[Update, March 2013: I originally wrote this post in December 2012. Three months later, the FDA announced it “is evaluating unpublished new findings by a group of academic researchers that suggest an increased risk of pancreatitis, or inflammation of the pancreas, and pre-cancerous cellular changes called pancreatic duct metaplasia in patients with type 2 diabetes treated with a class of drugs called incretin mimetics.” Several news agencies ran with the news, including AP and Bloomberg, as did some pharma industry bloggers. The JAMA Internal Medicine medical journal ran a column urging more research into the link between the drugs and pancreatic cancer, an article with a concerning, but perhaps harmless, revision after it was published. We think the latest attention and research makes the case against these drugs even stronger, and we’re moving forward in our own litigation.]


Diabetes is a global epidemic, affecting over 25 million Americans and ten times that worldwide. That also makes it an economic opportunity: the diabetes control medication market is worth more than $40 billion in the United States alone. There are thirteen types of approved Type 2 Diabetes medications on the market today (comprising over two dozens drugs), with another seven therapies in various stages of research and development. There’s big money to be made, if you’re a pharmaceutical company — hence the recent advertising push for Januvia, Byetta, and Victoza (the one Paula Deen endorses), relatively new entries to the overcrowded diabetes control market.


I’ve discussed before on this blog how one of the biggest public health problems in America is the pharmaceutical industry’s reliance on the “blockbuster” drugs that exceed $1 billion in annual sales. The whole industry, from research, to clinical trials, to physician education, is oriented around creating and promoting drugs that will become household names — to the exclusion of other useful medicines and to the detriment of patient safety. A year ago, I wrote about why Merck still didn’t admit Propecia caused persistent erectile dysfunction more than eight years after competent research showed the problem. The reason is quite simple: Propecia / Proscar was routinely bringing in more than half a billion dollars a year for Merck, and they wanted to keep it going for as long as possible.


Which brings us to Januvia, a drug that stock market analysts call a “real success story” for Merck. The Type 2 Diabetes market is huge, and Januvia (marketed as “Janumet” when mixed with metformin) has captured 75% of the dipeptidyl peptidase 4 (DPP-4) inhibitor market — for $4.6 billion in revenue in 2011 and likely topping $5 billion this year. It’s not hard to see why Januvia and other DPP-4 drugs have been successful and their sales are growing. They’re a one-a-day pill, not a shot, they haven’t been shown to cause weight gain, and they have a lower incidence of the nausea, abdominal pain, and digestive problems that characterize most diabetes treatments.


But there’s a big problem brewing. To understand it requires a little bit of background as to how Januvia and Janumet work (this same analysis also affects Byetta and Victoza, which work differently by altering the same metabolic pathway to treat diabetes):


Hyperglycemia in type 2 diabetes is due to inadequate insulin secretion in the setting of insulin resistance. A new class of drugs has been introduced for treatment of type 2 diabetes that takes advantage of the properties of the gut hormone glucagon-like peptide-1 (GLP-1). GLP-1 is secreted by L-type endocrine cells in the distal ileum in response to food ingestion and amplifies glucose-mediated insulin secretion.


GLP-1 has a short half-life, degraded by the enzyme dipeptidyl peptidase-4 (DPP-4) in the circulation. To accomplish sustained GLP-1 receptor activation therapeutically, 2 strategies have been developed. In one, GLP-1 agonists that are resistant to DPP-4 degradation are administered by injection, including exenatide (Byetta; Amylin Pharmaceuticals, San Diego, CA) and liraglutide (Victoza; Novo Nordisk, Bagsværd, Denmark). The alternative strategy is use of inhibitors of DPP-4, such as sitagliptin (Januvia; Merck & Co, Inc, Whitehouse Station, NJ), when administered orally enhance levels of endogenously secreted GLP-1.


This study from the July 1, 2011 issue of Gastroenterology  is not too hard to follow, all in all: GLP-1 is suppose to tell the pancreas to make insulin, but it’s degraded by DPP-4. Thus, in theory, we can increase insulin production by adding chemicals that act like GLP-1 (which is how Byetta and Victoza work) or by inhibiting DPP-4 (which is how  Januvia works).


But that’s not all that these drugs do. Part of the problem was briefly summed up a couple months ago by an article in the science journal Nature as, “drugs that mimic GLP-1 may inflame the pancreas, causing pancreatitis — a risk factor for pancreatic cancer.” But the connection between GLP-1 diabetes drugs and cancer is both more subtle, and more worrisome, than that. 90% of pancreatic cancer is actually pancreatic ductal adenocarcinoma, a tumor originating in the duct of the pancreas. Current research suggests that pancreatic adenocarcinoma most commonly begins in pancreatic duct glands in the form of pancreatic intraepithelial neoplasia (PanIN), which are lesions that produce the protein “sonic hedgehog (shh)” which many oncologists believe is “essential” to the maintenance of cancer stem cells.


Januvia / Janumet and Byetta / Victoza work differently from one another, but both work by disrupting the normal GLP-1 receptor pathway in the pancreas. And where is that pathway expressed? In pancreatic islets and exocrine duct cells — right where oncological research suggests most pancreatic cancer develops. Isolated or even sporadic disruptions of that pathway probably wouldn’t make much of a difference, but these drugs are meant to be used continuously for years, potentially decades. Could that sort of persistent disruption of the GLP-1 pathway to create an increased risk of pancreatic cancer?


The answer, at least in mice, seems to be yes: earlier this year, the medical journal Diabetes published a study that concluded that too much Byetta — Byetta is technically Exenatide, which is a synthetic form of exendin-4, a hormone found in the saliva of the Gila monster — expands pancreatic duct glands in mice, gives them chronic pancreatitis, and, perhaps most disturbingly, causes more pre-cancerous lesions to develop.


We’ve already seen similar effects in humans. Byetta has long been known to cause acute pancreatitis, including the more severe forms of hemorrhagic and necrotizing pancreatitis. In 2009, the FDA required Amylin Pharmaceuticals, the manufacturer of Byetta, to start studying these side effects more carefully.  Last month, a study in The Annals of Pharmacotherapy reported that Victoza (formally, “liraglutide”) appeared to cause acute pancreatitis. So we know these medications cause significant side effects the human pancreas like inflammation, including signs of serious side effects that are correlated with cancer.


Similarly, a 2011 review of FDA data showed that patients on Januvia or Byetta reported pancreatic cancer nearly three times as users of other diabetes drugs, while having similar rates of other cancers, which suggests their elevated pancreatic cancer rate wasn’t related to environmental exposure or some other factor. (Intriguingly, metformin seems to reduce the risk of many cancers, including pancreatic cancer, so it might turn out that Janumet is significantly safer than Januvia, if sitagliptin and metformin work independently.)


Does any of this prove that Januvia, Byetta, or Victoza cause an increased risk of pancreatic cancer? That depends on the level of proof you require: on the one hand, commentators on the internet love to dismiss burgeoning scientific theories with the argument that “correlation does not imply causation.” On the other hand, that phrase is thrown around way too easily, and there has to be some explanation for why users of diabetes medications that affect the GLP-1 pathway have an increased risk of pancreatic cancer. Perhaps, as one researcher argued, “If the suspected relationship exists, exenatide is likely to promote tumor progression rather than initiation, which corresponds with data showing that exenatide promotes pancreatic ductal hyperplasia.” In other words, perhaps these drugs accelerate pancreatic cancer but don’t cause it; that certainly wouldn’t be good news, but it might mean the damage is limited to patients who already have that type of cancer.


As a mass torts lawyer, I must admit that the slow revelation of these drugs’ dangers and the resulting preventable harm is painful to watch, because I’ve seen this pattern before, in which the evidence of a widely-used medication’s real dangers slowly became public, and were denied for far too long. A year ago, I wrote about a court throwing out a lawsuit alleging chronic use of recommended Tylenol doses caused liver damage, noting “The sad irony here is that, like with many other drug recall and class action lawsuits (Vioxx in particular comes to mind), in time new studies will be performed that will most likely show exactly what [the plaintiff] was alleging…” We’ve seen that time and again, most recently with Actos, another Type II Diabetes drug, and Pradaxa, a blood thinner that’s supposed to be more convenient, both of which turned out to be vastly more dangerous than initially thought when they were put on the market.


Time will tell what the research shows for these drugs — as will the consolidated Byetta and Januvia lawsuits already in progress. Public Citizen has already filed a petition with the FDA requesting Victoza be withdrawn, and the manufacturer has fought back vigorously. I hope, but sadly don’t expect, that the pharmaceutical companies will act quickly in response to any new research. If history is any guide they’ll keep selling each until the evidence is overwhelming and indisputable — at which point they’ll settle the lawsuits (having already made a huge profit on the drug) and move on to the next blockbuster drug.


If you or a family member developed pancreatic cancer after taking one of these drugs, please use the contact form on the right or give me a call for a no-obligation consultation. We’re on the forefront of this litigation: we and our co-counsel firm have brought 35 of the approximately 55 lawsuits pending in the federal courts, more than anyone else.