Type 2 Diabetes Drugs Under Review

(Wall Street Journal) Diabetes Drugs Scrutinized

March 15th, 2013

Facing growing evidence that some of America's top-selling diabetes medicines could lead to pancreatic disease, federal regulators on Thursday opened an unusual review of drugs from Merck MRK -0.72% & Co., Bristol-Myers Squibb Co. BMY -0.03% and other pharmaceutical makers.

The Food and Drug Administration said it was asking researchers for more information about how the drugs, used to treat type-2 diabetes, could lead to inflammation of the pancreas and cause precancerous changes in cells. However, the FDA stressed it hasn't concluded that the medicines "may cause or contribute to the development of pancreatic cancer."

Medical journal articles and case reports over several years have pointed to potential problems with Bristol-Myers's Byetta and Bydureon, Merck's Januvia and other related drugs that collectively had U.S. sales of more than $6 billion in 2012. The FDA said the immediate trigger for the investigation was an unpublished examination by researchers of pancreatic tissue from patients who died from other causes.

The companies defended their products, and some doctors called evidence of a link to pancreatic or thyroid cancer—or to large numbers of pancreas inflammation cases—unpersuasive.

The FDA review is the latest illustration of the difficulty pharmaceutical companies have had finding drugs that tackle diabetes without significant side effects. The disease, often tied to obesity, affects about 26 million Americans, according to the American Diabetes Association.

The diabetes drug Rezulin was withdrawn in 2000 due to associations with liver failure, and the FDA sharply restricted sales of another drug, Avandia, in 2010 after data linked it to heart-attack and stroke risk.

The latest questions involve drugs that work differently from Avandia. Byetta, Bydureon and Novo Nordisk A/S's NOVO-B.KO -1.04% Victoza are injected drugs that work on a hormone called GLP-1. Januvia is a pill that works indirectly on GLP-1. All of the drugs have won popularity among doctors because they can successfully control blood sugar without generally leading to weight gain, a side effect of some other diabetes drugs.

Researchers at Johns Hopkins University recently analyzed seven databases of insurance-billing records and compared patients taking Byetta, Bydureon or Januvia to other diabetic patients. Those taking the drugs had about a doubled rate of acute pancreatitis, or serious inflammation of the pancreas, according to the research published last month in the journal JAMA Internal Medicine.

"Our findings suggest a significantly increased risk of hospitalization for acute pancreatitis associated with the use" of those drugs by adults with diabetes, wrote Sonal Singh, an internal medicine doctor at the Johns Hopkins Bloomberg School of Public Health. He wrote that "such an association may be causal."

In a commentary published Feb. 27 in the British journal BMJ, Edwin A.M. Gale, former professor of diabetic medicine at Southmead Hospital in Bristol, England, wrote that the number of pancreatitis case reports to the FDA had reached "astronomical dimensions."

"Should we be worried about this?" he asked. "Very much so." He added that "all forms of pancreatitis, clinical or subclinical, predispose to carcinoma of the pancreas."

Other doctors say the evidence so far is too limited to change medical practice. They observe that the Johns Hopkins study wasn't a controlled trial but an after-the-fact analysis of a correlation that could have had other explanations.

"The level of evidence is unpersuasive," said Baylor University professor Alan Garber. The American Diabetes Association said patients shouldn't switch to other drugs despite the findings. It said the Johns Hopkins research shows "only two additional cases per 100 patients over a three-year period."

Bristol-Myers said Byetta "has been associated with acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis." But the company said it was "confident in the positive benefit-risk profile" of Byetta and Bydureon, an extended-release version of the same medicine.

Merck said it was "confident in the safety profile" of Januvia and has "seen no compelling evidence of a causal relationship" between the drug and pancreatic complications.

Byetta, developed from the venom of Gila monsters, was approved by the FDA in 2005. Reports of pancreatitis with Byetta ensued, and the FDA issued alerts in October 2007 and August 2008 that included references to two deaths. Some cases were hemorrhagic or necrotizing pancreatitis, which can be fatal.

An editorial in February 2010 in the journal Diabetes Care by Peter Butler, an endocrinologist at University of California, Los Angeles, questioned the emerging prominence of this new class of drugs. There is a "plausible risk" that patients may develop pancreatitis, he wrote, "and worse, subsequently a minority of individuals treated by this class of drugs may develop pancreatic cancer."

In 2011, Dr. Butler and colleagues from UCLA wrote in Gastroenterology about an analysis of the FDA's database of adverse events. "Use of sitagliptin [Januvia] or exenatide [Byetta and Bydureon] increased the odds ratio for reported pancreatitis 6-fold" compared with other drugs, they wrote.

The safety issues intensified with Novo Nordisk's Victoza, which the FDA approved despite evidence of pancreatitis in clinical trials and cancer in lab animals. The agency approved the drug, concluding that the benefits outweighed the risk.

But the health group Public Citizen last year called on the FDA to withdraw approval, contending the agency's reviewers saw enough safety issues that "this drug should never have been approved."

Novo Nordisk said "clinical studies have demonstrated the efficacy and safety profile of Victoza."