Balancing Risks and Benefits: Sifting Through the Incretin Debates

By Etie S. Moghissi, MD, FACP, FACE

DEFINITIONS

Benefit: The benefit of a drug or treatment relates to its ability to improve a condition or treat a disease. Although in clinical medicine results cannot be guaranteed, a benefit may be characterized as a reasonable expectation based on prior research and knowledge.

Risk: The concept of risk refers to the relationship between the severity of some future harm andthe probability of that harm occurring.

To be approved for marketing, any new medication must be proven safe and effective for its intended use, recognizing that all medications have some potential to cause side effects. The safety of a drug is assessed by determining whether its benefits outweigh its risks.

It is well established that diabetes is a serious disease and may be associated with many devastating complications. The good news is that research has proven that optimal control of diabetes and its associated conditions can prevent many of the complications of diabetes, and people with diabetes can live healthy and productive lives. The key to success is early diagnosis and attention to blood sugar control, as well as optimal blood pressure and cholesterol control.

Our understanding of the causes of diabetes is evolving. Although insulin-producing cells in the pancreas play a major role in blood sugar control, many other organs in the body such as the brain, gut, liver, muscles, fat cells and kidneys also play an important function in blood sugar regulation in normal individuals. In people with diabetes, many of these organs do not function or respond properly, which results in elevated blood sugar.

Today, there are more than 13 classes of diabetes medications, with different mechanisms of action, which may be used in combination to manage diabetes. Recently certain diabetes medications called incretins have been in the news, and there has been some concerning and confusing information in the media about these drugs.

So what are the facts?

In recent years, researchers discovered a group of natural intestinal hormones, called incretins, that play a very important role in glucose regulation in normal individuals. The most important of these hormones is GLP-1 (glucagon-like peptide-1). This hormone tends to be deficient or does not work properly in individuals with diabetes. To address this problem, a new class of medications called incretin mimetics have been developed. There are of two categories of these medications:

1. GLP1 Analogs: These medications are injectable therapies. Medications in this category include exenatide (marketed as Byetta®), a twice-daily injection; liraglutide (marketed as Victoza®), a once-daily injection; and a once-per-week slow release form of exenatide (marketed as Bydureon®).

2. DPP-4 inhibitors: The second category consists of oral medications called dipeptidyl peptidase IV or DPP-4 inhibitors, which slow the breakdown of the GLP-1 and allow it to remain active for a longer period of time, thus lowering blood sugar levels all day. There are four different DPP-4 inhibitors on the market: sitagliptin (marketed as Januvia®, Janumet®, Janumet XR® and Juvisync®); saxagliptin (marketed as Onglyza® and Kombiglyze™ XR); linagliptin (marketed as Tradjenta® and Jentadueto®); and alogliptin (marketed as Nesina®, Kazano® and Oseni®),

In April 2005, the U.S. Food and Drug Administration approved the first incretin mimetic, exenatide (Byetta), a GLP-1 analog, and in October 2006, the Food and Drug Administration approved the first oral DPP4 inhibitor sitagliptin (Januvia). Similar products have come to market over the past six to seven years. Even more are in the pipeline and will be available in the future.

Incretin therapy offers an alternative option to currently available anti-diabetic agents in adults with type 2 diabetes. It is effective in reducing blood sugar with no or minimal risk of hypoglycemia (unless the drugs are given in combinations with sulfonylurea or insulin) or weight gain. In fact, the GLP-1 analogs are associated with weight loss.

What are the concerns?

The main side effect of GLP-1 analog is nausea, which subsides in the vast majority of individuals if it even occurs. Post-marketing reports also suggest that incretin-like medications may be associated with an increased risk of pancreatitis, and although no causal link has been established, the FDA has added warnings about the risk of acute pancreatitis to the drug labels and medication guides for the entire class of these medications. It should be noted that pancreatitis is more common in patients with diabetes, regardless of the medication they are taking, which makes it difficult to determine a causal relationship between incretin therapy and pancreatitis. Nonetheless, patients should be aware of this risk and contact their health care professionals immediately if they have abdominal pain or vomiting. If the diagnosis of pancreatitis is established, the medication should be discontinued. Also, this class of medications probably should not be prescribed for patients with a history of pancreatitis.

Furthermore, in a recent study, two researchers found cellular changes in the pancreas of deceased individuals who had been taking incretin-like medications, and the researchers suggested that these changes may have been re-cancerous. It is important to note that this was a small study that had many limitations, making it difficult to draw any definitive conclusions. For example, the researchers did not take into account what are known normal changes in the pancreas.

In fact, the FDA has responded to the issue, stating it “has not concluded these drugs may cause or contribute to the development of pancreatic cancer.” The FDA has further stated that it is continuing to evaluate all available data to further understand this potential safety issue. The FDA stresses that “at this time, patients should continue to take their medicine as directed until they talk to their health care professional, and health care professionals should continue to follow the prescribing recommendations in the drug labels.”

The European drug review board, the European Medicines Agency (EMA), came out this summer with its own independent review, stating that available data do not confirm concerns over an increased risk for pancreatic-adverse events with GLP-1-based type 2 diabetes therapies. The EMA added that the autopsybased study had many methodologic limitations and potential sources of bias, most importantly differences between the studied groups with respect to age, sex, disease duration and treatments, “which preclude a meaningful interpretation of the results.”

The Bottom Line:

Diabetes is a serious disease and needs aggressive therapy. People with diabetes require medication to control their blood sugars, and sometimes multiple forms of treatment, including incretin therapy, are necessary. All forms of treatment involve some degree of risk, but as long as the benefits outweigh these risks, it is reasonable to accept the risk. Patients should stay informed, discuss any medication side effects with their doctor, and always consider the benefits of a particular treatment in conjunction with its risks. Also, keep your eyes and ears open for additional data coming out soon from several studies currently in progress that incretin therapy might have beneficial effects in heart disease.

Dr. Etie Moghissi is board certified in endocrinology, diabetes and metabolism and is in private practice in Marina del Rey, California. She is a Clinical Associate Professor of Medicine at UCLA. Dr. Moghissi is a recognized expert in the field of diabetes and is actively involved in direct patient care, as well as in professional medical education. She serves as Editor of EmPower Magazine.