Lead author, Professor Rury Holman from the Diabetes Trials Unit of Oxford University reported the results of the three-year randomised, controlled, multicentre study, in which 708 patients with suboptimal glycated haemoglobin levels (HbA1c) on metformin and sulfonylurea therapy were assigned to receive NovoMix® 30 (biphasic insulin aspart) twice daily, mealtime NovoRapid® (insulin aspart) three times daily, or Levemir® (insulin detemir) once daily. A second insulin was added after year one, or later, if HbA1c was more than 6.5%; NovoRapid® once daily, Levemir® once daily or NovoRapid® three times daily, respectively. Among the outcome measures after three years were mean HbA1c, the proportion of patients with an HbA1c level of 7% or less, the rate of hypoglycaemia, and weight gain.
It is well known that long-term improvements in blood glucose control can reduce the risk of diabetic complications, but large-scale direct comparisons of different insulin regimens to maintain safe glycaemic control have not been performed until now.
The design of the 4-T trial made it possible to report differences between three different initiation and intensification regimens (all with insulin analogues) over the longest randomised 'treat-to-target' comparison of insulin therapies yet published.
The study showed that at three years, the mean HbA1c level did not differ between groups (an overall value of 6.9%, 95% confidence interval, 6.8 to 7.1). The proportion of patients achieving an HbA1c level of 7% or less was high, and similar in the NovoRapid® (67%) and Levemir® initiation groups (63%), but somewhat lower in the NovoMix® (51%) group. In the NovoMix® group, however, fewer patients received intensification with a second insulin preparation during the three-year treatment period.
The median numbers of hypoglycaemic events per patient per year were relatively low at all levels of HbA1c, but highest for the NovoRapid® initiation group: 1.7 for Levemir®, 3.0 for NovoMix® and 5.5 for NovoRapid® initiation groups, and the mean weight gains over three years were 3.6 kg, 5.7 kg and 6.4 kg respectively. Thus, the group initiated on once-daily Levemir® therapy experienced a statistically significant lower weight gain even when being intensified to a basal bolus therapy with NovoRapid®. The rates of adverse events were similar among all groups.
Mads Krogsgaard Thomsen, chief science officer of Novo Nordisk, calls the results very encouraging. "It is a widespread belief in the diabetes community that tight blood glucose control is difficult to achieve in a real-life setting because of a high risk of hypoglycaemia. The 4-T study shows that this need not be the case. By following a relatively simple treatment algorithm, all groups in the study achieved good results with a high completion rate and a low risk of adverse events such as hypoglycaemia, even among those with an HbA1c of less than 6.5%."
Type 2 diabetes is a progressive disease, which means that both dosing and treatment regimens must be changed over time when a patient's current therapy is no longer able to control blood sugar levels satisfactorily.
Mads Krogsgaard Thomsen says: "Another encouraging result of the 4-T study is that it confirms findings from other, shorter studies: that initiation of insulin therapy with Levemir® is associated with a low risk of hypoglycaemia and the lowest degree of weight gain[2,3]. It's also interesting to note that fewer patients who started insulin treatment with twice-daily NovoMix® 30 dropped out or were intensified during the study, making it a convenient yet effective treatment option."
"We are proud to have - together with Diabetes UK - supported this trial, which I believe in the future will be seen as a significant advancement in our understanding of how to initiate and intensify insulin treatment in patients with type 2 diabetes as their disease progresses," says Mads Krogsgaard Thomsen.
Novo Nordisk is a healthcare company and a world leader in diabetes care. In addition, Novo Nordisk has a leading position within areas such as haemostasis management, growth hormone therapy and hormone replacement therapy. Novo Nordisk manufactures and markets pharmaceutical products and services that make a significant difference to patients, the medical profession and society. With headquarters in Denmark, Novo Nordisk employs more than 28,500 employees in 81 countries, and markets its products in 179 countries. Novo Nordisk's B shares are listed on the stock exchanges in Copenhagen and London. Its ADRs are listed on the New York Stock Exchange under the symbol 'NVO'. For more information, visit novonordisk.com.
1. Grade 3 Hypoglycemic events no./patient/yr Median (95% CI) per three arms: 0, Holman R et al, NEJM Oct 29, 2009.
2. Philis Tsimikas A et al, Clin Ther 2006; 28(10):1569â81. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes.
3. Rosenstock J et al, Diabetologia 2008; 51:408â416. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when added to glucose-lowering drugs in insulin-naive people with type 2 diabetes.