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Merck's Januvia not included in new ADA/EASD diabetes treatment guidelines; reimbursement concerns draw criticism from physicians
Main article Merck's (NYSE:MRK) Januvia and other branded type-II diabetes drugs may face a harder time with reimbursement due to a recent consensus statement on the medical management of hyperglycemia in type II diabetes, according to physicians.

Most physicians disagreed against the proposed "one size fits" all approach, and also raised caution against the new recommendation of giving a patient insulin earlier on in treatment, after failure on metformin and sulfonylureas.

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) late last year released a joint consensus statement to suggest lifestyle changes and metformin as the initial treatment to help newly diagnosed type II diabetes patients achieve A1C goals.

"My feeling, which echoes that of most of my colleagues, is the recent guidelines are based on the current economic situation, and are trying to make physicians prescribe less expensive medications," said Dr Joel Zonszein, director of the clinical diabetes center at the University Hospital of the Albert Einstein College of Medicine, a division of Montefiore Medical Center.

The FDA has now asked for long-term trials with cardiovascular outcomes, and diabetes has become a disease for which it will become harder to develop new drugs, Zonszein noted. There will be more and more limitations placed on pharmaceutical companies developing new drugs in diabetes, due to political reasons, and many companies are going to be discouraged from developing new products, he said.

Suggested second-line treatment from the new recommendations included the addition of pioglitazone (Takeda's [TYO:4502] Actos) or a GLP-1 agonist as well as lifestyle changes and metformin. If these measures do not maintain A1C goals, under the new revisions, initiation of basal insulin, and then transition to intensive insulin is recommended.

Several classes were not included in either the Tier I or Tier II categories. The consensus statement stated that these agents were not included owing to their lower or equivalent overall glucose-lowering effectiveness compared with the Tier I and Tier II agents and/or their limited clinical data or relative expense. These agents included acarbose (Precose), nateglinide (Novartis' Starlix), pramlintide (Amylin's Symlin), repaglinide (Novo Nordisk's Prandin) and sitagliptin (Januvia).

The consensus statement did include one of the newer medications, Amylin's (NASDAQ:AMLN) Byetta, a GLP-1 agonist, as a Tier II agent. But it also indicated that there is insufficient clinical use to be confident regarding long-term product safety.

A spokesperson for Amylin said a majority of managed care providers have added Byetta to their formularies, with about 85% of covered lives able to obtain Byetta for the lowest branded co-pay amount. "With education and updated guidelines, attitudes are shifting towards an increased understanding of the importance of managing both A1C and weight," she said.

The revised treatment guidelines introduced Byetta as the only new addition, placing it in a much more prominent position and suggesting it as the treatment of choice in patients for whom both weight management and hypoglycemia are a concern. About 80% to 90% of the 25m people living with Type II diabetes in the United States fall into this category, according to the spokesperson.

Dr Carol Wysham, a member on Amylin's North American Advisory Board and an endocrinologist at Washington State University, Rockwood Clinic, said the physicians who wrote the consensus statement are more conservative in their approach and treatment of diabetes. Insulin and the sulfonylureas have the best outcomes evidence, she noted, adding, "Byetta and Januvia haven't been subjected to the same randomized trials."

But since Byetta was part of the statement - albeit a Tier II drug - the associations lend very strong support to using a GLP-1 agonist, Wysham said. "We just didn't have enough long term safety and outcomes data to put Byetta into a Tier I category yet," she said.

A spokesperson for Merck said the company is in ongoing conversations with managed care companies. "We look forward to working with ADA and EASD to work on the inclusion of additional classes, which include DPP-4 inhibitors," she said.

Dr Gerald Bernstein, former president of the American Diabetes Association and vice president for medical affairs at biotech company Generex, said the recommendation to use insulin after failure on metformin and sulfonylureas has a lot to do with cost issues. "The push to use insulin earlier has been emerging. But now it's a shift, when organizations have made these statements," he said.

Dr Narinder Duggal, a clinical pharmacy specialist, internist and medical director of Liberty Bay Internal Medicine, who specializes in diabetes care, said under this new statement, physicians may have a harder time with reimbursement for more expensive branded drugs. "With these hard economic times, patients will have a pretty expensive co-pay. With the cost of these drugs, people are very sensitive to that," Duggal said.

Unfortunately, these guidelines are not based on hard clinical data, Zonszein said. There are no clinical studies to show that one medication is better over another, and the problem with the push to ask physicians to use insulin earlier on in treatment, after failure on metformin and sulfonylureas, will be patient monitoring. "Insulin also causes a greater risk for hypoglycaemia and hospitalization, especially in elderly patients," he added.

Reimbursement concerns were cited by a number of physicians, as under the new treatment guidelines, branded drugs may face a higher uphill battle for coverage. "Unfortunately, the people who ultimately look at these guidelines are the HMOs. The result is more hardship for physicians," Zonszein said.

One of his patients, who was denied Januvia, ended up getting hypoglycaemia from using insulin. "They want to save the hundred dollars for Januvia, but don't think about hospitalization costs," Zonszein said, adding that he did not agree with the decision to place DPP-4 inhibitors out of mainstream therapy when they may be very effective in elderly patients.

This new treatment algorithm certainly continues to push for metformin's use, as its safety margin is unprecedented, said Duggal. But insulin may come in as a third-line agent now, he explained, even though it may not be the most appropriate agent to use in some patients. "But it's the easy way for physicians. Doctors will take the path of least resistance to bring the HbA1c levels down to normal," said Duggal.

Dr Sonal Singh, an assistant professor of internal medicine at Wake Forest University Baptist Medical Center, said this is why physicians need a center for comparative effectiveness that can decide if newer therapies are cost-effective. "Pushing insulin use quicker in the treatment doesn't mean Lantus, it just means insulin," he said, referring to Sanofi-Aventis' branded drug.

Actos will likely benefit from this statement, and is going to be there as a third-line drug, under the guidelines, Duggal added. Panel members unanimously advised against GSK's (NYSE:GSK) Avandia based on the potential associated cardiovascular risks.

Sulfonylureas are basically are out of the picture, or should be, said Bernstein. Clinicians and researchers believe this class either causes too much hypoglycaemia, or increases cardiovascular risks, he said, adding that the use of this class probably only has one advantage - it's cheap.

The spokesperson for Merck said the company is not surprised or concerned that the DPP-4 class was not included, as it typically takes more time for newer drugs to be included in the treatment algorithm. Other guidelines that include DPP-4s include those from the American Association of Clinical Endocrinologists, the Canadian Diabetes Association, and the recently updated NICE guidelines.

Two-year safety data on Januvia was published in October 2008, and showed a favorable risk-benefit profile, the spokesperson said. Januvia offers a strong efficacy profile with no associated weight gain or increased risk of hypoglycemia, she added. "Januvia works. The side-effect profile is actually pretty good," Bernstein said.

"Many patients will respond better to some medications than others. To use a one size fits all approach is not a very smart thing to propose," said Zonszein.

Merck has a market cap of USD 55bn.
by Kimberly Ha and Sasha Damouni