Treating To Target in Type 2 Diabetes

Principal investigator:Rury Holman

Co-investigators:Jonathan Levy
Andrew Farmer
Melanie Davies

Sponsor:Novo Nordisk Limited (UK)

Funder:Novo Nordisk

Reference number:ISRCTN51125379

The Treating To Target in Type 2 diabetes (4-T) study was a three-year, multi-centre, open-label, randomised, parallel-group trial comparing the safety and efficacy of three different analogue insulin treatment regimens in 700 participants with Type 2 diabetes inadequately controlled by oral therapy.

One-year results

The 4-T One-Year results were presented as a "late breaking trial" at the 43rd EASD meeting in Amsterdam on 21st September 2007.

Download the full slide set here.

Brief overview

The Treating To Target in Type 2 Diabetes (4-T) study is an open-label, three-year, randomised controlled trial in 58 UK and Irish centres comparing the efficacy and safety of three analogue insulin regimens in 708 patients with type 2 diabetes inadequately controlled on maximally tolerated sulphonylurea and metformin therapy. Patients with a suboptimal HbA1c level (7.0 to 10.0%) were assigned at random to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). At one year, mean HbA1c levels were similar (P = 0.08) in the biphasic group (7.3%) and the prandial group (7.2%), but higher in the basal group (7.6%, P<0.001 for both comparisons). The respective proportions of patients with an HbA1c level of 6.5% or less were 17.0%, 23.9%, and 8.1%; respective mean numbers of hypoglycemic events per patient per year were 5.7, 12.0, and 2.3; and respective mean weight gains were 4.7 kg, 5.7 kg, and 1.9 kg. Rates of adverse events were similar among the three groups.

The one-year results show that a single analogue-insulin formulation added to metformin and sulfonylurea resulted in an HbA1c level of 6.5% or less in a minority of patients at one year. The addition of biphasic or prandial insulin aspart reduced levels more than the addition of basal insulin detemir, but were associated with greater risks of hypoglycemia and weight gain. This first year of the three-year 4-T study suggests that most patients are likely to need more than one type of insulin to achieve target glucose levels. The final two years of the trial will examine specifically the use of complex insulin regimens in these patients.

Full one-year results

These are published in the New England Journal of Medicine with an accompanying editorial.

Final results

The final 4-T results were presented during the "Latest clinical trials" symposium at the IDF World Diabetes Congress in Montreal, Canada on Thursday 22nd October 2009.

Download the slide set here.

Brief Overview

Patients who added a basal or prandial insulin-based regimen to oral therapy had better glycated haemoglobin control than patients who added a biphasic insulin-based regimen. Fewer hypoglycaemic episodes and less weight gain occurred in patients adding basal insulin.

The 4-T trial enrolled patients whose glycaemic control was inadequate despite therapy with two oral agents (metformin and sulfonylurea). They were assigned at random to receive biphasic insulin injections twice a day (biphasic insulin aspart 30, NovoMix 30®), prandial insulin injections three times a day (insulin aspart, NovoRapid®), or basal insulin injected once a day (insulin detemir, Levemir®), aiming to achieve glycated haemoglobin (HbA1c) levels of 6.5% or less. If after the first year of the trial their glycated haemoglobin levels remained above 6.5%, sulfonylurea therapy was stopped and a second type of insulin commenced. For those on biphasic insulin, once daily prandial insulin was added; for those on prandial insulin, once daily basal insulin was added; and for those on basal insulin, three times a day prandial insulin was added.

At three years the median glycated haemoglobin overall was 6.9% (7.1% in the biphasic arm, 6.9% in the basal arm and 6.8% in the prandial arm), with three-quarters (74.3%) patients taking two types of insulin. More patients commencing therapy with a basal (43.2%) or prandial (44.8%) insulin achieved glycated haemoglobin levels of 6.5% or less than those commencing with a biphasic insulin (31.9%). Weight gain over three years in those commencing with basal insulin was less (3.6 kg) than with biphasic insulin (5.7 kg) or prandial insulin (6.4 kg). In addition, those randomized to the basal insulin approach had fewer hypoglycaemic episodes (1.7 per patient per year) than the biphasic (3.0 per patient per year) or prandial (5.7 per patient per year) insulin approaches.