EU agency has no new concerns about incretin diabetes drugs

July 26, 2013

London, UK - The European Medicines Agency (EMA) says currently available data do not confirm recent concerns over an increased risk of 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 two classes of medicines: GLP-1 agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors.

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

Concerns arose most recently following a study published online in March 2013 in Diabetes by Dr Peter Butler (David Geffen School of Medicine, University of California, Los Angeles). Researchers found abnormal changes, including precancerous lesions, in the pancreases of eight organ donors who had been taking GLP-1-based drugs.

Following the publication of Butler's study, BMJ published an in-depth investigation of the issue, and the US National Institute of Diabetes, Digestive , and Kidney Diseases held a two-day meeting, where dozens of experts discussed the topic. The meeting experts concluded that currently there is little evidence of an increased risk of pancreatic cancer associated with incretin use.

EMA says Butler study has limitations, sources of bias

The EMA says the findings of Butler et al "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 a number of methodological limitations and potential sources of bias, most importantly differences between study groups with respect to age, gender, disease duration, and treatments, "which preclude a meaningful interpretation of the results," the EMA states. And data from clinical trials do not indicate an increased risk of pancreatic cancer with these medicines, it concludes.

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

In the US, too, experts say that much longer-term data are needed to provide a definitive answer as to whether GLP-1-based drugs increase the risk of pancreatic cancer. Organizations, including the American Diabetes Association and 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 side effects of incretin-based therapy and the symptoms of pancreatitis with patients, especially those with other risk factors for the condition, and to balance the risks and benefits.

EMA will harmonize warnings on pancreatitis

EMA says a small number of cases of pancreatitis 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."

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 EU, "so that patients and healthcare professional receive consistent advice."

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 regularly report their findings to the agency for assessment. "Marketing authorization holders will update the risk-management plans for these medicines accordingly," the agency states.

GLP-1-based therapies approved in the EU include exenatide (Byetta, Bydureon, AstraZeneca/Bristol-Myers Squibb), 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).

EMA committee announces positive opinion on alogliptin

Also announced by the EMA today, the CHMP has issued a positive opinion on the DPP-4 inhibitor alogliptin, plus two fixed-dose combinations of alogliptin with metformin and pioglitazone, respectively, for the treatment of type 2 diabetes in adults.

The products, which will be marketed by Takeda Pharmaceuticals as Vipidia (alogliptin), Vipdomet (alogliptin/metformin), and Incresync (alogliptin/pioglitazone), require final approval from the European Commission, which typically follows CHMP recommendations within 60 days. The same three formulations of alogliptin were approved in January in the US and launched there last month as Nesina, Kazano, and Oseni, respectively, for adults with type 2 diabetes.

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