European Regulator Finds Little Risk in Diabetes Drugs

Regulators in Europe have concluded that there was little evidence that widely used drugs to treat Type 2 diabetes could cause pancreatic inflammation or pancreatic cancer, a finding that might reassure patients while also removing a potential sales threat for Merck and some other drug companies.

“Presently available data do not confirm recent concerns over an increased risk of pancreatic adverse events with these medicines,” the European Medicines Agency said in a news release on Friday.

Both the European agency and its American counterpart, the Food and Drug Administration, have been reviewing the safety of a big class of drugs that includes Merck’s Januvia and the drugs Byetta, Bydureon and Onglyza, which are sold by Bristol-Myers Squibb and AstraZeneca.

The F.D.A. has not yet released its conclusions.

The concerns have been raised over the last few years mainly by Dr. Peter Butler, the chief of endocrinology at the University of California at Los Angeles. Dr. Butler has been hailed by some drug safety watchdogs as a hero for standing up to the drug companies but criticized by many diabetes experts as a zealot.

In his latest study, the one that triggered the reviews, Dr. Butler and colleagues examined the pancreases from 34 organ donors, some with diabetes and some without, who had died from causes other than diabetes. They found that the pancreases of the people who had used Januvia or Byetta tended to have more signs of inflammation and precancerous cellular changes than the pancreases from diabetics who had not taken those drugs and those from nondiabetics.

But the European Medicines Agency said Friday that the study had “a number of methodological limitations and potential sources of bias.” The donors who had taken Januvia or Byetta were older and had diabetes for far longer than the diabetics who had not taken the drugs, making it difficult to draw conclusions on the possible effects of the drugs.

The agency said the prescribing information for the drugs already contained warnings about pancreatic inflammation, known as pancreatitis. It said clinical trials had shown no increased risk of pancreatic cancer, though that the trials were too small to draw firm conclusions. It said “some uncertainties remain’’ regarding the long-term effects of the drugs, but much larger trials are under way to answer those questions.

The drugs involved, which the F.D.A. calls incretin mimetics and the European agency calls GLP-1-based therapies, effectively increase the body’s levels of a hormone called glucagon-, like peptide-1, which helps control blood sugar levels. Some of the drugs, known as GLP-1 agonists, mimic the effect of the hormone, while others, known as DPP-4 inhibitors, slow the breakdown of the body’s own hormone.

Collectively, the drugs had more than $9 billion in global sales last year, led by Merck’s Januvia and a related drug, Janumet, which together had sales of $5.7 billion. Other drugs include Victoza from Novo Nordisk and Tradjenta from Eli Lilly and Boehringer Ingelheim.

Roche Abandons New Diabetes Drug

Roche, the Swiss pharmaceutical giant, has discontinued development of a potentially important diabetes drug, a move that could raise new safety questions about the entire category of drugs, which includes the controversial diabetes medicine Avandia.

Roche said Wednesday that a safety monitoring committee had recommended halting a late-stage clinical trial of the drug, aleglitazar, because of “safety signals and lack of efficacy.” The company said that it decided to halt that study and all others involving the drug.

“We are disappointed by this outcome as we hoped that aleglitazar would provide significant benefit for patients with Type 2 diabetes who are at risk of cardiovascular disease,” Dr. Hal Barron, the chief medical officer, said in a statement.

A spokesman for the company, which is based in Basel, Switzerland, said the drug had caused an increase in fractures, kidney problems and heart failure in the trial.

Aleglitazar was designed to treat not only diabetes but cardiovascular risk factors like cholesterol as well. In a bold move, Roche was testing the drug not for its ability to lower blood sugar, the usual yardstick for a diabetes drug, but rather to see if it could prevent heart attacks and strokes in people with Type 2 diabetes.

A success would have been considered a major advance for diabetes because until now, better control of blood sugar has not generally been shown to lower the risk of heart attacks and strokes.

Still, it was, perhaps, a long shot. Many other companies developing similar drugs abandoned their efforts years ago after running into various safety problems.

The failure of aleglitazar could conceivably play into the U.S. Food and Drug Administration’s deliberations over GlaxoSmithKline’s diabetes drug Avandia, which has a somewhat similar mechanism of action.

Avandia’s use was severely restricted in the United States and banned in Europe in 2010 because of concerns it could raise the risk of heart attacks and stroke. But an advisory committee to the F.D.A. recommended last month that the restrictions be eased. The agency itself has yet to make a decision.

Critics of Avandia could point to the setback to Roche’s drug to argue that the entire class of drugs is dangerous and that the restrictions on Avandia should remain in place.

However, while Roche’s statement indicated that aleglitazar did not lower the risk of heart attacks and strokes, it did not appear that the drug increased those risks, either, since the safety issues that ended trial were unrelated to heart attacks and strokes. Supporters of Avandia might say this offers more evidence that Avandia also does not raise cardiovascular risks.

Last year, Roche gave up on another potential blockbuster cardiovascular drug, dalcetrapib, which was aimed at increasing levels of so-called good cholesterol. In that case, a trial showed the drug did not work.

Despite these failures in cardiovascular drugs, investors in Roche typically care most about its main business of cancer drugs, including Avastin, Herceptin and Rituxan.

The study of aleglitazar involved more than 7,000 people with diabetes in numerous countries, all of whom had also suffered a recent heart attack or the onset or worsening of cardiac pain. The study was supposed to last five years, until around the beginning of 2015.

Aleglitazar works by activating two receptors in the body, known as PPAR alpha and PPAR gamma.

Avandia activates mainly the gamma receptor, as does a similar diabetes drug, Takeda’s Actos. Other drugs known as fibrates, which are used to lower triglycerides and raise good cholesterol, activate the alpha receptor.

Roche aimed for a drug that activated both receptors equally, hoping it would improve both blood lipids and blood sugar, and lower the extra cardiovascular risks that diabetics face.

But several other dual PPAR agonists, as the drugs are called, failed because of various safety issues years ago, leaving Roche perhaps the last big company pursuing that type of drug.

Previous failures included AstraZeneca’s Galida, which led to kidney problems, Merck’s MK-767, which produced tumors in mice, and Takeda’s TAK-559, which caused liver problems.

Bristol-Myers Squibb’s Pargluva was actually recommended for approval by an F.D.A. advisory committee in 2005. But shortly thereafter, Dr. Steven Nissen and other researchers at the Cleveland Clinic published an analysis showing that the drug might increase the risk of heart attacks and strokes. The F.D.A. also requested more safety data, and Bristol-Myers discontinued development.

Invokana Wins F.D.A. Approval for Diabetes Treatment

The drug, Invokana, will be sold by Johnson & Johnson and treats patients with type 2 diabetes in a new way, by causing blood sugar to be excreted in the urine. Many existing drugs work by affecting the supply or use of insulin.

“We continue to advance innovation with the approval of new drug classes that provide additional treatment options for chronic conditions,” Dr. Mary Parks, who oversees drugs for metabolic diseases at the F.D.A., said in a statement.

Invokana will have a wholesale price of $8.77 per tablet, with one tablet taken daily. Johnson & Johnson said the price was competitive with that of some other diabetes drugs.

Clinical trials of more than 10,000 patients showed that Invokana improved patients’ blood-sugar levels and also led to weight loss and reductions in blood pressure. But the drug, whose generic name is canagliflozin, also has potentially serious side effects. The clinical trials revealed some signs of elevated stroke risk and a small increase in patients’ experiencing heart attacks within the first 30 days of taking the medicine. The drug also was shown to raise LDL, or “bad” cholesterol levels, although it also raised the level of HDL, or “good” cholesterol.

However, an F.D.A. spokeswoman said Friday that the significance of those findings was unclear, and the label of the drug includes no warnings about heart attacks or strokes. The F.D.A. is requiring Johnson & Johnson to conduct five post-marketing studies, including a clinical trial to determine more definitively if the drug increases those risks.

The F.D.A. said the drug’s most common side effects were vaginal yeast infections and urinary tract infections.

In January, an F.D.A. advisory panel voted 10 to 5 in favor of approval. But panel members called on Johnson & Johnson to closely monitor patients enrolled in long-term safety studies. Some of the members said they did not think the drug should be prescribed to people with moderate kidney disease.

The drug wasn’t as effective in such patients, and they were at a higher risk for the negative side effects, compared to people with normal kidney function. Invokana is not recommended for patients with severe kidney disease.

An estimated 26 million Americans have type 2 diabetes, and many of the medications on the market come with side effects like weight gain and hypoglycemia, or a dangerous drop in blood sugar. Patients taking Invokana experienced fewer episodes of hypoglycemia than those taking another diabetes drug, glimepiride, or Amaryl, but a similar number as patients taking the drug sitagliptin, or Januvia.

Invokana is in a class of drugs called SGLT2 inhibitors. They block the action of the sodium-glucose co-transporter 2, which puts sugar removed from the blood by the kidneys back into the bloodstream.

Last year, the Food and Drug Administration rejected another drug in that class, dapagliflozin from Bristol-Myers Squibb and AstraZeneca, because of safety concerns, including a possible increased risk of breast and bladder cancers. But it was approved in Europe in November under the name Forxiga.

Johnson & Johnson is also seeking approval in Europe for Invokana, which it licensed from Japan’s Mitsubishi Tanabe Pharma.

Wall Street analysts have predicted that Invokana could be a good seller for Johnson & Johnson. Lawrence Biegelsen, of Wells Fargo, estimated early this year that the drug could bring in $111 million in 2013, with sales increasing to $667 million by 2016.