EU Agency Has No New Concerns on Incretin Diabetes Drugs

July 26, 2013

The European Medicines Agency (EMA) says currently available data do not confirm recent concerns over an increased risk for pancreatic adverse events with glucagonlike peptide-1 (GLP-1)–based type 2 diabetes therapies.

"There is no change in evidence regarding the risks," concludes the EMA's Committee for Medicinal Products for Human Use (CHMP), which has finalized a review of GLP-1–based diabetes therapies, also known as incretins. These comprise 2 classes of medicines: GLP-1 agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors.

Although a slightly increased risk for pancreatitis with these products is well recognized and noted in their labeling, there is unease about the potential of a class carcinogenic effect.

Concerns in this regard arose most recently following a study, published in Diabetes in March, by Peter Butler, MD, from the David Geffen School of Medicine, University of California, Los Angeles, and colleagues. The researchers found abnormal changes, including precancerous lesions, in the pancreases of 8 organ donors taking GLP-1–based drugs.

Following the publication of Dr. Butler's study, BMJ published an in-depth investigation of the issue, and the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) held a 2-day meeting, at which dozens of experts discussed the topic, concluding there is currently little evidence for an increased risk for pancreatic cancer associated with use of incretins.

EMA Says Butler Study Has Limitations, Sources of Bias

The EMA says the findings of Dr. Butler and colleagues "were based on examination of a small number of pancreatic tissue samples obtained from organ donors with and without diabetes mellitus, who died due to causes other than diabetes."

Also, the study itself 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," EMA states.

In addition, data from clinical trials do not indicate an increased risk for pancreatic cancer with these medicines, it concludes.

However, EMA acknowledges that the number of events is too small to allow final conclusions.  "Due to their mechanism of action (stimulation of beta-cell and suppression of alpha cell function) some uncertainties remain in respect to the long-term effect of these medicines on the pancreas, and more data collection efforts are under way."

In the United States, too, experts say that much longer-term data will be needed to provide a definitive answer to the question of whether GLP-1–based drugs increase the risk for pancreatic cancer. Organizations including the American Diabetes Association and the Endocrine Society agree and have called on pharmaceutical companies to be transparent with their data.

In the meantime, doctors are being urged to discuss the potential adverse 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.

EMA Will Harmonize Warnings on Pancreatitis

EMA says a small number of cases of pancreatitis associated with these agents have been reported in clinical trials, and a significant number of cases have been recorded through adverse-event reporting, "although these need to be interpreted cautiously."

All these medicines already carry pancreatitis warnings in their product information, but the agency intends to harmonize the wording of these warnings across all GLP-1–based therapies in the European Union, "so that patients and healthcare professional receive consistent advice," it notes.

The EMA also points out that the marketing authorization holders of these medicines are closely monitoring them for adverse effects, including effects on the pancreas, and they report their findings regularly to the agency for assessment. "Marketing authorisation holders will update the risk-management plans for these medicines accordingly," it states.

GLP-1–based therapies approved in the EU include exenatide (Byetta, Bydureon, AstraZeneca/Bristol-Myers Squibb Alliance), liraglutide (Victoza , Novo Nordisk), lixisenatide ( Lyxumia, Sanofi), sitagliptin (Efficib, Januvia, Janumet, Ristaben, Ristfor, Tesavel, Velmetia, Xelevia, Merck), saxagliptin (Komboglyze, Onglyza, AstraZeneca/Bristol-Myers Squibb), linagliptin (Jentadueto, Trajenta , Boehringer Ingelheim/Lilly), and vildagliptin ( Eucreas, Galvus, Icandra, Jalra, Xiliarx, Zomarist, Novartis).

Ongoing and Planned Studies Will Yield More Info

The EMA adds that several studies are planned or ongoing, including large outcome studies aimed at increasing the ability to understand and quantify risks associated with these medicines, including the occurrence of pancreatitis and pancreatic cancer.

In addition, 2 large independent studies have been under way since 2011 to study the risk profile of diabetes treatments in general and, more specifically, their risk profile in relation to the pancreas. First results of these studies, which are funded by the European Commission, are expected in the spring of 2014. 

"In the meantime the EMA continues to closely monitor and assess all information that is becoming available on these medicines to ensure that their benefit-risk balance remains positive."


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