Insulin degludec. Uncertainty over cardiovascular harms.

Insulin isophane (NPH) is the standard long-acting human insulin for patients with type 1 and type 2 diabetes. Long-acting human insulin analogues are also available: insulin glargine and insulin detemir. Uncertainties remain concerning their long-term adverse effects. Insulin degludec (Tresiba, Novo Nordisk) is another long-acting human insulin analogue, also approved in the EU for patients with type 1 and type 2 diabetes. It was authorised at a concentration of 100 units per ml, like other insulins, and also at a concentration of 200 units per ml. There are no comparative data on insulin degludec 200 units per ml in patients using high doses of insulin. Insulin degludec has mainly been evaluated in ten randomised, unblinded, "non-inferiority" trials lasting 26 to 52 weeks, nine versus insulin glargine and one versus insulin detemir. Insulin degludec was administered at a fixed time each evening, or in either the morning or evening on alternate days, at varying intervals of 8 to 40 hours between doses. Efficacy in terms of HbA1c control was similar to that of the other insulin analogues administered once a day. The frequency of severe hypoglycaemia was similar in the groups treated with insulin degludec and those treated with the other insulins (10% to 12% among patients with type 1 diabetes and less than 5% in patients with type 2 diabetes). Deaths and other serious adverse events were similarly frequent in the different groups. A meta-analysis of clinical trials, carried out by the US Food and Drug Administration, suggested an increase of about 60% in the incidence of cardiovascular complications, based on a composite endpoint combining myocardial infarction, stroke and cardiovascular death. Other adverse effects observed in these trials were already known to occur with human insulin and its analogues, including weight gain, hypersensitivity reactions, reactions at the injection site, etc. The trials were too short in duration to assess long-term harms, particularly cancer. Clinical experience with insulin degludec in pregnant women is very limited. It is therefore best to avoid using this analogue during pregnancy. In France, the concentration of all other insulins injected with a syringe or prefilled pen is 100 units per ml. The new concentration of 200 units per ml contained in insulin degludec prefilled pens creates a risk of confusion and overdose. In practice, there is already a relatively wide range of options available for patients with type 1 or type 2 diabetes who require insulin therapy. As insulin degludec has no proven advantages, it is better to avoid using it, at least pending further data on the risk of cardiovascular events. Insulin isophane remains the first-choice long-acting insulin, while insulin glargine is most appropriate for some patients with type 1 diabetes.