Sam Grossman, BS Pharm, PharmD, CDE weighs in on the benefits, the mechanisms of action, and the pancreatic health risks associated with GLP-1 analogs and DPP-4 inhibitors.

By: John Parkinson, Clinical Content Coordinator, DiabetesCare.net

Incretin-based therapies include two classes of medications, GLP-1 analogs and DPP-4 inhibitors. Both are being used for pharmacological therapy for patients with type 2 diabetes. And while the medicines are FDA-approved, recent studies have indicated that specific drugs in both classes may be associated with a higher risk for acute pancreatitis or pancreatic cancer.

While the controversy and debate is warming up with incretin therapies, in the background, and related to the topic, is that rosiglitazone (Avandia) is again being discussed. This once very popular type 2 drug has seen its share of challenges.

Today’s debate on Avandia centers on whether the FDA should modify or remove measures that limit patient access to Avandia.  

In 2006, Avandia was the most highly prescribed type 2 diabetes drug on the market with sales reaching a peak of approximately $2.5 billion. After concerns about heart issues were raised, subsequent lawsuits were filed, and settlements were made between plaintiffs and the drug’s manufacturer, GlaxoSmithKline. And while the FDA did not take the drug off the U.S. market, its sales decreased rapidly. Yet, here we are several years later, and the FDA is looking at Avandia again.

So, will Avandia have a third act and begin to be prescribed again? A bigger question could be will the incretin-therapies receive the same fate as Avandia, going from well-received to fraught with doubts about their risks and ultimately having to deal with extensive lawsuits?   

While these questions remain, it’s important to focus on what is known at this time. To help decipher some of the literature and get a medical provider’s perspective we turn to Dr. Samuel Grossman.

Grossman (pictured right) is a doctor of clinical pharmacy and a diabetes educator at the Department of Veterans Affairs New York Harbor Health Care System. He also serves as the president and clinical coordinator of Diabetes Care On-The-Go Inc., a diabetes education center that serves the diabetes population of New York and New Jersey. In addition, Dr. Grossman serves as an Adjunct Associate Professor at Hunter-Bellevue School of Nursing of the City University of New York and a Clinical Assistant Professor of Pharmacy at Arnold & Marie Schwartz College of Pharmacy of Long Island University. He is also the Advocacy chair and a member of the New Jersey Community Leadership Board for the American Diabetes Association. Grossman is also a contributor to DiabetesCare.net’s Ask the Professionals Column.

DiabetesCare.net sat down with Grossman to talk about the benefits of the two classes of medications, and address some of the pancreatic health concerns associated with taking the medicines.

DiabetesCare.net: Can you provide an overview of each of the classes known as DPP-4 inhibitors and GLP-1 analogs and explain their differences in the mechanisms of action and their benefits?

Grossman: Both classes of medications work on the incretin hormones. These incretin-based therapies increase the release of insulin but also inhibit the release of glucagon. Both classes of medications have the benefit of the glucose dependent effect, which mean that when the glucose levels are at their lowest, insulin and glucagon levels return to near-baseline or baseline levels. Essentially this means there is less of a risk for hypoglycemia.  

The difference in the two classes lies is in the duration of therapy. The GLP-1s, (Byetta, Bydureon, and Victoza), for example, because they are synthetic, they resist degradation of the DPP-4 enzyme, and the duration of action is longer. GLP-1 agonists induce satiety, so patients don’t feel as hungry. Being that GLP-1s’ duration is longer they also induce satiety, so patients don’t feel as hungry. It also reduces gut motility, so the stomach is not emptying as fast. This can lead to weight loss. Another benefit for GLPs is that they can reduce systolic blood pressure, and the DPP-4s do not.

This last benefit is important because patients with type 2 diabetes often suffer from metabolic syndrome, which includes hyperlipidemia and hyper tension, so GLPs help in treating these comorbidities as well.

On the other hand, the differences in the DPP-4 inhibitors is that they are oral tablets as opposed to injectable medications and they are weight neutral, so they are not affecting weight.

DiabetesCare.net: There appears to be some confusion in the general public about the two classes. Why so?

Grossman: I believe the confusion lies in the fact that both classes of drugs work on the incretin hormones. The mechanism of action is the same in that they both work on the beta and alpha receptors. However, one class (DPP-4s) is inhibiting the enzyme that destroys the incretin hormones and the other(GLP-1s) is acting as a synthetic incretin hormone.

DiabetesCare.net: An article was published that showed that taking either sitagliptin (Januvia) or exenatide (Byetta) increased the risk of hospitalization for acute pancreatitis. Can you explain the results and offer your insights into this?

Grossman: The point of this article is that patients who are at risk for pancreatitis should not be taking these medications. Of course, having diabetes by itself can put the patient at risk for pancreatitis. However, patients with high triglyceride levels, those who have a history of gallstones, or those with history of alcohol abuse should not take these medications.

There are so many variables that may affect the risk to contract pancreatitis that the FDA has decided to not label these medications as black box drugs.

FDA-Approved Incretin-Based Therapies
GLP-1 Analogs (injectables)
exenatide (Byetta, Bydureon)
liraglutide (Victoza)

DPP-4 Inhibitors (oral tablets)
sitagliptin (Januvia)
linagliptin (Tradjenta)
saxagliptin (Onglyza)

Combination Medications
saxagliptin and metformin HCl ER (Kombiglyze XR)
sitagliptin and metformin HCl (Janumet)

DiabetesCare.net: A study was published talking about the possibility of an increased risk of pancreatic cancer in taking the DPP-4, sitagliptin, (Januvia). How do you interpret the study’s findings?

Grossman: If you look at the study, you realize that there are many variables that could have led to the pancreatic cancer. As a clinician, this is an alert for me when I’m seeing my patients, but at the same time it’s difficult to tell if this medication causes cancer, because I can come up with other factors that could also cause cancer. For example if a patient took Januvia and lived in a city like New York, was it pollution? Was it second-hand smoke? Any other medications? What else could have contributed? I will have to see more studies to believe it causes cancer.

DiabetesCare.net: What type of prescribing guidance do you use for GLP-1s and DPP-4s?

Grossman: DPP-4s and GLP-1s present a lower risk for hypoglycemia as compared to sulfonylureas, and I believe incretin-based therapies should be used as first-line therapies. And, they are also recommended by the American College of Endocrinology as a first-line therapy. Of course, metformin is viewed as a first line of therapy, but I believe incretin therapies should be used first alone or in combination with metformin depending on the individual patient. Incretin-based therapies and their benefits have been well-documented, and I’m not concerned about using them. There are many drugs in each of the classes and insurance often dictates which medications we use. However, overall I am a believer in incretin-based therapy.