Clinical Trial
Adding insulin to oral therapy in type 2 diabetes significantly improves glucose control but many patients will need more than one type of insulin to achieve target glucose levels

Results of the 4-T trial presented at the 43rd European Association for the Study of Diabetes (EASD) meeting, Amsterdam, Holland Results from a UK study by Oxford University have shown that three different types of insulin all improve glucose control when added to oral therapy.

Those designed to be given two or three times a day improved glucose control more than the type given once a day, but they were associated with more frequent hypoglycaemia (glucose values that are too low) and greater weight gain. Only a small proportion of patients were able to reach current best practice glucose targets whichever insulin was used. The 4-T (Treating to Target in Type 2 Diabetes) trial enrolled patients whose glucose control was inadequate despite taking two different antidiabetic tablets.

The trial compared the effects over one year of adding biphasic insulin injections two times a day (biphasic insulin aspart 30), mealtime insulin injections three times a day (insulin aspart), or basal insulin injected once a day (insulin detemir). Adding these analogue insulins to existing dual oral therapy with metformin and sulfonylurea lowered glycosylated haemoglobin (HbA1c) values within three months and then sustained these reductions to give a drop at one year of 1.3% with biphasic, 1.4% with mealtime and 0.8% with basal insulin. A minority of patients, however, achieved target HbA1c values of 6.5% or less. The final two years of the 4-T study, due to report in 2009, are designed to determine how often a second insulin needs to be added and whether glucose targets can be met when two types of insulin are used together. ‘We know from the UK Prospective Diabetes Study that type 2 diabetes is a progressive condition in which the majority of patients eventually require insulin therapy’, commented Prof. Rury Holman of Oxford University, Principal Investigator of the study. “This largescale study will help patients and physicians choose which type of insulin to use first by knowing their expected impact on glucose control, weight and hypoglycaemia, but suggests also that most patients are likely to need more than one type of insulin if they are to maintain recommended glucose levels in the longer term.”

Dr. Jonathan Levy of the Oxford Centre for Diabetes, Endocrinology and Metabolism, Co-Principal Investigator added: “This is the first trial to have compared specifically three different ways of adding insulin to tablets in patients with type 2 diabetes, and to have followed them for a full year. The methods used in the trial can be applied directly to a primary care setting.” Dr. Melanie Davies of Leicester University, Co-Principal Investigator stated: “4-T is a unique and long awaited clinical trial that finally gives clinicians clear information as to the relative benefits and risks of using these three approaches to insulin management in people with type 2 diabetes. Our practice can now be based on good research evidence rather than anecdote.”

Full results of the 4-T study are published online in the New England Journal of Medicine on Friday 21st September 2007.

The details
* The UK Prospective Diabetes Study (UKPDS) demonstrated that improved glycaemic control reduces the risk of complications in type 2 diabetes. It showed also that type 2 diabetes is a progressive condition in which HbA1c levels rise inexorably, secondary to declining beta cell function. As a result, oral therapy needs to be escalated repeatedly with the majority of patients requiring insulin in the longer term. There remains, however, considerable uncertainty as to which insulin regimen should be used when oral therapy becomes insufficient. Analogue insulin preparations have been shown to reduce the risk of hypoglycaemia whilst minimising weight gain, but there is no consensus about whether to commence therapy with a short acting, a long acting or a biphasic preparation. It is also uncertain how best to select an appropriate starting dose given that insulin requirements are often 2-3 times higher in type 2 than in type 1 diabetes. In addition, when insulin is initiated there is often concern regarding risks of hypoglycemia and weight gain, with continued debate as to the preferred insulin regimen and the role of continuing OADs, particularly sulfonylureas. Even when insulin is initiated using conventional regimens, many subjects do not reach the suggested HbA1c targets. To date there has been no large-scale direct comparison of initiating insulin therapy using different analogue insulin regimens in combination with OADs, or guidance concerning appropriate starting doses.

* The Treating to Target in Type 2 Diabetes (4-T) trial is a three-year, randomized controlled trial in 58 centres that is comparing the efficacy and safety of 3 different analogue insulin regimens in 708 patients with type 2 diabetes inadequately controlled on their current doses of oral anti-diabetic medication, in this case, maximally tolerated doses of sulphonylurea and metformin therapies. See www.dtu.ox.ac.uk/4-T.

At randomisation, patients were allocated to open-label therapy with:

• Twice a day biphasic insulin aspart 30)
• Three times a day aspart insulin with meals)
• Once a day detemir insulin)

During the first year of the trial insulin therapy was restricted to a single insulin formulation (unless unacceptable hyperglycaemia occurred, defined as a HbA1c >/=10% or two consecutive values >/=8% at or after 24 weeks), aiming to achieve HbA1c levels </=6.5%. Year 1 of 4-T is designed to provide the evidence base that will assist:

• The choice of an appropriate insulin regimen when treatment with sulphonylurea and/or metformin becomes insufficient
• Determination of an appropriate insulin starting dose for individual patients.

During the second and third years of the trial more complex insulin regimens will be introduced when HbA1c levels are greater than 6.5%. Years 2 to 3 of 4-T are designed to provide the evidence base that will assist:

• Assessing the need for more than one insulin formulation to achieve glucose targets.
• Managing cessation of sulphonylurea therapy and transition to a more complex insulin regimens if target glucose levels are not met.

The 4-T trial was designed and developed by the University of Oxford Diabetes Trials Unit (DTU) in an academic collaboration with Novo Nordisk. The data arising from the trial are owned, analysed and published independently by the Diabetes Trials Unit. Novo Nordisk (www.novnordisk.com) provides funding, logistical support and study medication. Diabetes UK fund a 4-T continuous glucose monitoring sub study.

* The Diabetes Trials Unit (DTU), founded in 1985 by Prof. Holman, is one of the largest European clinical diabetes research groups. It is based within the Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), a part of Oxford University. The DTU investigates the pathophysiology of type 2 diabetes, evaluates potential therapeutic and preventative treatments and runs several multi-centre clinical-outcome trials including AFORRD, the Treating To Target in Type 2 diabetes (4-T) study and the UK Prospective Diabetes Study (UKPDS). See www.dtu.ox.ac.uk.

* OCDEM (the Oxford Centre for Diabetes, Endocrinology and Metabolism) is a pioneering centre at Oxford University which combines clinical care, research and education in diabetes, endocrine and metabolic diseases. By promoting world-class research, it aims to enhance understanding of these diseases and to accelerate the search for new treatments and cures. See  www.ocdem.ox.ac.uk.