More Calls for More Research on Incretin Diabetes Drugs

Barbara Boughton and Lisa Nainggolan

June 24, 2013

SAN FRANCISCO — The Endocrine Society is the latest organization to issue a statement indicating that more research is needed before any conclusion can be reached about a possible link between incretin-based type 2 diabetes therapies and pancreatic cancer.

This ties in with the conclusions from a recent two-day meeting at the US National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), where dozens of experts discussed the issue; the overriding conclusion was that currently there seems to be little evidence for an increased risk for pancreatic cancer associated with use of incretin therapies. But much longer-term data will be needed to provide a definitive answer to this question, attendees said.

And at the American Diabetes Association (ADA) 2013 Scientific Sessions yesterday, Vanita R Aroda, MD, from MedStar Health Research Institute, Hyattsville, Maryland, presented a recap of the NIDDK meeting for attendees.

She said ongoing trials, such as the Safety Evaluation of Adverse Reactions in Diabetes (SAFEGUARD) program in the European Union, will further inform this risk, as will data, in due course, from 9 ongoing cardiovascular-outcomes studies of diabetes drugs.

Meanwhile, Dr. Aroda urged restraint. In response to a question as to what her advice would be to a doctor seeing a patient who had concerns about pancreatitis and pancreatic cancer associated with their medication, Dr. Aroda called for a show of hands. The overwhelming majority of the packed auditorium said they would not stop the therapy but would rather try to reassure their patient.

"What emerges is the need to spend more time educating patients on what is out there and the comparative risks and benefits," she observed. "Doctors should continue to be doctors and personalize therapy."

And the Endocrine Society, in its statement, agrees. Clinicians should discuss the potential side effects of incretin-based therapy and the symptoms of pancreatitis with patients, especially those with other risk factors for the condition, and balance the risks and benefits, it states.

SAFEGUARD Program and CV-Outcomes Trials Will Yield More Data

The concerns about pancreatitis and pancreatic cancer relate to some relatively new type 2 diabetes drugs, the glucagonlike peptide-1 (GLP-1) agonists and dipeptidyl peptidase (DPP-4) inhibitors, collectively known as GLP-1–based drugs, or "incretins." These include 2 widely prescribed injectable GLP-1 agonists, exenatide (Byetta, AstraZeneca/Bristol-Myers Squibb Alliance) and liraglutide (Victoza, Novo Nordisk), and the oral DPP-4-inhibitor market leader, sitagliptin (Januvia, Merck).

At ENDO 2013: the Endocrine Society 95th Annual Meeting last week, there was also a special session called to review the controversy, which has just been the subject of a BMJ in-depth investigation. This stemmed from research, including a recent study by Peter Butler, MD, director of the Larry L. Hillblom Islet Research Center at David Geffen School of Medicine, University of California, Los Angeles, that found abnormal changes, including precancerous lesions, in the pancreases of 8 organ donors taking GLP-1–based drugs; Dr. Butler's study was published in Diabetes in March.

At that ENDO session, Steven Kahn, MD, from the University of Washington, who wrote an editorial on Dr. Butler's research, told Medscape Medical News: "There have been many different confounders in the studies published so far, and in [Dr. Butler's] study in Diabetes, the groups in the study were not well-matched." Other limitations of Dr. Butler's study and other recent work was discussed at NIDDK and reiterated again by Dr. Aroda at the ADA meeting yesterday.

She stressed that important safety data will result from the SAFEGUARD program, which will combine data from 9 population-based healthcare databases in 6 countries in the European Union and the United States from 1999 to 2012. This is slated to finish in 2015.

And results from several of the large CV safety trials with DPP-4 inhibitors, including the EXAMINE study, which is studying alogliptin (Takeda), and CAROLINA, a trial on linagliptin, will become available in the next few years, as will findings from studies with GLP-1–receptor agonists such as dulaglutide (Eli Lilly), exenatide, and liraglutide.

In summary, Dr. Aroda said there are potential mechanisms to explain the safety issues discussed but there is "insufficient concrete evidence to suggest an alteration of the current risk/benefit profile of these agents," and no substantial changes in clinical recommendation should be made based on these recent studies.

This is in line with the stance taken by both the US Food and Drug Administration and the European Medicines Agency at the current time.

However, "there is a need to pool together appropriate expertise, databases, and methodologies to address these questions with scientific rigor," Dr. Aroda concluded.


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