on insulin? I have patient using Lantus or Levemir who I think may benefit from adding sitagliptin, but there is not much in the literature. Increasing the insulin may produce lows – especially in working people trying to control their weight and eating light lunches. Adding Januvia 50 or 100mg a day seems like a better answer to me. What do you think?

  • Dr. L.K. Shankhdhar, M.D.

    To my mind these drugs are no better than the previous drugs, since their main action is Insulin secretogogue and glucagon suppression with them is minimal and just for name. Regarding beta cell neogenesis, all evidence is animal based and even if it does exist, it is not enough to reverse the glycemic status to IGT or NGT.

    Since there is no dearth of Insulin secretogogues and there are variety of Insulin available, these drugs are being used only because all physicians are always hoping for best with newer molecules. Their disproportionate cost too is unjustified.

  • Nancy Peeler, RN

    I am still learning in the diabetes field and am trying to understand the underlying “why’s” of medications. Can you explain what’s the physiological reason behind the side effects of UTI’s, upper respiratory and sinus effects, and the headaches? How is that related to DPP4 inhibitors? Thank you.

  • Mark T Marino

    The role of DPP4 inhibitors in the slightly higher rate of infections seen in patients treated with them is not completely understood. We do know that DPP4 is on the surface of immune cells (T Cells and B Cells) and that inhibition of the DPP4 on these cells can diminish the immune response in laboratory animals. What this means for humans is not certain but the clinical data do demonstrate that DPP4 inhibition is associated with a slightly increased risk of certain infections.

    (Transplantation: 27 May 1997 – Volume 63 -Issue 10 – pp 1495-1500 Immunobiology (abstract) and Int J Clin Pract, November 2006, 60, 11, 1454–1470)

  • ashish

    I want to know the effects of dpp 4 inhibitors onliver functions.

  • Mark T. Marino

    There were no significant issues with liver function reported in the approvals of the DPP-4 inhibitors but an isolated report has been made (see http://www.theannals.com/cgi/reprint/44/2/394). Often it is only after a drug has been on the market, in a larger number of patients, that these reports surface.


    I am curious with all the DPP-4 inhibitors that can essentially accomplish everything that the GLP 1 agonists can do, with the added benefit that it can be dosed PO rather than injected 2x/day, why are GLP-1 agonists so highly pursued? What would be the benefits of the GLP-1 agonists/analogues over the DPP-4 inhibitors.


  • Mark T. Marino

    DPP-4 inhibitors decrease the body’s ability to degrade GLP-1 and thus increase GLP-1 blood levels, resulting in an increase of insulin secretion, as well as other effects associated with GLP-1. The result is a 2–3 fold increase of GLP-1. This effect is enough to reduce postprandial glucose excursions and, over a longer treatment period, reduce HbA1c by ~0.7%.

    The GLP-1 agonists directly interact with the GLP-1 receptor, in essence supplementing the effect of the body’s own GLP-1. In addition to enhancing the secretion of insulin, these drugs also effect gastric motility and appetite. The result is a reduction in postprandial glucose, reductions in HbA1c of ~0.9%, and reductions in body weight of ~2.9 kg.

    The GLP-1 agonists now approved for clinical use can be given once a day.

  • Carol G.

    My understanding is that DPP-4 could interfere with the ability of the body to suppress cancer cells. This would certainly seem to be the “downside” of this medication. Your comments on this would be appreciated.

  • Raghav

    There are few DPP4 inhibitors on market. is any one better than other? Either in efficacy or in side effect profile. Is there an article where some comparisions are made head to head on these DPP4 inhibitor.

  • Dr.Irappa Madabhavi

    What is the Effect of dpp_4 inhibitors on the hypothalamic appetite centre?.How safely can we use these drugs in CKD patients?