Insulin Added to Oral Medication in Type 2 Diabetes Improves Glucose Control

September 21, 2007 — Adding a single analog insulin formulation to metformin and sulfonylurea resulted in current best practice targets of a glycated hemoglobin level of 6.5% or less in fewer than one quarter of patients at 1 year, according to the results of the Treating to Target in Type 2 Diabetes (4-T) trial reported in the September 21 Online First issue of the New England Journal of Medicine. These results were presented at the 43rd Annual Meeting of the European Association for the Study of Diabetes, held in Amsterdam, Holland.
"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," lead author Rury Holman, from Oxford University, United Kingdom, says in a news release. "This large-scale 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."
The 4-T trial is a 3-year, randomized controlled study in which 708 patients with type 2 diabetes and inadequate glucose control (glycated hemoglobin level of 7.0% - 10.0%) despite taking maximally tolerated doses of metformin and sulfonylurea were enrolled at 58 centers. Participants continued their usual doses of metformin and sulfonylurea and were randomized to receive open-label injections of biphasic insulin 2 times a day (biphasic insulin aspart 30), prandial insulin injected 3 times a day (insulin aspart), or basal insulin injected once a day (insulin detemir) for 1 year.
"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," says co-principal investigator Jonathan Levy, of the Oxford Centre for Diabetes, Endocrinology, and Metabolism. "The methods used in the trial can be applied directly to a primary care setting."
At 1 year, mean glycated hemoglobin level was 7.3% in the biphasic group, 7.2% in the prandial group (P = .08), and 7.6% in the basal group (P < .001 for basal vs biphasic or prandial). Each analog insulin lowered values of glycated hemoglobin within 3 months, with a sustained decrease at 1 year of 1.3% with biphasic, 1.4% with prandial, and 0.8% with basal insulin.
Target values of glycated hemoglobin of 6.5% or less were achieved by only 17.0%, 23.9%, and 8.1% of patients, respectively. Mean hypoglycemic episodes per patient per year were 5.7, 12.0, and 2.3, respectively; mean weight gains were 4.7, 5.7, and 1.9 kg, respectively. The 3 groups otherwise had a similar frequency of adverse events.
"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," says co-principal investigator Melanie Davies, from Leicester University, United Kingdom. "Our practice can now be based on good research evidence rather than anecdote."
The 4-T trial is ongoing, with results from the final 2 years anticipated in 2009. These should help determine the need for more than 1 insulin formulation to achieve glucose targets and how to manage stopping sulfonylurea therapy and transitioning to more complex insulin regimens if target glucose levels are not met.
Novo Nordisk is funding and supporting this study and is providing the study medication. Diabetes UK is funding a 4-T continuous glucose monitoring substudy. Some of the authors have disclosed various financial relationships with Novo Nordisk, Novartis, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Merck, Amylin, Eli Lilly, Sanofi Aventis, Ajinomoto, and Servier.
In an accompanying editorial, the New England Journal of Medicine editors Graham T. McMahon, MD, MMSc, and Robert G. Dluhy, MD, note that the issue of how to initiate insulin therapy in patients with type 2 diabetes has become increasingly complicated, thanks to the enlarging range of available preparations.
"The 4-T study provides a clear indication that prandial and biphasic insulin formulations are suboptimal choices for insulin initiation and probably expose patients to an unnecessarily high risk of hypoglycemia without clinically important benefit," Drs. McMahon and Dluhy write. "For now, the recommendations for starting insulin therapy need not change as a result of this study. For patients with a glycated hemoglobin of more than 7% on maximal doses of two oral agents, the best approach is to continue metformin and add a basal insulin; sulfonylureas are not synergistic with insulin and should generally be stopped."
Drs. McMahon and Dluhy have disclosed no relevant financial relationships.
N Engl J Med. Published online September 21, 2007.
43rd Annual Meeting of the EASD: Presented September 21, 2007.