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Basal Insulin Often Requires Adjuvant Therapy for Glycemic Control

By Caroline Helwick

AMSTERDAM, the Netherlands—Initiating insulin therapy early in the course of type 2 diabetes optimizes glycemic control, but most patients will need more than 1 insulin product, investigators reported at the European Association for the Study of Diabetes, based on new evidence from the Treating to Target in Type 2 Diabetes (4-T) trial.

Led by Rury Holman, MD, of Oxford University, United Kingdom, the study enrolled 708 patients (mean age, 62 years) from 58 centers in the United Kingdom and was published online first to coincide with the meeting (N Engl J Med. 2007;357:1716-1730).

To reflect patients in general practice, the 4-T study enrolled patients with type 2 diabetes of at least 1 year's duration who were receiving maximally tolerated doses of metformin (Glucophage) and sulfonylureas for at least 4 months. Patients' range of glycosylated hemoglobin (Hb) A1c levels was 7.0% to 10.0%; body mass index was ≤40 kg/m2.

To determine which insulin would be most appropriate for patients with poorly controlled disease, and when insulin therapy should be initiated, the patients were randomized to:

  • Biphasic insulin: aspart 30 (NovoMix 30) bid
  • Prandial insulin: aspart (NovoRapid) tid, w/meals
  • Basal insulin: detemir (Levemir) once daily.

All the patients were maintained on a single insulin formulation for 1 year, unless they developed unacceptable hyperglycemia.

Treatment goal was HbA1c ≤6.5%, a more aggressive target than the <7.0% standard of the American Diabetes Association. Insulin doses could be adjusted by physicians and patients using uniform criteria.

A total of 668 patients (equal numbers in all groups) completed the treatment. The 1-year results support the need for a combined regimen for achieving glycemic control and minimizing hypoglycemic episodes (Table).


More insulin was needed by 34% of patients in the basal insulin group. "Basal insulin alone was not able to keep patients in the acceptable range," Dr Holman notes. In his opinion, the clinical implication is "that you can use any of the insulins to improve glucose control," but a target of 6.5% is not likely to be achieved without a combined regimen.

"You can take 1 injection before bed and see if that works, or be more aggressive with 2 to 3 injections per day, though weight gain and hypoglycemic episodes may be greater," Dr Holman says. "We are not yet making conclusions about which insulin is best, but you can use the data to make informed decisions for individual patients."

In an accompanying editorial (pages 1759-1761), Graham T. McMahon, MD, and Robert G. Dluhy, MD, of Harvard Medical School and Brigham and Women's Hospital, observe that glycemic control in 4-T was relatively low compared with other published trials. They call the results with basal insulin "disappointing" and suggest that the poorer outcomes may have been due to the shorter half-life of this insulin compared with insulin glargine (not used in this study).

Drs McMahon and Dluhy maintain that the 4-T study clearly indicates that prandial and biphasic insulin formulations are suboptimal choices for insulin initiation and probably increase the risk for hypoglycemia, without clinically important benefits. They predict that the second phase of this study will help define the optimal next step for patients who do not reach their target using basal insulin alone.

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