The Safety of Incretin Therapy: Are Barriers Beginning to Fall?

On July 26, 2013 the European Medicines Agency (EMA), in a press release, stated that it sees no reason for concern about pancreatitis and pancreatic neoplasm in incretin-treated patients with type 2 diabetes. The US Food and Drug Administration and the American Diabetes Association (US FDA/ADA) have empanelled a similar committee to consider the safety of incretins. These findings are awaited.

Almost a decade ago incretin therapies made their appearance in the US, first as exenatide, a GLP-1 receptor agonist (GLP-1 RA). Subsequently, dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, saxagliptin, lingliptin, and alogliptin) became available. The GLP-1 RA group has expanded to include liraglutide and exenatide weekly and several others soon to follow. Because these treatments are effective and relatively free of hypoglycemia and weight gain, they are all finding favor in the primary care community. The 3 GLP-1 RAs currently on the market-exenatide twice daily and once weekly, and liraglutide once daily-are all associated with weight loss. GLP-1 RAs and DPP-4s work well as monotherapy and as add-on treatments to other antidiabetic agents.

So what is there not to like about such drugs? The DPP-4s are associated with very few side effects. Gastrointestinal side effects such as nausea, vomiting, diarrhea, and constipation are very frequent with the GLP-1 RAs, but these side effects usually decrease rapidly after the drug has been used for a short period of time.

But a major concern around the use of these drugs is coming largely from “bad drug” ads by plaintiff’s attorneys advertising for clients on TV. These ads tout the risk of pancreatitis and pancreatic cancer associated with the use of incretin therapies.

Many patients are distressed by these ads. Concerns are heightened by articles in the popular media that raise doubts over the safety of these drugs. One of the most frequent questions I’m asked in my office is “Am I in any danger taking my incretin therapy?”

These worries are not completely unfounded. Post-marketing studies have shown incretin treated patients experiencing non-fatal and fatal pancreatitis, but the numbers of people experiencing these complications are miniscule compared with millions of patient years of exposure to incretins.  The mechanism of action of these incretin drugs  that  impacts beta cells (glucose-dependent insulin secretion) and alpha cells (glucagon suppression) provides a plausible explanation for the development of pancreatic inflammation or possible neoplasm.

Paper is tipping point
But a paper published recently in Diabetes¹ significantly heightened uncertainty in the minds of clinicians and patients alike and compelled the EMA (and US agencies as well), to review carefully the existing data on the issue and to report to the public. The study in Diabetes looked at pancreatic specimens from organ donors, both with and without diabetes, and noted abnormal changes, including precancerous lesions in patients who had been taking GLP-1 RA-based drugs.

It was this work that the EMA focused on-and it expressed reservation. The agency cited the study’s very small number of patients and found a number of methodologic limitations and possibilities for bias. Most importantly, the EMA pointed out differences in the age, gender, disease duration, and other therapies used in patients, all of which confound interpretation.

The EMA said that based on all available clinical and non-clinical data, no new concerns for use of incretins are identified. Of course, they recommend continued data gathering and monitoring for pancreatic problems. These conclusions somewhat mirror the discussions at a recent National Institutes of Health conference in Washington. There is no reason for increased concern, but ongoing monitoring is reasonable.

We will know more soon. Two large studies commenced in 2011 to look at pancreatic safety should be completed by 2014. Then we may get our first definitive insight into the safety of these agents. 

For now, the words from the EMA should reassure clinicians and their patients alike. Incretin use appears safe. The US FDA/ADA committee should report on their findings soon and that should help us further.  The fact that this committee's work is ongoing suggests no immediate findings of danger that need immediate reporting. Today, August 2, there are rumors circulating  that the FDA “concurs” with the EMA that incretin medications and pancreatic disease are not related.

Given these reports, the use of DPP-4 inhibitors and GLP-1 RAs seems safer to me than uncontrolled type 2 diabetes or the use of many other antidiabetic agents.
 

Reference
1. Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes. 2013;62:2595-2604. (full paper)

For more information

Report: FDA comfortable with EMA's diabetes conclusions

EU agency has no new concerns about incretin diabetes drugsADA calls for independent review of incretins/cancer concernsBMJ digs deep into diabetes drug, pancreatic-cancer debate