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A Review of the ‘Gliptin’ Diabetes Drugs

Worst Pills, Best Pills Newsletter article March, 2012

Sitagliptin (JANUVIA), saxagliptin (ONGLYZA) and linagliptin (TRADJENTA) belong to the drug family called dipeptidyl peptidase-4 (DPP-4) inhibitors, or “gliptins.”

The Food and Drug Administration (FDA) has approved this family of drugs — the newest of 11 drug classes — for use with diet and exercise to manage blood sugar levels in patients with type 2 diabetes. Table 1 lists FDA-approved gliptins and gliptin combinations with other type 2 diabetes drugs. (See Table 2 for a list of other...

Sitagliptin (JANUVIA), saxagliptin (ONGLYZA) and linagliptin (TRADJENTA) belong to the drug family called dipeptidyl peptidase-4 (DPP-4) inhibitors, or “gliptins.”

The Food and Drug Administration (FDA) has approved this family of drugs — the newest of 11 drug classes — for use with diet and exercise to manage blood sugar levels in patients with type 2 diabetes. Table 1 lists FDA-approved gliptins and gliptin combinations with other type 2 diabetes drugs. (See Table 2 for a list of other drugs approved in the U.S. to manage blood sugar levels.)

Table 1. Gliptins Currently Available in the U.S.*
Generic Name Brand Name
sitagliptin JANUVIA
sitagliptin with metformin JANUMET
sitagliptin with simvastatin JUVISYNC
saxagliptin ONGLYZA
saxagliptin with metformin KOMBIGLYZE XR
linagliptin TRADJENTA

* All categorized as “Do Not Use”

The enzyme DPP-4 breaks down many peptide hormones (including hormones that increase insulin release), ending their effects. When DPP-4 is inhibited, the hormones are not broken down, or at least not as quickly. They then remain active for much longer times, allowing for more insulin release.

Table 2. Drugs Approved in the U.S. for Managing Type 2 Diabetes
Family Generic Name (Brand Name)
Alpha-glycosidase inhibitors acarbose (PRECOSE)
miglitol (GLYSET)
Amylin analogs pramlintide (SYMLIN)
Biguanides metformin (GLUCOPHAGE)*
Dipeptidyl peptidase-4 (DPP-4) inhibitors (or “gliptins”) sitagliptin (JANUVIA)*
saxagliptin (ONGLYZA)*
linagliptin (TRADJENTA)*
Incretin mimetics or glucagon-like peptide-1 (GLP-1) receptor agonists exenatide (BYETTA)*
liraglutide (VICTOZA)*
Insulin and insulin analog injections many preparations
Meglitinides nateglinide (STARLIX)*
repaglinide (PRANDIN)*
Sulfonylureas (first and second generation) acetohexamide (DYMELOR)*
chlorpropamide (DIABINESE, INSULASE)*
tolazamide (TOLINASE)**
tolbutamide (ORINASE)**
glimepiride (AMARYL)**
glipizide (GLUCOTROL)**
Thiazolidinediones (or “glitazones”) pioglitazone (ACTOS)*
rosiglitazone (AVANDIA)*

* Do Not Use
** Limited Use

Current research on gliptins

The highly respected Cochrane Collaboration has reviewed the gliptins and found that these drugs have some theoretical advantages over existing oral drugs used for blood sugar control. However, long-term data, especially on cardiovascular risk as well as on other safety issues, are urgently needed before widespread use of these new agents. Also necessary are long-term data investigating gliptins and patient health-related quality of life, diabetic complications and mortality rates.

Public Citizen’s analysis of the therapeutic value of the gliptins begins with the following facts:

  • There have been no clinical studies establishing conclusive evidence that any diabetes drugs, including the gliptins, reduce the risk of heart attack and stroke, the major concerns of type 2 diabetes.
  • There is no legal or regulatory requirement that new drugs must be either safer or more effective than drugs already on the market. For example, in the past 40 years, Public Citizen has successfully petitioned the FDA for the removal of 23 new drugs from the market for safety reasons.
  • New families of drugs, such as the gliptins, work in different ways than older families, creating the possibility for — if not certainty of — new adverse drug reactions.


The first gliptin drug on the market, sitagliptin was approved by the FDA in October 2006. An update to the “Warnings and Precautions” section of sitagliptin’s product label states that there have been reports of acute pancreatitis (inflammation of the pancreas) that included cases of fatal and nonfatal hemorrhagic or necrotizing (tissue death) pancreatitis.

You should stop taking sitagliptin and call your physician immediately if you experience the following symptoms of pancreatitis:

  • Pain in the stomach area that is severe and will not go away
  • Pain felt from the abdomen through to the back
  • Pain occurring with or without regurgitation

We reviewed sitagliptin in the June 2007 Worst Pills, Best Pills News, and our original recommendation was not to use sitagliptin until 2013. We invoked our Seven Year Rule because new drugs are tested in a relatively small number of people before being released and serious side effects or life-threatening drug interactions may not be detected until the new drug has been taken by hundreds of thousands of people. Now, because of the increased evidence of harm, we list it as a “Do Not Use” drug.

The FDA medical director in charge of reviewing sitagliptin expressed concern about potential kidney toxicity with the drug. He recommended that kidney function be monitored for early signs of kidney toxicity. The FDA decided not to follow his advice, and as a result, in April 2011, the FDA had to amend the “Warnings and Precautions” section of sitagliptin’s product label to include a statement that the agency had received reports of acute kidney failure, sometimes requiring dialysis.

The “Warnings and Precautions” section of the sitagliptin product label also reveals reports of serious allergic and hypersensitivity reactions, among them Stevens-Johnson syndrome. These reactions include patches of swelling involving the skin and the mucous membranes and shedding of the skin.

These symptoms constitute a serious allergic reaction to sitagliptin:

  • Rash
  • Raised red patches on the skin (hives)
  • Swelling of the face, lips and throat that may cause difficulty breathing or swallowing

If you experience an allergic reaction while taking sitagliptin, stop the drug immediately and contact your physician. Other side effects include liver toxicity, low blood sugar, constipation, vomiting and headaches.

Sitagliptin alone and sitagliptin in combination with metformin are top-selling drugs. Together, they accounted for more than 8.2 million prescriptions in 2010. (See March 2012 Worst Pills, Best Pills News for a review of sitagliptin with simva-statin [JUVISYNC].)


Saxagliptin, the second gliptin on the market, has been available since 2009. In its product label, saxagliptin carries the same warnings as sitagliptin for acute pancreatitis and serious hypersensitivity reactions.

We have categorized it as a “Do Not Use” drug.


Linagliptin, the newest gliptin, was approved in May 2011. At this time, there are no serious safety warnings concerning the use of linagliptin, but this is usually the case with any new drug. New drugs are approved on the basis of relatively short-term trials monitoring a few hundred or few thousand patients and use a substitute result for the actual expected outcome (in this case, lowering the level of HbA1c). Safety concerns may not emerge until hundreds of thousands of patients are prescribed the drug.

Because there are serious safety concerns with the first two gliptins that are likely to be shared by linagliptin, and because none of these drugs, including linagliptin, have been shown to reduce the risk of heart attack and stroke, we conclude that linagliptin should also be listed as a “Do Not Use” drug.

Gliptin Medication Guides

The FDA has the authority to require that, with each new and refill prescription, pharmacists distribute risk information for drugs posing significant public health concerns. Called a Medication Guide, this type of FDA-approved information must be written specifically for patients. Medication Guides provide patients with the information needed to decide whether to start or continue taking a drug.

The Medication Guides for sitagliptin and saxagliptin can be obtained by asking a pharmacist or accessing them on the FDA’s website at www.fda.gov/Drugs/DrugSafety/ucm085729.htm.

At this time, the FDA does not require a Medication Guide for linagliptin, an omission that will hopefully be remedied.

Other gliptins

Vildagliptin (GALVUS) was denied approval in the U.S. because of questions of liver toxicity and reports that some patients developed serious allergic reactions and complications, including Stevens-Johnson syndrome. It was approved in Europe in February 2008.

Japan approved alogliptin (NESINA) in 2010. An application for approval in the U.S. was filed in December 2007. The FDA has asked for additional data, but at this time, alogliptin is not approved in the U.S.

Patients with type 2 diabetes do not need more options in the form of more drugs, such as the gliptins, to manage blood sugar levels. They need better drugs that will reduce their risk of heart attack and stroke. Only when the FDA raises the approval standard for type 2 diabetes drugs, requiring that they safely reduce risk of heart attack and stroke, will the public get better drugs.

What You Can Do

You should avoid taking any of the gliptins because there is no convincing evidence that they reduce heart attack and stroke and because they are associated with significant safety concerns.

Consumers may report serious adverse events with drugs or product quality problems to the FDA’s MedWatch Adverse Event Reporting program online or by regular mail, fax or phone.