Pancreatic Cancer and Incretins: No Signal as Yet at NIDDK

June 14, 2013

The latest data from academics, physicians, and pharmaceutical-company scientists gathered at the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) in Bethesda for the past 2 days suggest there is likely no increased risk for pancreatic cancer associated with use of the glucagonlike peptide-1 (GLP-1)–based therapies, or incretins, for type 2 diabetes.

This, at least, was the conclusion of 2 experts at the meeting interviewed by Medscape Medical News. They acknowledged, however, that much longer-term data will be needed to provide a definitive answer to this question, and both stressed the immense complexity of the issue, including the interplay of all of the different diseases involved.

The meeting was planned long before this topic hit the headlines again this week but was perfectly timed to address the resurfacing of an ongoing controversy.

On Monday, BMJ published an in-depth investigation into the issue of pancreatitis and pancreatic cancer with incretins, and the topic was the subject of a Dispatches documentary on the United Kingdom's Channel 4. Later in the week, the American Diabetes Association called for all pharmaceutical companies involved to make their data available for independent review of this issue, and most firms indicated they would cooperate.

The concerns about pancreatitis and pancreatic cancer relate to some relatively new type 2 diabetes drugs, the GLP-1 agonists and dipeptidyl peptidase (DPP-4) inhibitors.

These include 2 widely prescribed injectable GLP-1 agonists, exenatide (Byetta, Amylin/Lilly) and liraglutide (Victoza, Novo Nordisk), and the oral DPP-4-inhibitor market leader, sitagliptin (Januvia, Merck).

No Compelling Reason Not to Prescribe

Following the NIDDK meeting yesterday, John Buse, MD, PhD, from the University of North Carolina School of Medicine, Chapel Hill, told Medscape: "The data from companies and other investigators suggest no signal of pancreatic cancer that can [currently] be detected. But it is going to take longer and larger studies to address this." Dr. Buse said it will be another 1.5 to 2 years before "substantial" data are available to further inform this issue.

"As a clinician, this is a concern,” he admitted. But there is a difference between "the known known" and "the known unknown," he said.

"There is the risk of diabetes and the alternative medications available for treatment. For me, there doesn't seem to be a compelling reason not to prescribe them [the incretins], whereas there are compelling reasons why you might choose to prescribe these agents," Dr. Buse said.

Similarly, David Whitcomb, MD, PhD, chief of the division of gastroenterology, hepatology, and nutrition at University of Pittsburgh, Pennsylvania, an expert on the pancreas, who was a cochair of the 2-day NIDDK meeting, said: "This [idea of pancreatic cancer from these drugs] is something horrendous, almost too horrible to believe, coming out of the blue. But we just don't see those kinds of signals. There was a lot of concern and anxiety going into the meeting, but afterward, it was very reassuring. We are not seeing a lot of bad things happening. There is a higher rate of pancreatitis and pancreatic cancer because of the disease [type 2 diabetes], but if you control appropriately there is no difference, and that wasn't just the pharma-industry perspective."

 
People were reassured that there is no reason to panic; the FDA is being very vigilant. Dr. David Whitcomb
 

The Food and Drug Administration (FDA) presentation at the NIDDK was key in setting people's minds at rest, said Dr. Whitcomb: "They discussed what they are doing in a public format. Normally, we never hear about it. People were reassured that there is no reason to panic; the FDA is not panicking, and they are being very vigilant, so the level of concern was diminished."

Dr. Whitcomb also praised all of the attendees and said the conference was an unprecedented occasion during which everyone learned something: "The more the different types of experts presented the challenges [with these issues], the more it really taught all of us that we have to take a much broader perspective. You learn something in medical school and then you forget it. But this was an incredibly successful cross-community exchange of ideas with dozens of experts, where we learned there are multiple different types of pancreatitis and diabetes and a complex interaction between pancreatitis, pancreatic cancer, and diabetes."

Nevertheless, he acknowledges, "There are lots of things that need to be done to follow up. Cancer takes time to develop, so whether these drugs [incretins] are going to have an effect over 10 to 20 years, we don't know."

Questions Over Controls, Antibodies, and Types of Cancer

Drs. Buse and Whitcomb praised the presentation at NIDDK by Peter Butler, MD, from the University of California, Los Angeles, who talked about his animal work as well as findings with regard to precancerous lesions in the pancreases of eight organ donors who had been taking GLP-1–based drugs [7 on sitagliptin, 1 on exenatide] compared with patients taking other antidiabetic drugs.

This research was published earlier this year and triggered the latest safety reviews into the incretin medications by FDA and the European Medicines Agency.

However, there were a number of questions about Dr. Butler's research, both physicians said.

"One of the biggest concerns was the huge difference in age between the patients [cases of pancreatic cancer] and the controls," explained Dr. Whitcomb. "The pancreatic cancer cases were in their 50s, whereas the control group was in their 30s."

Defining the appropriate control group "is the critical issue, and when the proper control group is used there is no evidence of increased risk," he added.

Also, "The type of lesion that Dr. Butler saw, the alpha-cell hyperplasia, is the wrong kind of cancer. It's not pancreatic cancer. It's not cancer at all, it's hyperplasia, and the type of cancer you would expect is what they call a glucagonoma, and nobody's ever seen that. So there are lots of things that just don't fit," Dr Whitcomb commented.

And, "the mass of the cells that [Dr. Butler's group] used to calculate the hyperplasia was based on the weight of the pancreas, but in diabetics and with age the pancreas shrinks, and that's well-known. So that may have had an effect."

"These are questions that were raised, and many people are now going to look at this in their own samples and reevaluate it. There was a lot of skepticism about the risk of cancer," Dr. Whitcomb concluded.

 
There was a lot of skepticism about the risk of cancer. Dr. David Whitcomb
 

Dr. Buse said: "Peter [Butler] did a nice job of describing how he got to where he is," but there were questions about whether the GLP-1 receptor is expressed on the ductal epithelia of the pancreas and in pancreatic cancer, he noted. Dr. Butler's work suggests that the receptor is expressed, "which would be key if these agents were causing pancreatic cancer," explained Dr. Buse.

However, a presentation from Alan Moses, MD, Novo Nordisk's global chief medical officer, found no expression of these receptors on the ductal epithelia and in pancreatic cancer. "Dr Moses suggested that perhaps Dr. Butler's antibody [being used to detect the GLP-1 receptors] is not as specific as it could be," Dr Buse noted.

Unfortunately, yesterday's meeting ran late, and Dr. Butler, along with many others, had to leave early and therefore was unavailable to respond to the questions raised about his research, said Dr. Whitcomb.

Medscape Medical News reached out to Dr. Butler, but he was unable to respond as this story went to press.

Industry Presentations and the FDA Perspective

Dr. Moses gave a presentation at the NIDDK meeting, consisting of an interim analysis of a 5-year pharmacoepidemiology study, Dr. Buse told Medscape Medical News. This analysis showed that the relative risk for pancreatic cancer with liraglutide was 0.7, compared with sulfonylureas, thiazolidinediones, and metformin. And regarding the risk for pancreatic cancer with liraglutide therapy compared with DPP-4 inhibitors, the relative risk was 1.0, but "the confidence interval was quite wide," he observed.

Next up was Sam Engel, MD, from Merck, "who basically went through a similar exercise with the DPP-4 inhibitors," said Dr. Buse. This included an updated meta-analysis with sitagliptin, which Merck said included more than 14,000 patients from 25 randomized clinical trials, "all of which suggests there isn't an increased risk of pancreatic cancer, with the limitation that there are no long-term data.

"Fundamentally, I don’t think anything has changed dramatically for me," Dr Buse commented. Dr Butler's observations raised concerns that there is potential over 10 to 20 years for pancreatic cancer if his observations are correct, he said, but he pointed out that these observations "either come from genetically manipulated animal models for the most part or a very restricted set of human autopsy data.

"The data from the companies and other investigators suggest that, as of today, there is no signal that can be detected," he concluded.

Dr. Whitcomb said that in its review, the FDA "replicated — independent of the pharmaceutical companies — many of the studies to make sure they got the same results that were reported by pharma, and they did. Everybody was very reassured that the FDA is all over this and has been very diligent in following this story, and so I think there was a lot of confidence that it's being monitored appropriately."

Complex Interplay of Diabetes, Pancreatitis, and Cancer

Another important issue that came up during the course of the meeting, "which was discussed at length," explained Dr. Whitcomb, was how "extremely difficult these studies are, because diabetes is a risk factor for pancreatitis, both acute and chronic; acute and chronic pancreatitis can cause diabetes; plus chronic pancreatitis can cause cancer; and cancer causes pancreatitis. And the development of diabetes in itself can be an early indicator of cancer!

"So the potential for someone getting diabetes because they have cancer and being treated with an agent and then the agent being blamed for causing cancer is a legitimate concern," he said.

"[When] the different types of experts — the pancreatologists, the pathologists, the diabetologists, the oncologists, and the epidemiologists — presented the challenges…[it] really taught all of us that we need to take a much broader and careful perspective in moving forward," Dr. Whitcomb noted.

Dr. Buse said the labels for these GLP-1 based agents, which note pancreatitis as a possible side effect, "suggest that, in general, you wouldn't use them in people with a prior history of pancreatitis. And in people who develop pancreatitis on the drug, you certainly discontinue it. It's not an absolute contraindication, but it does seem prudent."

However, he noted that, in the company presentations, there were examples of patients "who developed pancreatitis on the drug and stayed on the drug and the pancreatitis resolved. Or patients who had prior pancreatitis who were on the drug and didn't have any issues."

One of the big problems that was pointed out, Dr. Buse added, was that, until very recently, pancreatitis cases hadn't been adjudicated.

 
Cases of pancreatitis are being adjudicated in a blinded fashion, so we will have much more precision…in the future. Dr. John Buse
 

Pancreatitis "is not like a cavity in your tooth. It's not always clear, there's a fair amount of judgment around it," he noted. "There's a lot of uncertainty. In the large studies that are now being done, all the cases of pancreatitis are being adjudicated in a blinded fashion, and so we will have much more precision around the data in the future."

Asked if he would use GLP-1–based agents, Dr. Whitcomb said: "I'm not a diabetologist, but I'm a physician. If the drug were indicated for the disease the patient had and was beneficial, nothing I heard today would change my prescribing habits."

Dr. Buse reports being a consultant and investigator under contracts between his university and many of the companies marketing and developing GLP-1 agents, including Novo, Lilly, Sanofi, Merck, and Bristol-Myers Squibb. Dr. Whitcomb has consulted for Lilly on the issue of pancreatitis, but not pancreatic cancer.

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