Amylin Pharmaceuticals Inc. and Eli Lilly & Co.’s Byetta medicine and Novo Nordisk A/S’s Victoza face scrutiny after some researchers warned that prolonged use of the insulin-raising treatments may make diabetics more vulnerable to cancers.
A debate on the potential dangers of GLP-1 therapies, the class of drugs to which Byetta and Victoza belong, will be a highlight of the European Association for the Study of Diabetes conference in Lisbon this week. A review of a database of side effects showed patients taking Byetta and a Merck & Co. drug had a sixfold increased chance of pancreatitis, which in turn raises the risk of tumors, researchers led by Robert Elashoff of the University of California at Los Angeles said this year.
The manufacturers say the treatments are safe and there’s no evidence of increased cancer risk. Sales of GLP-1 analogues, which mimic a hormone called GLP-1 to stimulate natural insulin production in diabetics, are increasing as doctors seek alternatives to older drugs for a disease that affects 366 million people worldwide, according to a new estimate today from the International Diabetes Federation.
“It’s a very tricky story,” Viktor Joergens, executive director of the EASD, said in a telephone interview. “You probably need decades and incredible numbers of people to study things like that. It will be a very interesting debate particularly because these drugs are now widely prescribed.”
Regulators already have taken note of possible links between the new classes of diabetes drugs and pancreatitis and thyroid tumors. Still, the renewed debate may prompt authorities to seek additional safety data before approving new GLP-1 drugs, Ele Ferrannini of the University of Pisa School of Medicine said in a telephone interview.
‘Serious’ Side Effects
Most people suffering from diabetes have the Type 2 form of the disease linked to older age, excess weight and physical inactivity. The condition is caused by a lack of insulin needed to convert blood sugar into energy.
Elashoff and other researchers, including Peter Butler of UCLA, said in their study in the journal Gastroenterology in July that the GLP-1 drug class “could have serious unintended and unpredicted side effects.”
Their analysis of the U.S. Food and Drug Administration’s database of reported adverse events from 2004 to 2009 found that pancreatitis and pancreatic cancer were more common among patients who took exenatide and sitagliptin, a Merck drug sold as Januvia, as compared with other therapies to treat Type 2 diabetes.
The study didn’t look specifically at Novo’s Victoza, which is also known as liraglutide. Januvia belongs to another new class of diabetes drugs, called dipeptidyl peptidase-4 inhibitors.
Several researchers and drugmakers including Novo Nordisk criticized the analysis, saying the FDA’s voluntary side-effect reporting system can’t be used to calculate the incidence of side effects. Lilly, Amylin, Novo Nordisk and Merck say their products haven’t been shown to cause cancer.
“To date the available data do not demonstrate that exenatide increases the overall risk of cancer in humans,” Lilly and San Diego-based Amylin said in e-mailed statements.
Victoza has a “very benign side effect profile in real-life use” in terms of both pancreatitis and cancer risk, Novo Chief Science Officer Mads Krogsgaard Thomsen said in a telephone interview.
Letter of Complaint
“The more evidence we gather, the more we are seeing a level of pancreatitis that is well within the expected range for people who have Type 2 diabetes,” he said. Separate studies to assess liraglutide’s potential cancer risks also “are very reassuring,” he said. Thomsen wrote a letter to Gastroenterology Editor-in-Chief Anil Rustgi to complain about the Elashoff study.
A potential cancer link hasn’t been proved for sitagliptin either, according to Whitehouse Station, New Jersey-based Merck.
“Based on our careful review of the totality of safety data available to us, the data do not demonstrate a causal relationship between Januvia and pancreatitis or pancreatic or thyroid cancers,” Merck spokeswoman Pamela Eisele said in an e-mailed statement. “We remain confident in the safety and efficacy profile of Januvia.”
Butler says further study is needed of GLP-1 therapies. The drugs may act on the so-called exocrine pancreas, promoting unnecessary proliferation of pancreatic duct cells that may then partially obstruct the passage of digestive enzymes, a cause of local pancreatic inflammation, he said. Pancreatitis is a risk factor for pancreatic cancer.
“There are now several animal studies as well as clinical reports from humans that taken together raise concern that there may well be serious unexpected side effects of the GLP-1 class of drugs on the pancreas,” Butler wrote in e-mailed comments.
Edwin Gale, a diabetes researcher at the University of Bristol in England, said he would be “very reluctant” to use GLP-1 therapies “until the potential problem has been taken seriously.”
“If Butler is right, and the GLP-1 therapies as a class produce subclinical pancreatitis, and if that predisposes to cancer, we’re sitting on a time bomb,” he said in an interview. “We need answers, not reassurance.”
It’s hard to predict what impact the controversy will have on GLP-1 sales, said Ferrannini, of the University of Pisa. “It’s a battle fought through the media,” he said. “It will depend on how much noise those in favor and those against make.”
The data contained in the Elashoff and Butler study is “absolutely insufficient” to establish a link, he said.
Sales of Victoza, a daily shot, more than quadrupled in the second quarter to 1.25 billion kroner ($230 million). Bagsvaerd, Denmark-based Novo Nordisk may garner annual sales of 15 billion kroner by 2016, according to Alistair Campbell, a London-based analyst at Berenberg Bank.
Byetta, now sold as a twice-daily injection, had worldwide sales of $710.2 million last year, according to a Jan. 27 Eli Lilly statement. The Indianapolis-based company sells the drug outside the U.S. and splits U.S. revenue with Amylin. Byetta is Amylin’s biggest product.
The concerns also may call into question Amylin’s once-weekly version of Byetta, known as Bydureon, said Les Funtleyder, a money manager and health-care strategist at Miller Tabak & Co. in New York. The FDA rejected Bydureon in October over heart risk concerns. European regulators approved the drug this year.
UCLA’s Butler said he will present new data at the EASD meeting this week. The researcher will face Michael Nauck, head of the Diabeteszentrum Bad Lauterberg in Harz, Germany, whose opinions differ, at the Sept. 16 discussion.
Safety concerns have hurt sales of diabetes drugs in the past. GlaxoSmithKline Plc’s Avandia, once the world’s best-selling treatment for the disease, was withdrawn in Europe and limited in the U.S. last year after a three-year review of its heart risks. Takeda Pharmaceutical Co.’s Actos was pulled from the French market in June after a study showed it carried a slightly increased risk of bladder cancer.
The debate on the safety of GLP-1 therapies is now in the hands of epidemiologists and more informative prospective randomized trials are needed, said Ferrannini.
“We are lucky we have this topic to work on,” said Joergens, the diabetes association’s director. “This is a collateral effect of the fact that people with diabetes now have such a long life expectancy. When you go to the old data, you don’t see that. People died from diabetes.”