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Initiating Insulin in Type 2 Diabetes – The "4-T" Trial

First-year comparisons among prandial, biphasic, and basal insulins reveal tradeoffs in efficacy and safety.

We now have a variety of options for initiating insulin in type 2 diabetic patients. In this trial — dubbed "Treating to Target in Type 2 Diabetes," or "4-T" — U.K. researchers compared three options.

The study included 708 adults with type 2 diabetes and hemoglobin A_1c between 7% and 10% (mean, 8.5%) despite treatment with sulfonylurea plus metformin. Patients with recurrent major hypoglycemia were excluded. Patients continued oral agents initially and were randomized to receive twice-daily biphasic insulin aspart 30 (NovoMix 30), thrice-daily prandial insulin aspart (NovoRapid), or once-daily (twice if required) basal insulin detemir (Levemir). A protocol specified dose titration, glucose monitoring, and follow-up visits. Novo Nordisk supported the trial.

During 1 year of follow-up, the following outcomes occurred:

• Mean fall in HbA_1c was significantly greater in the biphasic and prandial groups (about 1.3%) than in the basal group (0.8%).
  
• The proportion of patients with HbA_1c 6.5% was significantly greater in the biphasic (17%) and prandial (24%) groups than in the basal group (8%). Better glycemic control with biphasic and prandial insulins occurred primarily among patients whose baseline HbA_1c exceeded 8.5%.
  
• Symptomatic hypoglycemia was more common with prandial than biphasic insulin, and with biphasic than basal insulin.
  
• Patients in the basal group gained less weight than those in the other two groups.
  

Comment: Biphasic or prandial insulin, added to two-drug oral therapy, was more effective than basal insulin in achieving optimal glycemic control, but at the expense of more hypoglycemia and weight gain. Weighing these tradeoffs — along with the greater ease of once-daily insulin injections — the authors and editorialists offer the reasonable conclusion that once-daily basal insulin is probably the best initial approach for initiating insulin in type 2 diabetic patients. If good glycemic control is not achieved with a simple basal regimen, more complex regimens can be introduced later; indeed, more complex regimens will be examined in the next 2 years of this trial. Finally, the editorialists state a preference for glargine (Lantus) as a basal insulin (because it appears to have less of a peak and is slightly longer-acting than detemir), and they believe that sulfonylureas should be stopped when insulin is begun (because their mechanism of action is not synergistic with insulin).

— Allan S. Brett, MD

Published in Journal Watch General Medicine October 23, 2007

Citation(s):

Holman RR et al. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med 2007 Oct 25; 357:1716. (http://dx.doi.org/10.1056/NEJMoa075392)

• Original article (Subscription may be required)
• Medline abstract (Free)

McMahon GT and Dluhy RG. Intention to treat – Initiating insulin and the 4-T study. N Engl J Med 2007 Oct 25; 357:1759. (http://dx.doi.org/10.1056/NEJMe078196)

• Original article (Subscription may be required)
• Medline abstract (Free)