Due to the progressive nature of type 2 diabetes, insulin therapy is often required to achieve glycaemic control after several years of disease.1 Insulin degludec (Tresiba®, Novo Nordisk) is an ultra-long-acting basal insulin analogue that offers a duration of action of more than 42 hours in adults.2 It therefore allows more flexibility compared with other long-acting insulin analogues in terms of daily dosing times, and has been associated with reduced rates of hypoglycemia. 3, 4 Following initial clinical trial data, interest in insulin degludec rocketed but was dented after a meta-analysis of clinical trials, carried out by the US Food and Drug Administration (FDA), suggested an increase of about 60% in the incidence of cardiovascular complications, based on a composite endpoint combining myocardial infarction (MI), stroke and cardiovascular death.5
In February 2013, the FDA mandated a cardiovascular safety trial for insulin degludec before they would approve it, although it had been approved by the European Union the previous month. Results of the Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Subjects With Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) were presented during the 77th Scientific Sessions of the American Diabetes Association (ADA) on June 12, 2017, in San Diego, California and simultaneously published in the New England Journal of Medicine.6 A total of 7637 patients with type 2 diabetes were randomly assigned to receive either insulin degludec or insulin glargine once daily. The primary outcome measure was the first occurrence of a major cardiovascular event (MACE, a composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke). The secondary endpoint was severe hypoglycaemia, as defined by the ADA. The majority of participants (85.2%) had established cardiovascular disease, chronic kidney disease, or both at the start of the study. The study met its endpoint of noninferiority to insulin glargine: MACE occurred in 8.5% of the degludec group and in 9.3% in the glargine group (hazard ratio, 0.91; p<0.001 for noninferiority). At 24 months, the mean glycated haemoglobin (HbA1c) level was 7.5±1.2% in each group, whereas the mean fasting plasma glucose level was significantly lower in the degludec group than in the glargine group (128±56 vs. 136±57 mg/dL, p<0.001).
Severe hypoglycaemia occurred in 187 patients (4.9%) in the degludec group and in 252 (6.6%) in the glargine group, a 40% reduction (p<0.001). There was also a 53% reduction in the rate of nocturnal severe hypoglycaemia in the degludec group. However, a limitation of the study was the fact that data on moderate hypoglycaemia were not collected, so the impact on the most common type of hypoglycaemia experienced by patients was not assessed. Rates of adverse events did not differ between the two groups and were consistent with those seen in previous studies of insulin degludec.3, 7
In a press statement, Mads Krogsgaard Thomsen, executive vice president and chief science officer of Novo Nordisk, said: “The risk of severe hypoglycaemia is a major cause for people with type 2 diabetes not reaching their treatment targets. However, with the DEVOTE data, we have demonstrated that the strong clinical profile of Tresiba leads to significant reduction in severe hypoglycaemia in people with type 2 diabetes.”
In two poster sessions at the ADA sessions, results of the EUropean TREsiba AudiT (EU-TREAT) real-world study were announced.8, 9 The first two investigated the effect of switching to insulin degludec from any other basal insulin in people with type 1 (n=1,717) and type 2 (n=833) diabetes. Outcome measurements were performed 6±3 and 12±3 months after initiation of insulin degludec and were compared to baseline measurements taken in the three months prior to the switch. People with type 1 diabetes and type 2 diabetes experienced a significant reduction in HbA1c (-0.2% for type 1 diabetes and -0.5% for type 2 diabetes) six months after switching to insulin degludec from another basal insulin, primarily insulin glargine and insulin detemir. These reductions were sustained at 12 months. Participants also reported significantly lower incidences of overall hypoglycaemia after switching to insulin degludec: an 85% reduction in people with type 1 diabetes, and a 92% reduction in people with type 2 diabetes. Similar results were reported at 12 months. In addition, fasting plasma glucose was significantly reduced at six months (-18.7 mg/dL for type 1 diabetes, and -23.7 mg/dL for type 2 diabetes) and maintained for 12 months. Participants were also able to lower their daily dose of insulin at six months, by 4.9 units in type 1 diabetes and by 2.5 units in type 2 diabetes. These doses remained stable at 12 months.
A third poster session presented the results of a US retrospective cohort analysis of data from the IBM Explorys database. This study assessing the impact of switching from any other basal insulin to insulin degludec in people with type 2 diabetes and included people who used a basal insulin 90 days prior to initiating insulin degludec. Measurements were collected 90 days before, and 90±45 days after, initiating insulin degludec. At 90 days after the switch, HbA1c decreased significantly (-0.75%), and the percentage of people reaching their target HbA1c of <7% more than doubled (from 5.3% to 12.4%). In addition, the proportion of people who experienced one or more hypoglycaemic events decreased from 7.3% to 6.9% following the switch to insulin degludec.
These new data add to the body of evidence in support of insulin degludec. The FDA approved insulin degludec in November 2015 on the basis of interim results from DEVOTE.10 In light of the latest findings, Novo Nordisk has submitted a supplemental application to the FDA for an expanded label indication, which, if successful, has the potential to expand the use of insulin degludec in type 2 diabetes.