Insulin Degludec Distribution to Cease in Germany

Gerda Kneifel, translated by Julia Rommelfanger and adapted by Lisa Nainggolan

September 10, 2015

Novo Nordisk's ultralong-acting basal insulin degludec (Tresiba) is soon to be withdrawn in Germany, because the company could not come to an agreement with the authorities there over pricing, with the result that around 40,000 German patients with type 1 and type 2 diabetes using the product will soon need to switch to a new type of insulin.

As of October 2015, insulin degludec will no longer be available in Germany, because a year ago, the German Institute for Quality and Efficiency in Health Care (IQWIG) reported no additional benefit of insulin degludec over existing insulins. This meant it was much harder for Novo Nordisk to negotiate a premium price for Tresiba, and despite discussions, the company has been unable to agree with the German health insurer so has instead decided to stop marketing the product there.

The German Diabetes Society and others are outraged about the loss of what they say is an individualized treatment option for patients with diabetes simply on economic grounds.

"Unfortunately, due to failed price negotiations, this important medication will no longer be available" in Germany, said Dr Dirk Müller-Wieland, media spokesperson of the German Diabetes Society (DDG) and director of general and internal medicine, diabetes, gastroenterology, endocrinology and metabolic disease at Asklepios Klinik St Georg, in Hamburg, Germany.

The DDG recommends that patients begin the switch to a different basal insulin now, with frequent monitoring and dose adjustments during the transition period, to avoid hypoglycemia.

Dr Thomas Danne, chair of diabetesDE, said he, too, regrets that this important therapy option won't be available in the future. "This will cause enormous costs and also entails health risks," Dr Danne warned. He thinks that certain patients experiencing complex difficulties adjusting to the new agents may even need to be admitted to the hospital. "All this needs to be terminated by the end of September."

Together with a patient, a journalist has initiated a petition against the withdrawal of insulin degludec. Around 1000 people have signed it, and it has now been forwarded to the German Federal Ministry of Health and the Central Federal Association of Health Insurance Funds. It remains to be seen whether or not they will react.

But not everyone agrees this is necessary.

Dr Til Uebel, speaker of the diabetics task force at the German Society for General and Family Medicine (DEGAM), has a different opinion: "I can easily do without degludec — from October on I am not going to miss anything. I think the IQWIG has made a very good decision, and I hope that pharmaceutical companies will direct their future research toward real innovations."

Are There Any Real Advantages to Insulin Degludec?

Insulin degludec was approved by the European Medicines Agency for use in adults with both type 1 and type 2 diabetes in January 2013 and has been on the German market since May 2014. It was approved for use in children in the European Union in December 2014.

The Food and Drug Administration denied US approval of the drug, however, requesting a study with cardiovascular end points, and Dr Uebel said last year that he did not know why the European authorities had not requested a similar trial.

Novo Nordisk resubmitted the US new drug application (NDA) for insulin degludec in April, saying it will complete the required trial by the second half of 2016.

Degludec differs from human insulin by just one detail in its primary structure, but this slightly altered anatomy means it is longer-acting than some already established long-acting insulin analogs, although the exact length of time it is bioavailable is a subject of much debate.

The manufacturer also claims a lower rate of hypoglycemia with degludec, particularly at night, although this is disputed by some.

Nevertheless, the long-acting nature of the agent means more flexibility for patients, many of whom have had difficulties with other basal insulins. Insulin degludec is especially suitable for older patients, patients who need to be cared for, and adolescents who do not cope well with their disease, say some doctors.

"Thanks to degludec, some of our patients are no longer dependent on an insulin pump," Dr Müller-Wieland noted.

The new insulin has also been called the "Sunday-sleeping-in insulin," due to its markedly more flexible time management in terms of injections. Compared with conventional basal insulins, degludec does not require injections at exactly the same time every day.

However these claims are nothing but "advertising," Dr Uebel maintains. In his view, there is no evidence that the apparently unique properties attributed to degludec result in any real advantages for the patient.

"According to its manufacturer it is supposed to act for 48 hours. However, in a phase 2 study a great deal of hypoglycemia occurred in a 48-hour timeframe. Therefore, it is approved for only 24 hours of action," Dr Uebel noted.

But it is "still longer-acting than, for instance, the established insulin detemir and probably a bit longer than glargine," he admitted.

IQWIG Could Not Find Evidence for Additional Benefit

Insulin degludec has always been under the spotlight in Germany. When the IQWIG reported no additional benefit for adults receiving this long-acting insulin a year ago, it said it was because the manufacturer did not allow the publication of "essential data" concerning methods and results of certain studies.

The IQWIG said this lack of data particularly "influenced the claims concerning additional benefit of insulin degludec" in combination with oral antidiabetic agents or with short-acting insulin.

There is also a question mark as to whether there is any additional benefit to treating children with insulin degludec.

Although insulin degludec is approved for children 1 year or older, the IQWIG's investigators found instances of several adverse outcomes in girls — severe symptomatic hypoglycemia and ketoacidosis. And Novo Nordisk did not distinguish between type 1 and type 2 diabetes in its studies conducted in children and adolescents, it maintains.

However, Dr Müller-Wieland thinks that concluding harm from such observations is "simply false. We had, of course, hoped to clarify this matter and other clinical aspects concerning this clinically important therapy in a reasonable manner in the future."

But Dr Uebel stressed he does not prescribe degludec at all.

"Why should I? Conventional [neutral protamine Hagedorn] NPH insulins are established and very effective. When I see patients who are treated with degludec, I discontinue the treatment. None of the studies with this agent have had positive end points. I am not exposing my patients to this."

He also argues that degludec is about 30% to 50% more expensive than glargine and costs about three times as much as conventional insulin therapy.

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