Monday, October 29, 2007

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 A1c 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 HbA1c was significantly greater in the biphasic and prandial groups (about 1.3%) than in the basal group (0.8%).

The proportion of patients with HbA1c 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 HbA1c 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)

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