The Treat-to-Target Trial

Randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients

  1. Matthew C. Riddle, MD1,
  2. Julio Rosenstock, MD2,
  3. John Gerich, MD3 and
  4. on behalf of the Insulin Glargine 4002 Study Investigators*
  1. 1Oregon Health and Science University, Portland, Oregon
  2. 2Dallas Diabetes and Endocrine Center, Dallas, Texas
  3. 3University of Rochester Medical Center, Rochester, New York
  1. Address correspondence and reprint requests to Matthew C. Riddle, MD, Oregon Health and Science University, Section of Diabetes L-345, 3181 S.W. Sam Jackson, Portland, OR 97201. E-mail: riddlem{at}


OBJECTIVE—To compare the abilities and associated hypoglycemia risks of insulin glargine and human NPH insulin added to oral therapy of type 2 diabetes to achieve 7% HbA1c.

RESEARCH DESIGN AND METHODS—In a randomized, open-label, parallel, 24-week multicenter trial, 756 overweight men and women with inadequate glycemic control (HbA1c >7.5%) on one or two oral agents continued prestudy oral agents and received bedtime glargine or NPH once daily, titrated using a simple algorithm seeking a target fasting plasma glucose (FPG) ≤100 mg/dl (5.5 mmol/l). Outcome measures were FPG, HbA1c, hypoglycemia, and percentage of patients reaching HbA1c ≤7% without documented nocturnal hypoglycemia.

RESULTS—Mean FPG at end point was similar with glargine and NPH (117 vs. 120 mg/dl [6.5 vs. 6.7 mmol/l]), as was HbA1c (6.96 vs. 6.97%). A majority of patients (∼60%) attained HbA1c ≤7% with each insulin type. However, nearly 25% more patients attained this without documented nocturnal hypoglycemia (≤72 mg/dl [4.0 mmol/l]) with glargine (33.2 vs. 26.7%, P < 0.05). Moreover, rates of other categories of symptomatic hypoglycemia were 21–48% lower with glargine.

CONCLUSIONS—Systematically titrating bedtime basal insulin added to oral therapy can safely achieve 7% HbA1c in a majority of overweight patients with type 2 diabetes with HbA1c between 7.5 and 10.0% on oral agents alone. In doing this, glargine causes significantly less nocturnal hypoglycemia than NPH, thus reducing a leading barrier to initiating insulin. This simple regimen may facilitate earlier and effective insulin use in routine medical practice, improving achievement of recommended standards of diabetes care.


  • * A list of the Insulin Glargine 4002 Study Investigators can be found in the appendix.

  • M.C.R. has served on advisory panels for, received honoraria or consulting fees from, and received grant support from Aventis, GlaxoSmithKline, and Novo Nordisk. J.R. has served on advisory panels for Aventis, Pfizer, Novo Nordisk, Takeda, and Johnson & Johnson; holds stock in Pfizer, GlaxoSmithKline, and Lilly; has received honoraria or consulting fees from Aventis, Pfizer, Takeda, and GlaxoSmithKline; and has received grant support from Aventis, Novo Nordisk, Lilly, Pfizer, Takeda, GlaxoSmithKline, Novartis, and AstraZeneca. J.G. has served on advisory boards for and has received honoraria and grant support from Pfizer, Novo Nordisk, Aventis, GlaxoSmithKline, and Novartis.

    A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

    • Accepted July 23, 2003.
    • Received February 18, 2003.
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