FDA raises concerns about ultra-long acting insulins given green light in Europe and Japan

BMJ 2012; 345 doi: (Published 30 October 2012) Cite this as: BMJ 2012;345:e7323
  1. Ingrid Torjesen
  1. 1London

The US drug regulator has announced that it intends to take a close look at the cardiovascular safety of the ultra-long acting insulin degludec next week, because data had indicated that the drug was associated with “an excess risk for cardiovascular events” in comparison with other insulins, it said.

The Food and Drug Administration will assess the safety and efficacy of two products, insulin degludec (marketed as Tresiba) and the combination of insulin degludec and insulin aspart (Ryzodeg) for the treatment of type 1 and type 2 diabetes mellitus at a meeting on 8 November.

A document published by the FDA committee ahead of this meeting said, “This meeting will focus on the cardiovascular safety of two products, insulin degludec/insulin aspart [rDNA origin] and insulin degludec [rDNA origin], as meta-analyses of several clinical trials suggest an excess risk for cardiovascular events with this insulin over its comparators.”1

The Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) issued a positive opinion on the two products on 18 October, recommending that they be licensed in Europe. Japan’s Pharmaceuticals and Medical Devices Agency approved insulin degludec on 28 September.

Edwin Gale, professor of diabetes medicine at the University of Bristol, said that there were precedents for antidiabetes drugs causing cardiovascular events: an increased risk was found with a proinsulin during development, and rosiglitazone (Avandia) was withdrawn after it was linked to cardiac events.2

He said that the FDA had “burnt its fingers” on rosiglitazone so was now “very hot on cardiovascular safety.”

Gale added, “FDA processes aren’t supposed to be more stringent. Either EMA didn’t see that meta-analysis, or they saw it and thought it was okay. It is quite irrational for two regulatory authorities to look at the same data and draw opposite conclusions, so this has to be resolved somehow.”

Mike Rulis, a spokesman for Novo Nordisk, which makes degludec, said that the European and Japanese authorities had received the same data as the FDA had.

A spokeswoman for the European Medicines Agency confirmed that the meta-analyses on cardiovascular safety about which the FDA was concerned had been assessed by the Committee for Medicinal Products for Human Use.

She said, “Following evaluation of all available data, the committee concluded that the demonstrated benefits of Tresiba and Ryzodeg outweigh their known risks and recommended authorization of these two medicines to the European Commission.”

In its summary evaluation the committee said that the benefits of Tresiba and Ryzodeg were their ability to lower blood glucose concentrations and HbA1c respectively,3 4 resulting in the risk of nocturnal hypoglycemia being lower than that with the insulin glargine. For both products overall hypoglycemia remained the most common side effect, and the response did not highlight any particular concerns about cardiovascular safety. The European committee’s full detailed evaluation and conclusions will be published as part of the European public assessment report on the drugs once the European Commission has issued its marketing authorization decision, which is expected in two to three months.

The assessment report from Japan’s drug regulator said that the prespecified major adverse cardiovascular event meta-analysis showed an incidence rate of 1.48 such events per 100 patient years of exposure in the combined Tresiba and Ryzodeg group and of 1.44 in the comparator group. The estimated hazard ratio for Tresiba and Ryzodeg versus the comparators was not statistically significant (1.1 (95% confidence interval 0.7 to 1.8)). The regulator therefore concluded there was no marked difference in cardiovascular risk between the Tresiba and Ryzodeg group and the comparator group.5

The FDA had been expected to be the first regulator to assess the drugs, but in June the agency extended the review period by three months,6 and in July it extended it again, a move that is likely to push the final decision on the insulins to next year.7


Cite this as: BMJ 2012;345:e7323